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  • CLASSES

    Selective Serotonin Reuptake Inhibitor Antidepressants, SSRIs

    BOXED WARNING

    Children, growth inhibition, suicidal ideation

    Paroxetine is not FDA-approved for use in children and adolescents less than 18 years of age. According to the FDA, there are 3 well-controlled trials that have shown paroxetine is no more effective than placebo for the treatment of depression in pediatric patients. In October 2004, the FDA directed manufacturers of all antidepressants to include a boxed warning detailing the risk of suicide in pediatric patients with MDD and other psychiatric disorders (OCD, social anxiety disorder). A causal role has been established for antidepressants in inducing suicidality in pediatric patients. The risk of suicidality for these drugs was identified in a pooled analysis of 24 placebo-controlled trials (n = 4,400) lasting up to 16 weeks in pediatric patients with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. The analysis showed a greater risk of suicidality during the first few months of treatment in those receiving antidepressants (SSRIs and others). The average risk of such events on drug was 4% and 2% for placebo; however, no suicides occurred in these trials. Pooled analysis of short-term clinical trials during early phase treatment of SSRIs and other antidepressants in young adults (18 to 24 years) also showed an increased risk of suicidal thinking and behavior. The clinical need for an antidepressant in children or young adults for any use must be weighed against the risk of increased suicidality; patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior, particularly within the first few months of starting therapy or at the time of dose increase or decrease. It is unknown if the suicidality risk in children and young adults extends to longer-term therapy (i.e., beyond several months). In a meta-analysis conducted by the manufacturer in adult patients with and without psychiatric disorders, a higher frequency of suicidal behavior occurred in young adults and adults treated with paroxetine compared with placebo. This difference was statistically significant; however, as the number of events were small, these data should be interpreted with caution. All of the reported events of suicidal behavior in the adult patients with depression were non-fatal suicide attempts, and the majority of these attempts (8 of 11) were in younger adult patients. The possibility of a suicide attempt is inherent in all patients with depressive symptoms, whether these occur in primary depression or in association with another primary disorder such as OCD. All patients with a history of suicidal ideation or behaviors and those with a prominence of suicidal ideation prior to treatment are considered at an increased risk for suicidal ideation or attempts, and should be closely monitored during treatment with paroxetine. In patients who exhibit changes in symptoms, worsening of depression or suicidality, a decision should be made to change or discontinue treatment. If discontinuing, the medication should be tapered as rapidly as possible, but with recognition that abrupt discontinuation can also cause adverse symptoms. All antidepressants should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. The potential for growth inhibition in pediatric patients should be monitored during SSRI therapy; monitor height and weight periodically. 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 paroxetine.

    DEA CLASS

    Rx

    DESCRIPTION

    Selective serotonin reuptake inhibitor (SSRI)
    FDA-approved for depression, OCD, social anxiety, GAD, panic disorder, and PTSD in adults; used for hot flashes associated with menopause or for premenstrual dysphoric disorder (PMDD) in adult females; used off-label for childhood anxiety disorders
    Requires close monitoring in pediatrics and young adults due to increased risk of suicidality during the initial stages of treatment; do not use during pregnancy

    COMMON BRAND NAMES

    Brisdelle, Paxil, Paxil CR, Pexeva

    HOW SUPPLIED

    Brisdelle/Paroxetine Oral Cap: 7.5mg
    Paroxetine/Paroxetine Hydrochloride/Paxil CR Oral Tab ER: 12.5mg, 25mg, 37.5mg
    Paroxetine/Paroxetine Hydrochloride/Paxil/Pexeva Oral Tab: 10mg, 20mg, 30mg, 40mg
    Paxil Oral Susp: 5mL, 10mg

    DOSAGE & INDICATIONS

    For the treatment of major depression.
    Oral dosage (immediate-release formulations e.g., Paxil, Pexeva)
    Adults

    20 mg PO once daily initially, usually in the morning. Increase as needed in increments of 10 mg at a minimum of weekly intervals. Max: 50 mg/day PO. DEBILITATED ADULTS: 10 mg PO once daily initially, with increases as needed by 10 mg at a minimum of weekly intervals up to a maximum of 40 mg/day PO. Acute episodes of depression require several months or longer of sustained pharmacologic therapy. Periodically reassess to determine the need for ongoing treatment. Whether the dose of antidepressant needed to induce remission is identical to the maintenance dose needed is unknown. DISCONTINUATION: A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or discontinuation, then resuming the previous dose may be considered. Subsequently, the dose may be discontinued, but at a more gradual rate.

    Geriatric Adults

    10 mg PO once daily initially. May increase as needed in increments of 10 mg at a minimum of weekly intervals. Max: 40 mg/day PO. Acute episodes of depression require several months or longer of sustained pharmacologic therapy. Periodically reassess the need for ongoing treatment. Whether the dose of antidepressant needed to induce remission is identical to the maintenance dose needed is unknown. DISCONTINUATION: A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or discontinuation, then resuming the previous dose may be considered. Subsequently, the dose may be discontinued, but at a more gradual rate.

    Oral dosage (controlled-release formulations e.g., Paxil CR)
    Adults

    25 mg PO once daily initially, usually in the morning. May increase as needed in increments of 12.5 mg at a minimum of weekly intervals. Max: 62.5 mg/day PO. DEBILITATED ADULTS: The recommended initial dose is 12.5 mg/day, may titrate by 12.5 mg at a minimum of weekly intervals. Max: 50 mg/day. Acute episodes of depression require several months or longer of sustained pharmacologic therapy. Periodically reassess the need for ongoing treatment. Whether the dose of antidepressant needed to induce remission is identical to the maintenance dose needed is unknown. DISCONTINUATION: A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or discontinuation, then resuming the previous dose may be considered. Subsequently, the dose may be discontinued, but at a more gradual rate.

    Geriatric Adults

    12.5 mg PO once daily initially. May increase as needed in increments of 12.5 mg at a minimum of weekly intervals. Max: 50 mg/day PO. Acute episodes of depression require several months or longer of sustained pharmacologic therapy. Periodically reassess the need for ongoing treatment. Whether the dose of antidepressant needed to induce remission is identical to the maintenance dose needed is unknown. DISCONTINUATION: A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or discontinuation, then resuming the previous dose may be considered. Subsequently, the dose may be discontinued, but at a more gradual rate.

    For the treatment of generalized anxiety disorder (GAD).
    Oral dosage (immediate-release formulations e.g., Paxil, Pexeva)
    Adults

    20 mg PO once daily initially, usually in the morning. Additional benefit does not appear to be gained with dosages higher than 20 mg/day; however efficacy has been established for doses ranging from 20 to 50 mg/day. May titrate the dose by 10 mg/day at weekly intervals if needed and tolerated. Max: 50 mg/day PO. DEBILITATED ADULTS: 10 mg PO once daily initially, with a maximum of 40 mg/day. Anxiety disorders are chronic conditions; consider continuation of the drug in a responding patient. Maintain on the lowest effective dosage and periodically reassess the need for continued treatment. DISCONTINUATION: A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or discontinuation, then resuming the previous dose may be considered. Subsequently, the dose may be discontinued, but at a more gradual rate.

    Geriatric Adults

    10 mg PO once daily initially, usually in the morning. Doses may be titrated by 10 mg/day at weekly intervals if needed and tolerated. Usual effective adult dose: 20 mg PO once daily. Max: 40 mg/day PO. Anxiety disorders are chronic conditions; consider continuation of the drug in a responding patient. Maintain on the lowest effective dosage and periodically reassess the need for continued treatment. DISCONTINUATION: A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or discontinuation, then resuming the previous dose may be considered. Subsequently, the dose may be discontinued, but at a more gradual rate.

    For the treatment of premenstrual dysphoric disorder (PMDD).
    Oral dosage (controlled-release tablets e.g., Paxil CR)
    Adult females

    12.5 mg/day PO initially, either daily throughout the menstrual cycle or limited to the luteal phase of the menstrual cycle, depending on provider assessment. In clinical trials, doses of 12.5 to 25 mg/day were effective. Dose changes should occur at intervals of at least 1 week. Effectiveness has not been evaluated for a period exceeding 3 menstrual cycles; however, symptoms generally continue and sometimes worsen until permanent cessation of menstruation occurs. Therefore, it is reasonable to continue treatment in a responding patient. DISCONTINUATION: If the patient takes continual treatment, a gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or discontinuation, then resuming the previous dose may be considered. Subsequently, the dose may be discontinued, but at a more gradual rate.

    Oral dosage (immediate-release formulations†, e.g., Paxil, Pexeva)
    Adult females

    Dosages have ranged from 5 mg/day to 30 mg/day PO, dependent on clinical response and tolerance. Continuous daily dosing or, alternatively, luteal phase administration during the 7 to 14 days prior to menses, has been effective. DISCONTINUATION: If the patient takes continual treatment, a gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or discontinuation, then resuming the previous dose may be considered. Subsequently, the dose may be discontinued, but at a more gradual rate.

    For the treatment of moderate to severe hot flashes associated with menopause, including in women who have been treated for breast cancer.
    Oral dosage (i.e., Brisdelle)
    Adult females

    7.5 mg PO once daily at bedtime with or without food. The North American Menopause Society (NAMS) Guidelines for non-hormonal therapy indicate that paroxetine is an effective choice for treating vasomotor symptoms of menopause when hormonal therapy is not desired or is contraindicated.

    Oral dosage (controlled-release tablets†, e.g., Paxil CR)
    Adult females

    Initially, 12.5 mg PO once daily. If 12.5 mg/day PO does not provide relief, the dose can be titrated to 25 mg PO once daily after 1 week if needed. Clinical trials indicate either dose is equally effective and to individualize dosage. The North American Menopause Society (NAMS) Guidelines for non-hormonal therapy indicate that paroxetine is an effective choice for treating vasomotor symptoms of menopause when hormonal therapy is not desired or is contraindicated. In 165 menopausal women, after 6 weeks, the frequency of hot flashes was reduced by 62.2% in women taking 12.5 mg/day, 64.6% in women taking 25 mg/day, and 37.8% in women taking placebo (p = 0.007 for 12.5 mg/day compared to placebo and p = 0.03 for 25 mg/day compared to placebo).

    For the treatment of obsessive-compulsive disorder (OCD).
    Oral dosage (immediate-release formulations; e.g., Paxil, Pexeva)
    Adults

    20 mg PO once daily initially, usually in the morning. May increase by 10 mg/day at weekly intervals if tolerated. Usual target dose: 40 mg PO once daily. Max: 60 mg/day PO. DEBILITATED ADULTS: 10 mg PO once daily initially, with a maximum recommended dose of 40 mg/day PO. Periodically reassess the need for ongoing treatment. DISCONTINUATION: A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or discontinuation, then resuming the previous dose may be considered. Subsequently, the dose may be discontinued, but at a more gradual rate.

    Geriatric Adults

    10 mg once daily initially. May increase by 10 mg/day at weekly intervals if needed and tolerated. Max: 40 mg/day PO. Periodically reassess the need for ongoing treatment. DISCONTINUATION: A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or discontinuation, then resuming the previous dose may be considered. Subsequently, the dose may be discontinued, but at a more gradual rate.

    Children† and Adolescents† 7 years and older

    10 to 50 mg/day PO has been studied. In 1 large randomized, placebo-controlled trial (n = 207), paroxetine was initiated at 10 mg/day PO for 1 week, followed by 10 mg/day increases at intervals of at least 7 days based upon response and tolerability. Max: 50 mg/day PO. Of the 145 patients who completed the 10-week study, the mean dose in children was 30.1 mg/day and the mean dose in adolescents was 36.5 mg/day. The change in the primary efficacy measure (the Children's Yale-Brown Obsessive-Compulsive Scale) and 3 of 6 secondary efficacy measures were statistically significant in favor of paroxetine. The global assessments showed no change between the groups. Children improved more than adolescents, independent of the treatment received. Periodically reassess the need for ongoing treatment. Evaluation of the long-term safety and efficacy of paroxetine in the treatment of childhood OCD is needed. DISCONTINUATION: A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or discontinuation, then resuming the previous dose may be considered. Subsequently, the dose may be discontinued, but at a more gradual rate.

    For the treatment of panic disorder, with or without agoraphobia.
    Oral dosage (immediate-release formulations; e.g., Paxil, Pexeva)
    Adults

    10 mg PO once daily initially, usually in the morning. Doses should be increased by 10 mg/day at weekly intervals as tolerated to the usual target dose of 40 mg/day. Max: 60 mg/day PO. DEBILITATED ADULTS 10 mg PO once daily initially, Max: 40 mg/day PO. Anxiety disorders are chronic conditions; consider continuation of the drug in a responding patient. Maintain on the lowest effective dosage and periodically reassess to determine the need for continued treatment. DISCONTINUATION: A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or discontinuation, then resuming the previous dose may be considered. Subsequently, the dose may be discontinued, but at a more gradual rate.

    Geriatric Adults

    10 mg PO once daily initially, usually in the morning. Doses should be increased by 10 mg/day at weekly intervals as tolerated to the usual target dose of 40 mg/day. Max: 40 mg/day PO. Anxiety disorders are chronic conditions; consider continuation of the drug in a responding patient. Maintain on the lowest effective dosage and periodically reassess to determine the need for continued treatment. DISCONTINUATION: A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or discontinuation, then resuming the previous dose may be considered. Subsequently, the dose may be discontinued, but at a more gradual rate.

    Children† and Adolescents† 7 years and older

    Initially, 10 mg/day PO. 10 to 40 mg/day PO has been studied. To minimize the frequency and severity of adverse effects, slowly titrate based on response and tolerability. Periodically reassess to determine the need for ongoing treatment. Further study is needed to establish the safety and efficacy of SSRIs in the treatment of childhood panic disorder. Results from 1 naturalistic study (n = 18) in which patients were followed for up to 24 months showed a mean initial dose of 8.9 mg/day PO followed by titration up to 40 mg/day PO depending on response and tolerability. Improvement began after a mean duration of 3 weeks. The final mean daily dose was about 24 mg/day (range: 10 to 40 mg/day). At study end, 83.3% of patients were considered responders, with 55.5% showing marked improvement on the CGI-Improvement scale score and 27.8% with moderate improvement. Two patients experienced no change and 1 patient worsened. Most patients had comorbid anxiety or mood disorders. The most common side effects were nausea, tension/agitation, sedation, insomnia, palpitations, and headache; however, no patient discontinued treatment or required dosage reductions.  DISCONTINUATION: A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or discontinuation, then resuming the previous dose may be considered. Subsequently, the dose may be discontinued, but at a more gradual rate.

    Oral dosage (controlled-release tablets; e.g., Paxil CR)
    Adults

    12.5 mg PO once daily initially, usually in the morning. May increase as needed in increments of 12.5 mg, at a minimum of weekly intervals. The effective dosage range was 12.5 to 75 mg/day in clinical trials. Max: 75 mg/day PO. DEBILITATED ADULTS: Initiate with 12.5 mg/day PO. Max: 50 mg/day PO. Anxiety disorders are chronic conditions; consider continuation of the drug in a responding patient. Maintain on the lowest effective dosage and periodically reassess to determine the need for continued treatment. DISCONTINUATION: A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or discontinuation, then resuming the previous dose may be considered. Subsequently, the dose may be discontinued, but at a more gradual rate.

    Geriatric Adults

    12.5 mg PO once daily initially, usually in the morning. May increase as needed by 12.5 mg at weekly intervals. The effective dosage for adults was 12.5 to 75 mg/day in clinical trials; however, the maximum recommended dose for geriatric adults is 50 mg/day PO. Anxiety disorders are chronic conditions; consider continuation of the drug in a responding patient. Maintain on the lowest effective dosage and periodically reassess to determine the need for continued treatment. DISCONTINUATION: A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or discontinuation, then resuming the previous dose may be considered. Subsequently, the dose may be discontinued, but at a more gradual rate.

    For the treatment of posttraumatic stress disorder (PTSD).
    Oral dosage (immediate-release formulations; e.g., Paxil, Pexeva)
    Adults

    20 mg PO once daily, usually given in the morning, is the initial and effective usual dose. Effective dose range: 20 to 50 mg/day during clinical trials. Max: 50 mg/day PO. DEBILITATED ADULTS: 10 mg PO once daily initially, with titration by 10 mg/week if needed. Max: 40 mg/day PO. Paroxetine is effective in treating PTSD symptoms including re-experiencing/intrusion, avoidance/numbing, and hyperarousal.  In one fixed-dose study, 40 mg/day PO did not show greater efficacy than 20 mg/day. Anxiety disorders are chronic conditions; consider continuation of the drug in a responding patient. Maintain on the lowest effective dosage and periodically reassess to determine the need for continued treatment. DISCONTINUATION: A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or discontinuation, then resuming the previous dose may be considered. Subsequently, the dose may be discontinued, but at a more gradual rate.

    Geriatric Adults

    10 mg PO once daily initially, usually in the morning. Doses should be increased by 10 mg/day at a minimum of weekly intervals if needed and tolerated. Max: 40 mg/day PO. Anxiety disorders are chronic conditions; consider continuation of the drug in a responding patient. Maintain on the lowest effective dosage and periodically reassess to determine the need for continued treatment. DISCONTINUATION: A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or discontinuation, then resuming the previous dose may be considered. Subsequently, the dose may be discontinued, but at a more gradual rate.

    For the treatment of social phobia (social anxiety disorder).
    Oral dosage (immediate-release formulations; e.g., Paxil, Pexeva)
    Adults

    20 mg/day PO is the recommended initial and usual effective dose, usually given in the morning. Effective dose range: 20 to 60 mg/day; however, doses above 20 mg/day do not appear to provide additional benefit. May titrate by 10 mg/day at weekly intervals if needed and tolerated. Max: 60 mg/day PO. DEBILITATED ADULTS: 10 mg PO once daily initially, with dose increases by 10 mg/day at weekly intervals if needed and tolerated. Max: 40 mg/day. Periodically assess the need for continued treatment. DISCONTINUATION: A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or discontinuation, then resuming the previous dose may be considered. Subsequently, the dose may be discontinued, but at a more gradual rate.

    Geriatric Adults

    10 mg PO once daily initially, usually in the morning. May titrate by 10 mg/day at weekly intervals if needed and tolerated. Usual target adult dose is 20 mg/day. Max: 40 mg/day PO. Periodically assess the need for continued treatment. DISCONTINUATION: A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or discontinuation, then resuming the previous dose may be considered. Subsequently, the dose may be discontinued, but at a more gradual rate.

    Children† and Adolescents† 8 years and older

    10 to 50 mg/day PO has been studied. Paroxetine is initiated at 10 mg/day PO, and titrated by 10 mg/day at intervals of at least 7 days based on response and tolerability. Max: 50 mg/day PO. In a multicenter, placebo-controlled clinical trial (n = 322), at study end (16 weeks) the mean dose for children was 26.5 mg/day and for adolescents was 35 mg/day. Overall, the percentage of patients considered responders on the primary efficacy measure (CGI-I score) was statistically significant in favor of paroxetine over placebo (77.6% vs. 38.3%). The remission rate for paroxetine was statistically significantly greater than placebo (47.8% vs. 14.9%). Adverse effects occurring in at least 5% of patients receiving paroxetine and at a rate twice that of placebo included insomnia, decreased appetite, vomiting, drowsiness, nervousness, hyperkinesia, asthenia, and hostility. Four paroxetine-treated patients experienced suicidal ideation or threatened suicide, although there was no clear evidence of a suicide attempt. Periodically reassess to determine the need for ongoing treatment. Further study is needed to evaluate the safety and efficacy of SSRIs in the treatment of childhood anxiety disorders. DISCONTINUATION: A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or discontinuation, then resuming the previous dose may be considered. Subsequently, the dose may be discontinued, but at a more gradual rate.

    Oral dosage (controlled-release formulations; e.g., Paxil CR)
    Adults

    12.5 mg/day PO initially, usually given in the morning. If needed, titrate at intervals of at least 1 week, in increments of 12.5 mg/day. Max: 37.5 mg/day PO. During clinical trials, effectiveness was demonstrated in a range of 12.5 to 37.5 mg/day. Periodically assess the need for continued treatment. DISCONTINUATION: A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or discontinuation, then resuming the previous dose may be considered. Subsequently, the dose may be discontinued, but at a more gradual rate.

    For the treatment of premature ejaculation†.
    Oral dosage (immediate-release formulations e.g., Paxil, Pexeva)
    Adult males

    10 to 40 mg/day PO has been shown to increase ejaculatory latency; however, the benefit of increasing the dose to 40 mg/day is not well established. Based on the available evidence, treatment guidelines support a daily dose of 20 mg/day. In 1 study, 60 men with lifelong rapid ejaculation (i.e., an intravaginal ejaculation latency time of 1 minute or less) were randomly assigned to receive paroxetine 20 mg/day PO, another SSRI (fluoxetine, fluvoxamine, sertraline), or placebo for 6 weeks. Compared with the placebo group, which had a mean intravaginal ejaculation latency time (IELT) of 20 seconds, patients treated with paroxetine had an increase in IELT to about 110 seconds. In 1 study of men with lifelong rapid ejaculation (IELT of 1 minute or less), paroxetine 20 mg/day PO increased mean IELT by 480% (from a mean of 83 seconds to a mean of 602 seconds). Alternatively, 20 mg PO given 3 to 4 hours pre-intercourse has demonstrated efficacy and is suggested per treatment guidelines. It is unclear if daily or situational dosing is more effective in the management of premature ejaculation. Likewise, the optimal interval for situational dosing before intercourse is not well defined. The choice of regimen is ultimately defined by clinical judgement and patient preference in light of the frequency of sexual activity. DISCONTINUATION: A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or discontinuation, then resuming the previous dose may be considered. Subsequently, the dose may be discontinued, but at a more gradual rate.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    60 mg/day PO for immediate-release formulation; 75 mg/day PO for controlled-release formulation.

    Geriatric

    40 mg/day PO for immediate-release formulation; 50 mg/day PO for controlled-release formulation.

    Adolescents

    Safety and efficacy have not been established; however, doses up to 50 mg/day PO have been used off-label for anxiety disorders.

    Children

    7 to 12 years: Safety and efficacy have not been established; however, doses up to 50 mg/day PO have been used off-label for anxiety disorders.
    1 to 6 years: 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

    Immediate-release dosage forms (i.e., Paxil, Pexeva): Initially, 10 mg/day PO in adults; final adult dosage should not exceed 40 mg/day PO. There are no guidelines available for pediatric patients.
     
    Immediate-release 7.5 mg capsules (i.e., Brisdelle): No dose adjustment is considered necessary in patients with hepatic impairment.
     
    Controlled-release tablets (Paxil CR): The initial dose is 12.5 mg/day PO in adults, with final adult dosage not to exceed 50 mg/day PO, regardless of indication. There are no guidelines available for pediatric patients.

    Renal Impairment

    Patients with renal impairment receiving immediate-release 7.5 mg capsules (i.e., Brisdelle): No dosage adjustment is considered necessary.
     
    Patients with renal impairment receiving immediate-release dosage forms including Paxil or Pexeva:
    CrCl 30—60 ml/min: Dosage should be modified depending on clinical response and degree of renal impairment, but no quantitative recommendations are available. Lower doses may be needed.
    CrCl < 30 ml/min: Initially, 10 mg/day PO in adults; final adult dosage should not exceed 40 mg/day PO. There are no guidelines available for pediatric patients.
     
    Patients with severe renal impairment receiving controlled-release dosage forms including Paxil CR:
    The initial dose is 12.5 mg/day PO in adults, with final adult dosage not to exceed 50 mg/day PO, regardless of indication. There are no guidelines available for pediatric patients.
     
    Intermittent hemodialysis
    See dosage for patients with CrCl < 30 ml/min. Dosage adjustments are not necessary in patients receiving the Brisdelle brand. Paroxetine is unlikely to be significantly removed by hemodialysis given its large volume of distribution.

    ADMINISTRATION

    Oral Administration

    All oral dosage forms: Usually administered as a single dose in the morning. May be administered without regard to meals, however, food may minimize GI adverse effects.

    Oral Solid Formulations

    Controlled-release tablets: Patient should swallow tablets whole. Do not cut, chew, or crush. Do not administer concomitantly with antacids; the tablets are enteric-coated.

    Oral Liquid Formulations

    Oral suspension: Shake well before each use. To ensure accurate dosing, measure dosage with an oral syringe or other calibrated measuring device.

    STORAGE

    Brisdelle:
    - Avoid excessive humidity
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Paxil:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Paxil CR:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Pexeva:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Paroxetine is contraindicated in those patients with a hypersensitivity to paroxetine or any of the formulation components.

    Abrupt discontinuation

    Avoid abrupt discontinuation of any SSRI, like paroxetine, if possible. Gradual tapering is recommended during discontinuation of any SSRI to decrease or prevent the occurrence of potential withdrawal-like symptoms. Such symptoms have been reported with abrupt discontinuation of paroxetine. For example, the taper phase regimen used in some clinical trials of paroxetine involved an incremental decrease in the daily dose by 10 mg/day at weekly intervals. When a daily dose of 20 mg/day was reached, patients were continued on this dose for 1 week before treatment was stopped. In controlled trials of paroxetine CR, patients receiving 37.5 mg/day underwent an incremental decrease in the daily dose by 12.5 mg/day to a dose of 25 mg/day for 1 week before treatment was stopped. For patients receiving 25 mg/day or 12.5 mg/day, treatment was stopped without an incremental decrease in dose. Adverse events were reported, even with this gradual taper regimen. Patients should be monitored for withdrawal when discontinuing treatment, regardless of the indication for which the SSRI is being prescribed. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, continue decreasing the dose but at a more gradual rate.

    Bipolar disorder, mania

    All effective antidepressants, such as paroxetine, 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, paroxetine should be withheld and appropriate therapy initiated to treat the manic symptoms. Depression may 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 suicidality. It should be noted that paroxetine is not approved for use in treating bipolar depression.

    Children, growth inhibition, suicidal ideation

    Paroxetine is not FDA-approved for use in children and adolescents less than 18 years of age. According to the FDA, there are 3 well-controlled trials that have shown paroxetine is no more effective than placebo for the treatment of depression in pediatric patients. In October 2004, the FDA directed manufacturers of all antidepressants to include a boxed warning detailing the risk of suicide in pediatric patients with MDD and other psychiatric disorders (OCD, social anxiety disorder). A causal role has been established for antidepressants in inducing suicidality in pediatric patients. The risk of suicidality for these drugs was identified in a pooled analysis of 24 placebo-controlled trials (n = 4,400) lasting up to 16 weeks in pediatric patients with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. The analysis showed a greater risk of suicidality during the first few months of treatment in those receiving antidepressants (SSRIs and others). The average risk of such events on drug was 4% and 2% for placebo; however, no suicides occurred in these trials. Pooled analysis of short-term clinical trials during early phase treatment of SSRIs and other antidepressants in young adults (18 to 24 years) also showed an increased risk of suicidal thinking and behavior. The clinical need for an antidepressant in children or young adults for any use must be weighed against the risk of increased suicidality; patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior, particularly within the first few months of starting therapy or at the time of dose increase or decrease. It is unknown if the suicidality risk in children and young adults extends to longer-term therapy (i.e., beyond several months). In a meta-analysis conducted by the manufacturer in adult patients with and without psychiatric disorders, a higher frequency of suicidal behavior occurred in young adults and adults treated with paroxetine compared with placebo. This difference was statistically significant; however, as the number of events were small, these data should be interpreted with caution. All of the reported events of suicidal behavior in the adult patients with depression were non-fatal suicide attempts, and the majority of these attempts (8 of 11) were in younger adult patients. The possibility of a suicide attempt is inherent in all patients with depressive symptoms, whether these occur in primary depression or in association with another primary disorder such as OCD. All patients with a history of suicidal ideation or behaviors and those with a prominence of suicidal ideation prior to treatment are considered at an increased risk for suicidal ideation or attempts, and should be closely monitored during treatment with paroxetine. In patients who exhibit changes in symptoms, worsening of depression or suicidality, a decision should be made to change or discontinue treatment. If discontinuing, the medication should be tapered as rapidly as possible, but with recognition that abrupt discontinuation can also cause adverse symptoms. All antidepressants should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. The potential for growth inhibition in pediatric patients should be monitored during SSRI therapy; monitor height and weight periodically. 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 paroxetine.

    MAOI therapy

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

    Electroconvulsive therapy (ECT), seizure disorder, seizures

    Paroxetine should be used with caution in patients with a history of seizure disorder. Seizures have been reported rarely in patients taking SSRIs; however, they have occurred primarily in cases of overdose. Paroxetine's effects during electroconvulsive therapy (ECT) have not been evaluated in clinical studies to date.

    Dehydration, hyponatremia, hypovolemia

    Selective serotonin reuptake inhibitors (SSRIs), like paroxetine, may cause hyponatremia, which is frequently the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In some cases, serum sodium levels less than 110 mmol/L have been reported; however, the adverse effect appeared reversible upon discontinuation of the causative SSRI. Older patients (65 years of age or more), 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.

    Renal failure, renal impairment

    Paroxetine should be used with caution in patients with severe renal impairment or renal failure because paroxetine clearance is reduced. Specific dosage adjustments are recommended in adult patients with severe renal impairment (creatinine clearance less than 30 mL/minute). A lower starting dose should be used in patients receiving most paroxetine formulations. The exception is those patients receiving the the 7.5 mg dose for menopause (e.g., Brisdelle) for which no dose adjustment is considered necessary. Quantitative guidelines are not available for pediatric patients.

    Hepatic disease

    Paroxetine should be used cautiously in patients with hepatic disease. Adult patients with severe hepatic impairment have about a 2-fold increase in plasma concentrations of paroxetine compared to patients without hepatic impairment. Specific dosage adjustments are recommended in adult patients with severe hepatic impairment receiving all formulations except the 7.5 mg dose for menopause (e.g., Brisdelle) for which no dose adjustment is considered necessary. Quantitative guidelines are not available for pediatric patients.

    Anticoagulant therapy, bleeding, thrombolytic therapy

    Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion. Paroxetine and other SSRIs may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulant therapy may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients and practitioners should be cautioned about the risk of bleeding associated with the concomitant use of paroxetine and NSAIDs, aspirin, anticoagulants, or other drugs that affect coagulation, such as thrombolytic therapy. Monitor patients for signs and symptoms of bleeding.

    Cardiac disease, congenital heart disease

    Although clinical trial data indicate that paroxetine is not associated with the development of clinically significant ECG abnormalities in adults, the use of paroxetine has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable cardiac disease. Evaluation of electrocardiograms (ECGs) of 682 patients who received paroxetine in double-blind, placebo-controlled trials, however, did not indicate that paroxetine is associated with the development of significant ECG abnormalities. Paroxetine should be used with caution in patients with congenital heart disease or in those who are taking other medications concomitantly that might result in drug interactions. For example, QT prolongation, tachycardias, and other side effects have been reported in children taking clomipramine in combination with paroxetine for the treatment of obsessive-compulsive disorder (OCD), or in adult patients taking paroxetine (a CYP2D6 inhibitor) along with medications known to prolong the QT interval that are metabolized by CYP2D6. Additional monitoring may be necessary, especially when a patient receives combined treatments.

    Bone fractures, osteoporosis

    Use selective serotonin reuptake inhibitors (SSRIs), including paroxetine, 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 paroxetine-treated patient presents with unexplained bone pain, point tenderness, swelling, or bruising, consider the possibility of a fragility fracture. Patients at risk for osteoporosis, such as postmenopausal females, may benefit from more frequent monitoring of bone density during long-term use of an SSRI. 

    Closed-angle glaucoma, increased intraocular pressure

    Caution is recommended when prescribing paroxetine 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. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.

    Akathisia

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

    Anorexia nervosa

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

    Driving or operating machinery, ethanol ingestion

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

    Neonates, pregnancy

    All formulations of paroxetine may cause fetal harm during human pregnancy; the Brisdelle (brand for menopause) is contraindicated for use during pregnancy because menopausal vasomotor symptoms do not occur during pregnancy and paroxetine can cause fetal harm. Unless other treatment options are not available, do not initiate paroxetine during the first trimester of pregnancy or in women who plan to become pregnant in the near future. The FDA is evaluating data to better characterize the risk of congenital malformations resulting from infant exposure to paroxetine during pregnancy. Exposure in the first trimester may increase the risk for congenital malformations, particularly cardiac malformations. A retrospective, epidemiologic study derived from the Swedish National Registry, comprised of 6896 women prescribed antidepressants in early pregnancy (5,123 of these women exposed to SSRIs; 815 to paroxetine) suggests an increased risk of cardiovascular malformations, primarily ventricular (VSDs) and atrial (ASDs) septal defects in those with exposure to paroxetine. This increased risk was seen compared to the entire registry population (OR 1.8; 95% CI 1.1 to 2.8). The rate of cardiovascular malformations following paroxetine exposure was 2% vs. 1% in the entire registry population; however, there was no increase in the overall risk for congenital malformations in either group. In another retrospective, cohort study (a US health insurance claims database), evaluating infant outcomes in those whose mothers received antidepressants in the first trimester (n = 5,956 total ; 815 for paroxetine), a 1.5-fold elevated risk for cardiac malformations and a 1.8-fold elevated risk for overall congenital malformations was seen in the paroxetine group compared to the group that received other antidepressants in the first trimester (OR 1.5; 95% CI 0.8 to 2.9). The prevalence of cardiac malformations when drug was received in the first trimester was 1.5% for paroxetine and 1% for other antidepressants. Nine out of 12 newborns with cardiac malformations whose mothers received paroxetine in the first trimester had VSDs. Unlike the first study, there was an increased risk of overall major congenital malformations (inclusive of the cardiovascular defects) for paroxetine compared to other antidepressants (OR 1.8; 95% CI 1.2 to 2.8). The prevalence of all congenital malformations following first trimester exposure was 4% for paroxetine vs. 2% for other antidepressants. Results from 2 large case-control studies (each with more than 9,000 birth defect cases and more than 4,000 controls) showed a 2- to 3-fold increased risk of right ventricular outflow tract obstructions from infant exposures to paroxetine in utero during the first trimester of pregnancy, with 7 exposed in one study (OR 2.5; 95% CI, 1 to 6), and 6 exposed in the other study (OR 3.3; 95% CI 1.3 to 8.8). All of these studies were limited to first trimester exposure only, therefore the risk of fetal exposure to paroxetine in the second and third trimesters is not known. A prospective, cohort study was conducted to evaluate the outcome of newborns born to 267 women who took an SSRI during pregnancy (of whom 97 took paroxetine). Compared with a neonatal control group, SSRI-exposed neonates had similar rates of major malformation, spontaneous and elective abortion, and stillbirth. Mean birth weight and gestational age were similar among the two groups of neonates. In animal studies, SSRIs appear to downregulate serotonin receptors in the fetal cortex; the changes are present for a period of time after birth but the effect on neurological development is uncertain; the applicability of these findings to humans is also unknown. A neonatal abstinence syndrome has been reported at birth following in utero paroxetine exposure; exposed neonates may need to be monitored for associated symptoms. A cohort study of 55 women revealed that 22% (12 of 55) of neonates exposed to paroxetine in the third trimester had complications requiring treatment or extended hospitalization vs. 6% in comparison groups. Post-marketing reports indicate that premature births have occurred in pregnant women receiving paroxetine or other SSRIs. Additionally, epidemiologic reports suggest a possible association between maternal use of SSRIs after 20 weeks gestation and the development of persistent pulmonary hypertension (PPHN) of the newborn. More recent retrospective studies have not shown an increased risk of PPHN with SSRI exposure. In December 2011, the FDA issued a safety announcement stating that based on conflicting data, an increased risk of PPHN from SSRI exposure cannot be determined. The FDA advises that healthcare professionals should not alter their current practice of treating depression in pregnancy at this time. Increasing evidence suggests an association between antidepressant use during pregnancy and a subsequent diagnosis of autism spectrum disorder (ASD) in the offspring. In two separate population based case-control studies, an approximate 2-fold increased risk of autism spectrum disorder was observed. One study found the increased risk was associated only with SSRI use, while the other study found an increased risk associated with use of SSRIs and tricyclic antidepressants. Providers should inform women receiving paroxetine to the potential fetal risk if they should become pregnant or are currently in their first trimester. Discontinuing paroxetine and switching to another antidepressant should be considered when possible for these patients. Women who are pregnant, or are planning a pregnancy, and currently taking paroxetine should consult with their physician about whether to continue taking it. A prospective study of pregnant women receiving antidepressant treatment found that only 26% of those maintained on their antidepressant had relapsed versus 68% of those who had discontinued their medication. In individual cases, the benefits of continuing paroxetine may outweigh the potential risk to the fetus. The effect of SSRIs on labor and delivery in humans is unknown. The National Pregnancy Registry for Psychiatric Medications is dedicated to evaluating the safety of psychiatric medications that may be taken by women during pregnancy to treat a wide range of mood, anxiety, or psychiatric disorders. The primary goal of this Registry is to determine the frequency of major malformations, such as heart defects, cleft lip, or neural tube defects, in babies exposed to various psychiatric drugs during pregnancy. While the research concentrates on atypical antipsychotics and antidepressant use, pregnant women using other psychiatric medications are encouraged to register. For more information, contact the registry at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry or by phone 1-866-961-2388.

    Breast-feeding

    Paroxetine should be administered to a breast-feeding mother with caution. In one small trial, mothers ingested up to 50 mg/day PO of paroxetine for more than 10 days. Paroxetine was excreted into the breast milk, but at low concentrations (less than 2 ng/mL). None of the breast-fed infants had detectable serum concentrations and none experienced adverse effects from the medication. Other SSRIs (e.g., fluoxetine) are excreted in breast milk and have been reported to increase infant irritability. The long-term effects of paroxetine on a breast-feeding infant are unknown. There are suggestions that SSRI use during breast-feeding may be of concern; however, others have suggested that paroxetine and some of the other SSRIs may be safely continued during lactation with appropriate caution in prescribing. A pooled analysis found that maternal use of paroxetine, along with nortriptyline and sertraline, usually produced undetectable or low drug concentrations in infant serum and, therefore, may be the preferred antidepressants in breast-feeding mothers. Consider the benefits of breast-feeding, the risk of potential drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding baby experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Anticholinergic medications, geriatric

    Paroxetine should be used with caution in geriatric patients. Pharmacokinetic data indicate that paroxetine clearance is reduced in the elderly. Although no difference in safety has been recorded, slow titration of dosage is recommended in the elderly. SSRIs may cause hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH); elderly patients appear to be at greater risk. According to the Beers Criteria, paroxetine is considered a potentially inappropriate medication (PIM) for use in geriatric patients and should be avoided in this population due to the potential for orthostatic hypotension, anticholinergic effects and toxicity (e.g., constipation, urinary difficulties, blurred vision, dry mouth, delirium), or sedation. These effects may be additive with anticholinergic medications. In addition, the Beers expert panel recommends avoiding medications with anticholinergic properties, including paroxetine, in geriatric patients with the following disease states or symptoms due to the potential for exacerbation of the condition or increased risk of adverse effects: dementia/cognitive impairment (adverse CNS effects), delirium/high risk of delirium (possible new-onset or worsening delirium), or lower urinary tract symptoms/benign prostatic hyperplasia in men (possible urinary retention or hesitancy). The Panel also recommends avoiding paroxetine in geriatric patients with a history of falls or fractures, unless no other alternatives are available, since SSRIs have the potential to cause ataxia, impaired psychomotor function, syncope, and additional falls; if paroxetine must be used, consider reducing use of other CNS-active medications that increase the risk of falls and fractures and implement other strategies to reduce fall risk. Because SSRIs can cause or exacerbate hyponatremia and SIADH and the elderly are at increased risk of developing these conditions, sodium levels should be closely monitored when starting or changing dosages in older adults. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of antidepressants in residents of long-term care facilities. According to OBRA, the duration of therapy should be in accordance with pertinent literature for the condition being treated, including clinical practice guidelines. All residents being treated for depression with any antidepressant should be monitored closely for worsening of depression and/or suicidal behavior or thinking, especially during initiation of therapy and during dose changes. Antidepressants may cause dizziness, nausea, diarrhea, anxiety, nervousness, insomnia, somnolence, weight gain, anorexia, or increased appetite. Many of these effects can increase the risk for falls. In addition, paroxetine has significant anticholinergic properties, which may problematic in the elderly. Prior to discontinuation, many antidepressants may need a taper to avoid a withdrawal syndrome. Concurrent use of 2 or more antidepressants may increase the risk of side effects; in such cases there should be documentation of expected benefits that outweigh the associated risks and monitoring for any increase in side effects. Monitoring should consist of a review for continued need at least quarterly, and documentation of the rationale for continuation. When the drug is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt to taper the medication as outlined in the OBRA guidelines, unless a taper is clinically contraindicated.

    ADVERSE REACTIONS

    Severe

    visual impairment / Early / 1.0-5.0
    muscle paralysis / Delayed / 0.1-1.0
    bradycardia / Rapid / 0.1-1.0
    angioedema / Rapid / 0.1-1.0
    anaphylactoid reactions / Rapid / 0.1-1.0
    bronchospasm / Rapid / 0.1-1.0
    keratoconjunctivitis / Early / 0.1-1.0
    pancreatitis / Delayed / 0.1-1.0
    proteinuria / Delayed / 0.1-1.0
    peptic ulcer / Delayed / 0-0.1
    hematemesis / Delayed / 0-0.1
    GI obstruction / Delayed / 0-0.1
    ileus / Delayed / 0-0.1
    akinesia / Delayed / 0-0.1
    torticollis / Delayed / 0-0.1
    coma / Early / 0-0.1
    myelitis / Delayed / 0-0.1
    seizures / Delayed / 0.1-0.1
    myocardial infarction / Delayed / 0-0.1
    stroke / Early / 0-0.1
    atrial fibrillation / Early / 0-0.1
    heart failure / Delayed / 0-0.1
    pulmonary embolism / Delayed / 0-0.1
    thrombosis / Delayed / 0-0.1
    erythema nodosum / Delayed / 0-0.1
    exfoliative dermatitis / Delayed / 0-0.1
    erythema multiforme / Delayed / 0-0.1
    pulmonary fibrosis / Delayed / 0-0.1
    pulmonary edema / Early / 0-0.1
    hearing loss / Delayed / 0-0.1
    retinal hemorrhage / Delayed / 0-0.1
    ocular hypertension / Delayed / 0-0.1
    ocular hemorrhage / Delayed / 0-0.1
    oliguria / Early / 0-0.1
    epididymitis / Delayed / 0-0.1
    hyperkalemia / Delayed / 0-0.1
    laryngospasm / Rapid / Incidence not known
    Guillain-Barre syndrome / Delayed / Incidence not known
    suicidal ideation / Delayed / Incidence not known
    SIADH / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    aplastic anemia / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    ventricular fibrillation / Early / Incidence not known
    torsade de pointes / Rapid / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    pulmonary hypertension / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    optic neuritis / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    porphyria / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    serotonin syndrome / Delayed / Incidence not known
    bone fractures / Delayed / Incidence not known
    teratogenesis / Delayed / Incidence not known
    neonatal abstinence syndrome / Early / Incidence not known
    persistent pulmonary hypertension of the newborn / Delayed / Incidence not known

    Moderate

    ejaculation dysfunction / Delayed / 13.0-28.0
    constipation / Delayed / 5.0-16.0
    impotence (erectile dysfunction) / Delayed / 4.0-10.0
    peripheral vasodilation / Rapid / 2.0-4.0
    blurred vision / Early / 2.0-4.0
    hypertonia / Delayed / 0.1-3.0
    myoclonia / Delayed / 1.0-3.0
    chest pain (unspecified) / Early / 1.0-3.0
    palpitations / Early / 2.0-3.0
    dysuria / Early / 0.1-3.0
    mania / Early / 0.1-2.2
    amnesia / Delayed / 0.1-2.0
    memory impairment / Delayed / 2.0-2.0
    depression / Delayed / 0.1-2.0
    hypertension / Early / 1.0-2.0
    sinus tachycardia / Rapid / 1.0-2.0
    myopathy / Delayed / 0-2.0
    teeth grinding (bruxism) / Delayed / 0.1-1.0
    stomatitis / Delayed / 0.1-1.0
    colitis / Delayed / 0-1.0
    dysphagia / Delayed / 0.1-1.0
    melena / Delayed / 0-1.0
    gastritis / Delayed / 0.1-1.0
    hemorrhoids / Delayed / 0.1-1.0
    dyskinesia / Delayed / 0.1-1.0
    dystonic reaction / Delayed / 0.1-1.0
    nystagmus / Delayed / 0-1.0
    ataxia / Delayed / 0-1.0
    neuropathic pain / Delayed / 0-1.0
    confusion / Early / 1.0-1.0
    migraine / Early / 0.1-1.0
    euphoria / Early / 0.1-1.0
    hostility / Early / 0.1-1.0
    lymphadenopathy / Delayed / 0.1-1.0
    anemia / Delayed / 0.1-1.0
    leukopenia / Delayed / 1.0-1.0
    eosinophilia / Delayed / 0.1-1.0
    hematoma / Early / 0.1-1.0
    orthostatic hypotension / Delayed / 0.1-1.0
    hypotension / Rapid / 0.1-1.0
    supraventricular tachycardia (SVT) / Early / 0.1-1.0
    angina / Early / 0-1.0
    edema / Delayed / 0.1-1.0
    atopic dermatitis / Delayed / 1.0-1.0
    contact dermatitis / Delayed / 0.1-1.0
    dyspnea / Early / 0.1-1.0
    conjunctivitis / Delayed / 0.1-1.0
    elevated hepatic enzymes / Delayed / 0.1-1.0
    vaginitis / Delayed / 0.1-1.0
    urinary retention / Early / 0.1-1.0
    pyuria / Delayed / 0.1-1.0
    urinary incontinence / Early / 0.1-1.0
    cystitis / Delayed / 0.1-1.0
    myasthenia / Delayed / 0-1.0
    peripheral edema / Delayed / 0.1-1.0
    oral ulceration / Delayed / 0-0.1
    sialadenitis / Delayed / 0-0.1
    gingival hyperplasia / Delayed / 0-0.1
    glossitis / Early / 0-0.1
    cholelithiasis / Delayed / 0-0.1
    fecal incontinence / Early / 0-0.1
    esophagitis / Delayed / 0-0.1
    choreoathetosis / Delayed / 0-0.1
    dysarthria / Delayed / 0-0.1
    trismus / Delayed / 0-0.1
    hyperalgesia / Delayed / 0-0.1
    hyperreflexia / Delayed / 0-0.1
    meningitis / Delayed / 0-0.1
    aphasia / Delayed / 0-0.1
    neuritis / Delayed / 0-0.1
    psychosis / Early / 0-0.1
    delirium / Early / 0-0.1
    hyponatremia / Delayed / 0-0.1
    thrombocytopenia / Delayed / 0-0.1
    lymphopenia / Delayed / 0-0.1
    prolonged bleeding time / Delayed / 0-0.1
    lymphocytosis / Delayed / 0-0.1
    bundle-branch block / Early / 0-0.1
    phlebitis / Rapid / 0-0.1
    candidiasis / Delayed / 0-0.1
    skin ulcer / Delayed / 0-0.1
    bullous rash / Early / 0-0.1
    furunculosis / Delayed / 0-0.1
    hemoptysis / Delayed / 0-0.1
    dysphonia / Delayed / 0-0.1
    amblyopia / Delayed / 0-0.1
    blepharitis / Early / 0-0.1
    hyperacusis / Delayed / 0-0.1
    cataracts / Delayed / 0-0.1
    exophthalmos / Delayed / 0-0.1
    photophobia / Early / 0-0.1
    hyperbilirubinemia / Delayed / 0-0.1
    jaundice / Delayed / 0-0.1
    hepatitis / Delayed / 0-0.1
    vaginal bleeding / Delayed / 0-0.1
    prostatitis / Delayed / 0-0.1
    nephrolithiasis / Delayed / 0-0.1
    flank pain / Delayed / 0-0.1
    tetany / Early / 0-0.1
    hypothyroidism / Delayed / 0-0.1
    hyperthyroidism / Delayed / 0-0.1
    diabetes mellitus / Delayed / 0-0.1
    goiter / Delayed / 0-0.1
    hyperglycemia / Delayed / 0-0.1
    hypoglycemia / Early / 0-0.1
    hypercalcemia / Delayed / 0-0.1
    hypokalemia / Delayed / 0-0.1
    hypercholesterolemia / Delayed / 0-0.1
    hypocalcemia / Delayed / 0-0.1
    gout / Delayed / 0-0.1
    dehydration / Delayed / 0-0.1
    hyperphosphatemia / Delayed / 0-0.1
    osteoporosis / Delayed / 0-0.1
    withdrawal / Early / 0-0.1
    akathisia / Delayed / Incidence not known
    impulse control symptoms / Delayed / Incidence not known
    hallucinations / Early / Incidence not known
    bleeding / Early / Incidence not known
    platelet dysfunction / Delayed / Incidence not known
    pneumonitis / Delayed / Incidence not known
    hepatomegaly / Delayed / Incidence not known
    hyperprolactinemia / Delayed / Incidence not known
    priapism / Early / Incidence not known
    galactorrhea / Delayed / Incidence not known
    hematuria / Delayed / Incidence not known
    osteopenia / Delayed / Incidence not known
    growth inhibition / Delayed / Incidence not known

    Mild

    headache / Early / 6.3-27.0
    nausea / Early / 4.3-26.0
    insomnia / Early / 8.0-24.0
    drowsiness / Early / 9.0-24.0
    asthenia / Delayed / 12.0-22.0
    diarrhea / Early / 6.0-18.0
    xerostomia / Early / 3.0-18.0
    dizziness / Early / 6.0-14.0
    libido decrease / Delayed / 3.0-12.0
    tremor / Early / 4.0-11.0
    hyperhidrosis / Delayed / 6.0-11.0
    anorexia / Delayed / 1.0-9.0
    orgasm dysfunction / Delayed / 2.0-9.0
    sinusitis / Delayed / 4.0-8.0
    infection / Delayed / 5.0-8.0
    abdominal pain / Early / 3.0-7.0
    flatulence / Early / 4.0-6.0
    dyspepsia / Early / 2.0-5.0
    yawning / Early / 4.0-5.0
    agitation / Early / 3.0-5.0
    anxiety / Delayed / 2.0-5.0
    dysmenorrhea / Delayed / 1.0-5.0
    back pain / Delayed / 3.0-5.0
    myalgia / Early / 2.0-5.0
    malaise / Early / 0-4.9
    fatigue / Early / 0-4.9
    lethargy / Early / 0-4.9
    appetite stimulation / Delayed / 2.0-4.0
    paresthesias / Delayed / 1.0-4.0
    pharyngitis / Delayed / 1.0-4.0
    rhinitis / Early / 3.0-4.0
    weight gain / Delayed / 1.0-3.0
    vomiting / Early / 2.0-3.0
    rash (unspecified) / Early / 2.0-3.0
    increased urinary frequency / Early / 2.0-3.0
    chills / Rapid / 2.0-2.0
    cough / Delayed / 1.0-2.0
    fever / Early / 1.0-2.0
    dysgeusia / Early / 2.0-2.0
    arthralgia / Delayed / 1.0-2.0
    gingivitis / Delayed / 0-1.0
    dental pain / Delayed / 0.1-1.0
    eructation / Early / 0.1-1.0
    gastroesophageal reflux / Delayed / 0.1-1.0
    weight loss / Delayed / 0.1-1.0
    hyperkinesis / Delayed / 0.1-1.0
    vertigo / Early / 0.1-1.0
    hypoesthesia / Delayed / 0.1-1.0
    paranoia / Early / 0.1-1.0
    emotional lability / Early / 0.1-1.0
    purpura / Delayed / 0.1-1.0
    leukocytosis / Delayed / 0.1-1.0
    ecchymosis / Delayed / 0.1-1.0
    syncope / Early / 0.1-1.0
    urticaria / Rapid / 0.1-1.0
    xerosis / Delayed / 0.1-1.0
    alopecia / Delayed / 0.1-1.0
    acne vulgaris / Delayed / 0.1-1.0
    photosensitivity / Delayed / 0.1-1.0
    hyperventilation / Early / 0-1.0
    laryngitis / Delayed / 0.1-1.0
    ocular pain / Early / 0.1-1.0
    mydriasis / Early / 0.1-1.0
    otalgia / Early / 0.1-1.0
    amenorrhea / Delayed / 0.1-1.0
    libido increase / Delayed / 0.1-1.0
    menorrhagia / Delayed / 0.1-1.0
    urinary urgency / Early / 0.1-1.0
    polyuria / Early / 0.1-1.0
    nocturia / Early / 0-1.0
    polydipsia / Early / 0.1-1.0
    dental caries / Delayed / 0-0.1
    tongue discoloration / Delayed / 0-0.1
    hyporeflexia / Delayed / 0-0.1
    pallor / Early / 0-0.1
    hypothermia / Delayed / 0-0.1
    seborrhea / Delayed / 0-0.1
    maculopapular rash / Early / 0-0.1
    skin discoloration / Delayed / 0-0.1
    vesicular rash / Delayed / 0-0.1
    hirsutism / Delayed / 0-0.1
    hiccups / Early / 0-0.1
    diplopia / Early / 0-0.1
    parosmia / Delayed / 0-0.1
    ptosis / Delayed / 0-0.1
    gynecomastia / Delayed / 0-0.1
    leukorrhea / Delayed / 0-0.1
    mastalgia / Delayed / 0-0.1
    breast enlargement / Delayed / 0-0.1
    breast discharge / Delayed / 0-0.1
    pelvic pain / Delayed / 0-0.1
    muscle cramps / Delayed / 0-0.1
    pruritus / Rapid / 1.0
    tinnitus / Delayed / 1.0
    restless legs syndrome (RLS) / Delayed / Incidence not known
    petechiae / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abciximab: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving abciximab. Monitor closely for signs and symptoms of bleeding.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Minor) Impairment of CYP2D6 metabolism by paroxetine may reduce the conversion of codeine and hydrocodone to their active forms, thus reducing analgesic efficacy of these two opiates.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation. A cohort study in > 26,000 patients found that SSRI use alone increased the risk for serious GI bleed by 3.6-fold; when an SSRI was combined with aspirin the risk was increased by > 5-fold. The absolute risk of GI bleed from concomitant therapy with aspirin and a SSRI was low (20/2640 patients) in this cohort study and the clinician may determine that the combined use of these drugs is appropriate.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation. A cohort study in > 26,000 patients found that SSRI use alone increased the risk for serious GI bleed by 3.6-fold; when an SSRI was combined with aspirin the risk was increased by > 5-fold. The absolute risk of GI bleed from concomitant therapy with aspirin and a SSRI was low (20/2640 patients) in this cohort study and the clinician may determine that the combined use of these drugs is appropriate.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and paroxetine. 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, paroxetine is a potent CYP2D6 inhibitor and may interfere with dextromethorphan metabolism, potentially leading to serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and paroxetine. 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, paroxetine is a potent CYP2D6 inhibitor and may interfere with dextromethorphan metabolism, potentially leading to serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Acetaminophen; Codeine: (Minor) Impairment of CYP2D6 metabolism by paroxetine may reduce the conversion of codeine and hydrocodone to their active forms, thus reducing analgesic efficacy of these two opiates.
    Acetaminophen; Dextromethorphan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and paroxetine. 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, paroxetine is a potent CYP2D6 inhibitor and may interfere with dextromethorphan metabolism, potentially leading to serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Acetaminophen; Dextromethorphan; Doxylamine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and paroxetine. 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, paroxetine is a potent CYP2D6 inhibitor and may interfere with dextromethorphan metabolism, potentially leading to serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and paroxetine. 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, paroxetine is a potent CYP2D6 inhibitor and may interfere with dextromethorphan metabolism, potentially leading to serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and paroxetine. 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, paroxetine is a potent CYP2D6 inhibitor and may interfere with dextromethorphan metabolism, potentially leading to serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and paroxetine. 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, paroxetine is a potent CYP2D6 inhibitor and may interfere with dextromethorphan metabolism, potentially leading to serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Acetaminophen; Hydrocodone: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as paroxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Acetaminophen; Oxycodone: (Moderate) The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue the suspected drugs if serotonin syndrome is suspected and manage cliinically. There has been a case report of possible serotonin syndrome caused by the combination of oxycodone and selective serotonin reuptake inhbitors (SSRIs).
    Acetaminophen; Pentazocine: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions
    Acetaminophen; Tramadol: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as tramadol. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Several cases of serotonin syndrome have been reported after the administration of tramadol with a SSRI. Concomitant use of tramadol also increases the seizure risk in patients taking selective serotonin reuptake inhibitors (SSRIs). Post-marketing reports implicate the concurrent use of SSRIs with tramadol in some cases of seizures. Lastly, SSRIs such as paroxetine 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.
    Almotriptan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., almotriptan). Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen.
    Alprazolam: (Minor) The manufacturer of alprazolam states that in vitro studies suggest paroxetine may inhibit the metabolism of alprazolam via inhibition of CYP3A4. However, paroxetine is typically considered a major inhibitor of CYP2D6, for which alprazolam is not a substrate. The potential for clinical interaction is uncertain. Be alert for any change in psychomotor performance or other benzodiazepine-related side effects when paroxetine is combined with alprazolam.
    Alteplase, tPA: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SSRI.
    Amiodarone: (Minor) Amiodarone inhibits CYP2D6 and may theoretically increase concentrations of other drugs metabolized by this enzyme including paroxetine.
    Amitriptyline: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. In addition, paroxetine is a potent CYP2D6 inhibitor and may decrease the metabolism of amitriptyline, a CYP2D6 substrate. Because there is a risk of QT prolongation and torsade de pointes (TdP) with tricyclics at elevated serum concentrations, coadministration should be approached with caution and close monitoring. Lastly, both paroxetine and amitriptyline may exhibit significant anticholinergic effects that may be additive during concurrent use.
    Amitriptyline; Chlordiazepoxide: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. In addition, paroxetine is a potent CYP2D6 inhibitor and may decrease the metabolism of amitriptyline, a CYP2D6 substrate. Because there is a risk of QT prolongation and torsade de pointes (TdP) with tricyclics at elevated serum concentrations, coadministration should be approached with caution and close monitoring. Lastly, both paroxetine and amitriptyline may exhibit significant anticholinergic effects that may be additive during concurrent use.
    Amoxapine: (Moderate) Paroxetine is a potent inhibitor of CYP2D6, the isoenzyme partially responsible for the metabolism of amoxapine. In several cases, symptoms of toxicity, including seizures, have been reported when the structurally related tricyclic antidepressants were co-administered with an SSRI. At least one case report exists of a death thought to be due to impaired clearance of the amoxapine-related tricyclic antidepressant amitriptyline by fluoxetine. Patients receiving amoxapine should be monitored closely for toxicity if paroxetine is added.
    Amphetamines: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as paroxetine and amphetamines. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. The MAOI activity of amphetamines may also be of concern with the use of drugs that have serotonergic activity. All serotonergic agents should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. In addition, amphetamines and amphetamine derivatives are metabolized to some degree by CYP2D6 and a kinetic interaction is possible with strong CYP2D6 inhibitors, such as paroxetine. Increased systemic exposure to amphetamines from CYP2D6 inhibition may result in high blood pressure, tachycardia, anxiety, irritability, insomnia, or other amphetamine-related adverse effects. Patients receiving paroxetine and an amphetamine should be monitored for the emergence of serotonin syndrome or other adverse effects, particularly during treatment initiation and during dosage increases.
    Anagrelide: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Antithrombin III: (Major) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving anticoagulants, like antithrombin III. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with an anticoagulant medication.
    Apixaban: (Major) The concomitant use of selective serotonin reuptake inhibitors (SSRIs) and apixaban can increase the risk of bleeding. If given concomitantly, patients should be educated about the signs and symptoms of bleeding and be instructed to report them immediately or go to an emergency room.
    Ardeparin: (Major) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving low molecular weight heparins. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with molecular weight heparins.
    Aripiprazole: (Major) Paroxetine, a potent inhibitor of CYP2D6, may decrease the metabolism of CYP2D6 substrates such as aripiprazole. Decreased metabolism of aripiprazole may lead to adverse effects such as extrapyramidal symptoms, QT prolongation, and torsade de pointes (TdP). The manufacturer of aripiprazole recommends that the oral aripiprazole dose be reduced to one-half of the usual dose when coadministered with strong CYP2D6 inhibitors. Adults receiving 300 mg or 400 mg of Abilify Maintena should have a dose reduction to 200 mg or 300 mg, respectively, during coadministration of a potent CYP2D6 inhibitor if used for more than 14 days. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP2D6 inhibitor for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg of Aristada, if tolerated. Because aripiprazole is also metabolized by CYP3A4, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Aripiprazole dosage adjustments are not required when aripiprazole is added as adjunctive treatment to antidepressants for major depressive disorder provided that the manufacturer's dosing guidelines for this indication are followed.
    Asenapine: (Major) If paroxetine and asenapine are used together, reduce the paroxetine dose by half. Asenapine may enhance the inhibitory effects of paroxetine on its own metabolism; in one study, co-administration of paroxetine and asenapine increased paroxetine exposure by 2-fold compared to that seen during paroxetine use alone. In addition, there may theoretically be an increased risk of QT prolongation and other adverse events associated with asenapine use if the drugs are used together. CYP2D6 plays a minor role in asenapine's metabolism, and paroxetine is a potent CYP2D6 inhibitor. However, because asenapine is metabolized by multiple pathways, a clinically significant interaction is less likely to occur.
    Aspirin, ASA: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) The 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) Impairment of CYP2D6 metabolism by paroxetine may reduce the conversion of codeine and hydrocodone to their active forms, thus reducing analgesic efficacy of these two opiates.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
    Aspirin, ASA; Carisoprodol: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
    Aspirin, ASA; Carisoprodol; Codeine: (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) Impairment of CYP2D6 metabolism by paroxetine may reduce the conversion of codeine and hydrocodone to their active forms, thus reducing analgesic efficacy of these two opiates.
    Aspirin, ASA; Dipyridamole: (Moderate) Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding. (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
    Aspirin, ASA; Omeprazole: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
    Aspirin, ASA; Oxycodone: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation. (Moderate) The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue the suspected drugs if serotonin syndrome is suspected and manage cliinically. There has been a case report of possible serotonin syndrome caused by the combination of oxycodone and selective serotonin reuptake inhbitors (SSRIs).
    Aspirin, ASA; Pravastatin: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
    Atazanavir; Cobicistat: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
    Atomoxetine: (Major) Atomoxetine is primarily metabolized by CYP2D6 and paroxetine is a strong CYP2D6 inhibitor. In extensive metabolizers (EMs) taking atomoxetine who are treated concurrently with paroxetine, the atomoxetine AUC is roughly 6 to 8-fold and Cmax 3 to 4-fold greater than if atomoxetine is given alone. In children and adolescents up to 70 kg receiving a strong CYP2D6 inhibitor or who are known CYP2D6 poor metabolizers (PMs), atomoxetine should be initiated at 0.5 mg/kg/day and only increased to the usual target dose of 1.2 mg/kg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated. In children and adolescents over 70 kg and adults receiving a strong CYP2D6 inhibitor or who are known CYP2D6 poor metabolizers, atomoxetine should be initiated at 40 mg/day and only increased to the usual target dose of 80 mg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated. If concurrent use is necessary, monitor for adverse effects, such as dizziness, nervousness, insomnia, and cardiac effects (e.g., hypertension, increased pulse rate, QT prolongation). Because atomoxetine has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Severe) According to the manufacturer of paroxetine, treatment initiation with paroxetine 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 paroxetine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving paroxetine and requiring urgent treatment with IV methylene blue, paroxetine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Paroxetine 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.
    Barbiturates: (Moderate) Barbiturates may induce various hepatic CYP450 isoenzymes, including those responsible for the metabolism of paroxetine. Clinicians should be aware of the potential for reduced SSRI efficacy with concurrent administration of a barbiturate, especially in chronic use.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering SSRIs with other drugs that have serotonergic properties such as ergot alkaloids (e.g., ergotamine or dihydroergotamine). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, fluoxetine and fluvoxamine may reduce the metabolism of ergotamine, dihydroergotamine or methysergide via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects. Administration of fluoxetine or fluvoxamine with other ergot alkaloids, like ergonovine or methylergonovine, may also need to be approached with caution. Avoid coadministration of ergot alkaloids with fluoxetine or when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Severe) According to the manufacturer of paroxetine, treatment initiation with paroxetine 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 paroxetine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving paroxetine and requiring urgent treatment with IV methylene blue, paroxetine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Paroxetine 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.
    Betrixaban: (Major) Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if betrixaban and selective serotonin reuptake inhibitors (SSRIs) are used concomitantly. Coadministration of betrixaban and SSRIs may increase the risk of bleeding.
    Bismuth 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.
    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. Paroxetine 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 paroxetine, could theoretically impair timolol metabolism; the clinical significance of such interactions is unknown.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and paroxetine. 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, paroxetine is a potent CYP2D6 inhibitor and may interfere with dextromethorphan metabolism, potentially leading to serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Brompheniramine; Guaifenesin; Hydrocodone: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as paroxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as paroxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Buprenorphine: (Major) Concurrent use of opioids with other drugs that modulate serotonergic function, such as paroxetine, 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 with buprenorphine and paroxetine 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.
    Buprenorphine; Naloxone: (Major) Concurrent use of opioids with other drugs that modulate serotonergic function, such as paroxetine, 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 with buprenorphine and paroxetine 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.
    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 paroxetine. Although clinical evidence of interactions is lacking, plasma concentrations of SSRIs metabolized by CYP2D6 may be increased if bupropion is added. In addition, in vitro studies suggest that paroxetine inhibit the hydroxylation of bupropion.
    Bupropion; Naltrexone: (Moderate) Bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Coadministration of bupropion with medications that are metabolized by CYP2D6 should be approached with caution. Many selective serotonin reuptake inhibitors (SSRIs) are CYP2D6 substrates including paroxetine. Although clinical evidence of interactions is lacking, plasma concentrations of SSRIs metabolized by CYP2D6 may be increased if bupropion is added. In addition, in vitro studies suggest that paroxetine inhibit the hydroxylation of bupropion.
    Buspirone: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as buspirone and paroxetine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
    Cabergoline: (Moderate) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as cabergoline. Patients receiving cabergoline with an SSRI should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Caffeine; Ergotamine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering SSRIs with other drugs that have serotonergic properties such as ergot alkaloids (e.g., ergotamine or dihydroergotamine). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, fluoxetine and fluvoxamine may reduce the metabolism of ergotamine, dihydroergotamine or methysergide via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects. Administration of fluoxetine or fluvoxamine with other ergot alkaloids, like ergonovine or methylergonovine, may also need to be approached with caution. Avoid coadministration of ergot alkaloids with fluoxetine or when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
    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.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and paroxetine. 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, paroxetine is a potent CYP2D6 inhibitor and may interfere with dextromethorphan metabolism, potentially leading to serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as paroxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as paroxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Carvedilol: (Minor) Inhibitors of the hepatic CYP450 isozyme CYP 2D6, such as paroxetine, may inhibit the hepatic oxidative metabolism of carvedilol.
    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.
    Chlorpheniramine; Codeine: (Minor) Impairment of CYP2D6 metabolism by paroxetine may reduce the conversion of codeine and hydrocodone to their active forms, thus reducing analgesic efficacy of these two opiates.
    Chlorpheniramine; Dextromethorphan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and paroxetine. 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, paroxetine is a potent CYP2D6 inhibitor and may interfere with dextromethorphan metabolism, potentially leading to serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and paroxetine. 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, paroxetine is a potent CYP2D6 inhibitor and may interfere with dextromethorphan metabolism, potentially leading to serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as paroxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Chlorpheniramine; Hydrocodone: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as paroxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as paroxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as paroxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Chlorpromazine: (Major) Substantial increases in concentrations of phenothiazines such as chlorpromazine may occur due to CYP2D6 inhibition by paroxetine, which may increase the risk of adverse effects, including extrapyramidal symptoms. In addition, because chlorpromazine has been associated with QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events. Lastly, both paroxetine and chlorpromazine may exhibit significant anticholinergic effects that may be additive during concurrent use.
    Choline Salicylate; Magnesium Salicylate: (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation. A cohort study in > 26,000 patients found that SSRI use alone increased the risk for serious GI bleed by 3.6-fold; when an SSRI was combined with aspirin the risk was increased by > 5-fold. The absolute risk of GI bleed from concomitant therapy with aspirin and a SSRI was low (20/2640 patients) in this cohort study and the clinician may determine that the combined use of these drugs is appropriate.
    Cilostazol: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding.
    Cimetidine: (Moderate) Cimetidine inhibits cytochrome isoenzymes CYP1A2, CYP2C9, and CYP3A4 while paroxetine is metabolized by isoenzyme CYP2D6. Although one would assume no interaction would occur, several studies have shown that cimetidine can increase paroxetine AUC. While significant adverse effects have not been reported, patients should be monitored carefully for an increased response to paroxetine if cimetidine is coadministered. Dosage adjustments of paroxetine should be based on clinical effect for the individual.
    Cinacalcet: (Minor) Cinacalcet, a strong in vitro inhibitor of the CYP2D6 cytochrome P450 enzyme, may theoretically increase serum concentrations of other drugs metabolized by this enzyme, including paroxetine.
    Citalopram: (Severe) Due to the similarity in pharmacology of paroxetine 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. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SSRI to another SSRI.
    Class IC Antiarrhythmics: (Major) Paroxetine impairs metabolism of the cytochrome P-450 isoenzyme CYP2D6 pathway at therapeutic doses. Although no clinical data are available, paroxetine should be used cautiously in patients receiving type IC antiarrhythmics and mexiletine since these antiarrhythmics are metabolized by this isozyme. Inhibition of CYP2D6 can result in increased concentrations of Class IC antiarrhythmics which may increase the risk of side effects or proarrhythmia.
    Clomipramine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. 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, paroxetine is a potent CYP2D6 inhibitor and may decrease the metabolism of clomipramine, a CYP2D6 substrate. Because there is a risk of QT prolongation and torsade de pointes (TdP) with tricyclics at elevated serum concentrations, coadministration should be approached with caution and close monitoring. Lastly, both paroxetine and clomipramine may exhibit significant anticholinergic effects that may be additive during concurrent use.
    Clopidogrel: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving clopidogrel. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Clozapine: (Moderate) Paroxetine is a potent inhibitor of CYP2D6, which may result in decreased clearance of CYP2D6 substrates such as clozapine. Minor to modest (less than 2-fold) elevations in concentrations of clozapine and its metabolites have been reported during concurrent use of paroxetine. Clozapine is associated with a risk for QT prolongation and torsade de pointe (TdP). Elevated plasma concentrations of clozapine occurring through CYP2D6 inhibition may increase the risk of life-threatening arrhythmias. sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP2D6 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary. Lastly, both paroxetine and clozapine may exhibit significant anticholinergic effects which may be additive during concurrent therapy.
    Cobicistat: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
    Codeine: (Minor) Impairment of CYP2D6 metabolism by paroxetine may reduce the conversion of codeine and hydrocodone to their active forms, thus reducing analgesic efficacy of these two opiates.
    Codeine; Guaifenesin: (Minor) Impairment of CYP2D6 metabolism by paroxetine may reduce the conversion of codeine and hydrocodone to their active forms, thus reducing analgesic efficacy of these two opiates.
    Codeine; Phenylephrine; Promethazine: (Moderate) Promethazine is a substrate for CYP2D6 and paroxetine is a potent inhibitor of CYP2D6. Because promethazine is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events. In addition, both paroxetine and promethazine exhibit anticholinergic effects that may be additive during combined therapy. The risk of other adverse effects of promethazine may also be increased, including sedation and extrapyramidal symptoms. (Minor) Impairment of CYP2D6 metabolism by paroxetine may reduce the conversion of codeine and hydrocodone to their active forms, thus reducing analgesic efficacy of these two opiates.
    Codeine; Promethazine: (Moderate) Promethazine is a substrate for CYP2D6 and paroxetine is a potent inhibitor of CYP2D6. Because promethazine is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events. In addition, both paroxetine and promethazine exhibit anticholinergic effects that may be additive during combined therapy. The risk of other adverse effects of promethazine may also be increased, including sedation and extrapyramidal symptoms. (Minor) Impairment of CYP2D6 metabolism by paroxetine may reduce the conversion of codeine and hydrocodone to their active forms, thus reducing analgesic efficacy of these two opiates.
    Cyclobenzaprine: (Major) Cautious use of cyclobenzaprine and drugs that increase serotonin concentrations such as selective serotonin reuptake inhibitors (SSRIs) is advised because of the possibility of serotonin syndrome. If these drugs must be used together, closely monitor the patient for signs and symptoms of serotonin syndrome. If such a reaction develops, immediately discontinue cyclobenzaprine and the SSRI.
    Cyproheptadine: (Moderate) Cyproheptadine is a serotonin antagonist in the CNS and can oppose the pharmacologic actions of selective serotonin reuptake inhibitors (SSRIs). Cyproheptadine has been used for the management of orgasm dysfunction caused by the SSRIs and for the adjunctive treatment of SSRI overdose (i.e., serotonin syndrome) in emergency situations; however, a reversal of antidepressant effects may occur when cyproheptadine is given in a routine manner along with the SSRIs due to the serotonin antagonistic effects of cyproheptadine. Cyproheptadine reportedly has interfered with the antidepressant and anti-bulimia actions of fluoxetine but more data are needed to confirm a direct drug-drug interaction.
    Dabigatran: (Major) Patients should be instructed to monitor for signs and symptoms of bleeding while taking a selective serotonin reuptake inhibitor (SSRI) concurrently with dabigatran and to promptly report any bleeding events to their prescriber. Although clinical data are limited, SSRIs may potentiate the hypoprothrombinemic effects of anticoagulants, perhaps by inhibiting platelet aggregation.
    Dalteparin: (Major) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving low molecular weight heparins. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with molecular weight heparins.
    Danaparoid: (Major) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving anticoagulants, like danaparoid. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with an anticoagulant medication.
    Darifenacin: (Moderate) Paroxetine inhibits CYP2D6. Serum concentrations of darifenacin, a CYP2D6 substrate, may increase when used in combination with paroxetine. Patients should be monitored for increased anticholinergic effects if these drugs are coadministered.
    Darunavir: (Moderate) Use caution when coadministering darunavir with paroxetine, as decreased SSRI concentrations may be seen. If paroxetine is coadministered with darunavir, carefully titrate the dose of paroxetine based on a clinical assessment of antidepressant response.
    Darunavir; Cobicistat: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4. (Moderate) Use caution when coadministering darunavir with paroxetine, as decreased SSRI concentrations may be seen. If paroxetine is coadministered with darunavir, carefully titrate the dose of paroxetine based on a clinical assessment of antidepressant response.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) A dose reduction of paroxetine may be necessary during co-administration of ritonavir. Concurrent use of CYP2D6 substrates, such as paroxetine, with ritonavir could result in increases (up to 2-fold) in the AUC of paroxetine. Paroxetine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Delavirdine: (Moderate) Delavirdine is a potent inhibitors of cytochrome P450 2D6, and may theoretically decrease paroxetine metabolism leading to increased adverse reactions.
    Desipramine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. 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, paroxetine is a potent CYP2D6 inhibitor and may decrease the metabolism of desipramine, a CYP2D6 substrate. Because there is a risk of QT prolongation and torsade de pointes (TdP) with tricyclics at elevated serum concentrations, coadministration should be approached with caution and close monitoring. Lastly, both paroxetine and desipramine may exhibit significant anticholinergic effects that may be additive during concurrent use.
    Desmopressin: (Major) Additive hyponatremic effects may be seen in patients treated with desmopressin and drugs associated with water intoxication, hyponatremia, or SIADH including SSRIs. Use combination with caution, and monitor patients for signs and symptoms of hyponatremia.
    Desvenlafaxine: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, selective serotonin reuptake inhibitors (SSRIs) should generally not be administered with serotonin norepinephrine reuptake inhibitors like desvenlafaxine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Discontinuation symptoms have been reported when switching from other antidepressants to desvenlafaxine. It may be advisable to taper the previous antidepressant to minimize discontinuation symptoms. If serotonin syndrome is suspected, desvenlafaxine and concurrent serotonergic agents should be discontinued. Dosage adjustments of fluoxetine or paroxetine may be necessary during concurrent use of desvenlafaxine. Although clinical studies have shown that desvenlafaxine does not have a clinically relevant effect on CYP2D6 inhibition at doses of 100 mg/day, the manufacturer recommends that primary substrates of CYP2D6 be dosed at the original level when co-administered with desvenlafaxine 100 mg or lower or when desvenlafaxine is discontinued. The dose of these CYP2D6 substrates should be reduced by up to one-half if co-administered with desvenlafaxine 400 mg/day.
    Deutetrabenazine: (Major) Do not exceed 18 mg/dose or 36 mg/day of deutetrabenazine if must use concurrently with a strong CYP2D6 inhibitor. Paroxetine 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. After 8 days of paroxetine 20 mg PO daily, systemic exposure (AUC) of alpha- and beta-HTBZ increased 1.9-fold and 6.5-fold, respectively, following a single 22.5 mg dose of deutetrabenazine. The clearance of alpha- and beta-HTBZ was reduced, with corresponding increases in mean half-life of 1.5-fold and 2.7-fold, respectively. The Cmax of alpha- and beta-HTBZ increased 1.2-fold and 2.2-fold, respectively.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and paroxetine. 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, paroxetine is a potent CYP2D6 inhibitor and may interfere with dextromethorphan metabolism, potentially leading to serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Dexmethylphenidate: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dexmethylphenidate and selective serotonin reuptake inhibitors (SSRIs). There are rare reports of serotonin syndrome occurring during use of an SSRI and methylphenidate, a racemic compound containing dexmethylphenidate. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    Dextromethorphan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and paroxetine. 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, paroxetine is a potent CYP2D6 inhibitor and may interfere with dextromethorphan metabolism, potentially leading to serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and paroxetine. 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, paroxetine is a potent CYP2D6 inhibitor and may interfere with dextromethorphan metabolism, potentially leading to serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Dextromethorphan; Guaifenesin: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and paroxetine. 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, paroxetine is a potent CYP2D6 inhibitor and may interfere with dextromethorphan metabolism, potentially leading to serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and paroxetine. 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, paroxetine is a potent CYP2D6 inhibitor and may interfere with dextromethorphan metabolism, potentially leading to serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and paroxetine. 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, paroxetine is a potent CYP2D6 inhibitor and may interfere with dextromethorphan metabolism, potentially leading to serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and paroxetine. 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, paroxetine is a potent CYP2D6 inhibitor and may interfere with dextromethorphan metabolism, potentially leading to serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Dextromethorphan; Promethazine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and paroxetine. 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, paroxetine is a potent CYP2D6 inhibitor and may interfere with dextromethorphan metabolism, potentially leading to serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented. (Moderate) Promethazine is a substrate for CYP2D6 and paroxetine is a potent inhibitor of CYP2D6. Because promethazine is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events. In addition, both paroxetine and promethazine exhibit anticholinergic effects that may be additive during combined therapy. The risk of other adverse effects of promethazine may also be increased, including sedation and extrapyramidal symptoms.
    Dextromethorphan; Quinidine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and paroxetine. 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, paroxetine is a potent CYP2D6 inhibitor and may interfere with dextromethorphan metabolism, potentially leading to serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented. (Moderate) Quinidine inhibits CYP2D6 and may theoretically increase concentrations of other drugs metabolized by this enzyme. Caution is recommended when administering quinidine with CYP2D6 substrates, including paroxetine.
    Digoxin: (Minor) Paroxetine may slightly decrease mean digoxin area under the curve values. Until more clinical data are known, patients should be monitored for loss of digoxin clinical effect if paroxetine is added.
    Dihydroergotamine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering SSRIs with other drugs that have serotonergic properties such as ergot alkaloids (e.g., ergotamine or dihydroergotamine). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, fluoxetine and fluvoxamine may reduce the metabolism of ergotamine, dihydroergotamine or methysergide via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects. Administration of fluoxetine or fluvoxamine with other ergot alkaloids, like ergonovine or methylergonovine, may also need to be approached with caution. Avoid coadministration of ergot alkaloids with fluoxetine or when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as paroxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Dipyridamole: (Moderate) Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding.
    Diuretics: (Moderate) Patients receiving a diuretic during treatment with paroxetine 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 paroxetine should be considered in patients who develop symptomatic hyponatremia.
    Dolasetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering dolasetron with other drugs that have serotonergic properties such as paroxetine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, discontinue dolasetron and concurrent serotonergic agents and initiate appropriate medical treatment. In addition, because dolasetron is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events.
    Donepezil: (Major) Paroxetine is a potent inhibitor of CYP2D6, and concurrent use with donepezil, a CYP2D6 substrate, may lead to increased plasma levels of donepezil. An increased incidence of cholinergic-related side effects may occur. In addition, because donepezil is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events.
    Donepezil; Memantine: (Major) Paroxetine is a potent inhibitor of CYP2D6, and concurrent use with donepezil, a CYP2D6 substrate, may lead to increased plasma levels of donepezil. An increased incidence of cholinergic-related side effects may occur. In addition, because donepezil is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events.
    Dorzolamide; Timolol: (Moderate) Timolol is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as paroxetine, could theoretically impair timolol metabolism; the clinical significance of such interactions is unknown.
    Doxepin: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. 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, paroxetine is a potent CYP2D6 inhibitor and may decrease the metabolism of doxepin, a CYP2D6 substrate. Because there is a risk of QT prolongation and torsade de pointes (TdP) with tricyclics at elevated serum concentrations, coadministration should be approached with caution and close monitoring. Lastly, both paroxetine and doxepin may exhibit significant anticholinergic effects that may be additive during concurrent use.
    Doxercalciferol: (Moderate) Doxercalciferol is converted in the liver to 1,25-dihydroxyergocalciferol, the major active metabolite, and 1-alpha, 24-dihydroxyvitamin D2, a minor metabolite. Although not specifically studied, cytochrome P450 enzyme inhibitors, including selective serotonin reuptake inhibitors (SSRIs), may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy. Patients should be monitored for a decrease in efficacy if SSRIs are coadministered with doxercalciferol.
    Doxorubicin: (Major) Paroxetine is a potent CYP2D6 inhibitor and doxorubicin is a major substrate of CYP2D6. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. In addition, because doxorubicin is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes (TdP), concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events. Avoid coadministration of paroxetine and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression, cardiotoxicity, QT prolongation, and TdP.
    Duloxetine: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, selective serotonin reuptake inhibitors (SSRIs) should generally not be administered with serotonin norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine, desvenlafaxine, duloxetine, and milnacipran. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Dutasteride; Tamsulosin: (Moderate) Use caution when administering tamsulosin with a strong CYP2D6 inhibitor such as paroxetine. Tamsulosin is extensively metabolized by CYP2D6 hepatic enzymes. In clinical evaluation, concomitant treatment with paroxetine resulted in an increase in the Cmax and AUC of tamsulosin by a factor of 1.3 and 1.6, respectively. If concomitant use in necessary, monitor patient closely for increased side effects.
    Edoxaban: (Major) Selective serotonin reuptake inhibitors (SSRIs) can inhibit serotonin uptake by platelets, thus causing platelet dysfunction and increasing the risk for bleeding with edoxaban; however, the absolute risk is not known. If these drugs are administered together, instruct patients to monitor for signs and symptoms of bleeding, and to promptly report any bleeding events to their practitioner.
    Eletriptan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., eletriptan). Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen.
    Eliglustat: (Major) In extensive or intermediate CYP2D6 metabolizers (EMs or IMs), coadministration of paroxetine and eliglustat requires dosage reduction of eliglustat to 84 mg PO once daily; however, coadministration of eliglustat with both paroxetine and a strong or moderate CYP3A inhibitor is contraindicated. Paroxetine is a substrate and strong inhibitor of CYP2D6; eliglustat is a CYP2D6 and CYP3A substrate and a CYP2D6 inhibitor. Coadministration of eliglustat with CYP2D6 inhibitors, such as paroxetine, may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias). In addition, coadministration of eliglustat with CYP2D6 substrates (e.g., paroxetine) may result in increased concentrations of the concomitant drug; monitor patients closely and consider reducing the dosage of paroxetine and titrating to clinical effect. During clinical trials in EMs (n = 30), Cmax and AUC of eliglustat increased 7-fold and 8.4-fold, respectively, after co-administration of eliglustat 84 mg PO twice daily with paroxetine 30 mg. Physiology-based pharmacokinetic (PBPK) models suggest that paroxetine may increase the Cmax and AUC of eliglustat 2.1- and 2.3-fold, respectively, in IMs. In addition, PBPK modeling suggests concomitant use of eliglustat (84 mg PO twice daily) with paroxetine (strong 2D6 inhibitor) and ketoconazole (strong 3A4 inhibitor) may increase the Cmax and AUC of eliglustat 16.7- and 24.2-fold, respectively, in EMs and 7.5- and 9.8-fold, respectively, in IMs.
    Eluxadoline: (Moderate) The effect CYP enzymes have on the metabolism of eluxadoline has not been definitively established; therefore, the manufacturer recommends caution when administering eluxadoline concurrently with stong CYP2D6 inhibitors, such as paroxetine. When administering these drugs together, closely monitor patients for eluxadoline-related side effects, such as impaired mental and physical abilities need to safely drive or operate machinery.
    Encainide: (Major) Paroxetine impairs metabolism of the cytochrome P-450 isoenzyme CYP2D6 pathway at therapeutic doses. Although no clinical data are available, paroxetine should be used cautiously in patients receiving type IC antiarrhythmics and mexiletine since these antiarrhythmics are metabolized by this isozyme. Inhibition of CYP2D6 can result in increased concentrations of Class IC antiarrhythmics which may increase the risk of side effects or proarrhythmia.
    Enoxaparin: (Major) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving low molecular weight heparins. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with molecular weight heparins.
    Eptifibatide: (Moderate) Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding.
    Ergoloid Mesylates: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering SSRIs with other drugs that have serotonergic properties such as ergot alkaloids (e.g., ergotamine or dihydroergotamine). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, fluoxetine and fluvoxamine may reduce the metabolism of ergotamine, dihydroergotamine or methysergide via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects. Administration of fluoxetine or fluvoxamine with other ergot alkaloids, like ergonovine or methylergonovine, may also need to be approached with caution. Avoid coadministration of ergot alkaloids with fluoxetine or when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
    Ergonovine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering SSRIs with other drugs that have serotonergic properties such as ergot alkaloids (e.g., ergotamine or dihydroergotamine). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, fluoxetine and fluvoxamine may reduce the metabolism of ergotamine, dihydroergotamine or methysergide via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects. Administration of fluoxetine or fluvoxamine with other ergot alkaloids, like ergonovine or methylergonovine, may also need to be approached with caution. Avoid coadministration of ergot alkaloids with fluoxetine or when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
    Ergot alkaloids: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering SSRIs with other drugs that have serotonergic properties such as ergot alkaloids (e.g., ergotamine or dihydroergotamine). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, fluoxetine and fluvoxamine may reduce the metabolism of ergotamine, dihydroergotamine or methysergide via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects. Administration of fluoxetine or fluvoxamine with other ergot alkaloids, like ergonovine or methylergonovine, may also need to be approached with caution. Avoid coadministration of ergot alkaloids with fluoxetine or when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
    Ergotamine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering SSRIs with other drugs that have serotonergic properties such as ergot alkaloids (e.g., ergotamine or dihydroergotamine). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, fluoxetine and fluvoxamine may reduce the metabolism of ergotamine, dihydroergotamine or methysergide via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects. Administration of fluoxetine or fluvoxamine with other ergot alkaloids, like ergonovine or methylergonovine, may also need to be approached with caution. Avoid coadministration of ergot alkaloids with fluoxetine or when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
    Escitalopram: (Severe) Due to the similarity in pharmacology of paroxetine and escitalopram and the potential for serious adverse reactions, including serotonin syndrome, these selective serotonin reuptake inhibitors (SSRIs) should not be administered together. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SSRI to another SSRI.
    Ethanol: (Minor) Although paroxetine does not increase the impairment of mental and motor skills caused by ethanol, patients should be advised to avoid alcoholic beverages during treatment with paroxetine.
    Fentanyl: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as fentanyl. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring is recommended during co-administration of fentanyl and SSRIs for signs and symptoms of serotonin syndrome or other serious effects.
    Flecainide: (Major) Paroxetine impairs metabolism of the cytochrome P-450 isoenzyme CYP2D6 pathway at therapeutic doses. Although no clinical data are available, paroxetine should be used cautiously in patients receiving type IC antiarrhythmics and mexiletine since these antiarrhythmics are metabolized by this isozyme. Inhibition of CYP2D6 can result in increased concentrations of Class IC antiarrhythmics which may increase the risk of side effects or proarrhythmia.
    Fluoxetine: (Severe) Due to the similarity in pharmacology of fluoxetine and paroxetine 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. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SSRI to another SSRI. In addition, because fluoxetine is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events.
    Fluoxetine; Olanzapine: (Severe) Due to the similarity in pharmacology of fluoxetine and paroxetine 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. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SSRI to another SSRI. In addition, because fluoxetine is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events. (Major) Concurrent use of paroxetine and olanzapine may result in additive anticholinergic effects, such as urinary retention, constipation, blurred vision, and xerostomia. In addition, paroxetine is a potent inhibitor of CYP2D6, which is a minor isoenzyme pathway for the metabolism of olanzapine. Adverse effects of olanzapine that may become evident include fatigue, dizziness, weight gain, prolactin elevation, orthostatic hypotension, sedation, or extrapyramidal symptoms. In addition, olanzapine is associated with a possible risk of QT prolongation and should be used cautiously with strong CYP2D6 inhibitors such as paroxetine.
    Fluphenazine: (Moderate) Substantial increases in concentrations of phenothiazines, such as fluphenazine, may occur due to CYP2D6 inhibition by paroxetine, which may increase the risk of adverse effects, such as extrapyramidal symptoms. In addition, because fluphenazine is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events. Additive anticholinergic effects are also possible.
    Fluvoxamine: (Severe) Due to the similarity in pharmacology of paroxetine and fluvoxamine and the potential for serious adverse reactions, including serotonin syndrome, these selective serotonin reuptake inhibitors (SSRIs) should not be administered together. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SSRI to another SSRI.
    Fondaparinux: (Major) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving anticoagulants, like fondaparinux. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with an anticoagulant medication.
    Fosamprenavir: (Moderate) The combined use of fosamprenavir, boosted with ritonavir, and paroxetine significantly reduced plasma concentrations of paroxetine. Adjust paroxetine dosage based upon tolerability and efficacy of the combined regimen.
    Fosphenytoin: (Moderate) Paroxetine may interact with either phenytoin (or fosphenytoin), although studies have not addressed if clinically important interactions occur when the two drugs are chronically dosed. Initial studies suggested no significant effect of paroxetine on phenytoin serum concentrations, however, clinicians should keep in mind that paroxetine itself is a potent inhibitor of CYP2D6, and both phenytoin and paroxetine exhibit non-linear pharmacokinetics. One post-marketing case report of elevated phenytoin serum concentrations occurring in a patient after 4 weeks of concomitant therapy with paroxetine and phenytoin has been reported to the manufacturer. In addition, phenytoin, via hepatic enzyme induction, may reduce paroxetine AUC by 50% and half-life by 35%. No initial dosage adjustment is recommended, but subsequent dosage adjustments of paroxetine or phenytoin should be based on clinical effect. Monitoring of phenytoin concentrations during concomitant therapy is recommended.
    Frovatriptan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., frovatriptan). Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen.
    Galantamine: (Moderate) Galantamine is partially metabolized by CYP2D6 and systemic exposure may be increased during concurrent use of a strong CYP2D6 inhibitor, such as paroxetine. In one pharmacokinetic study, the bioavailability of galantamine was increased by about 40% when coadministered with paroxetine at a dose of 20 mg/day for 16 days. Monitor for galantamine-related adverse effects such as nausea, vomiting, loss of appetite, diarrhea, headache, confusion, and excessive sweating during concurrent use of these drugs.
    Gefitinib: (Moderate) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and paroxetine are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; paroxetine is a strong CYP2D6 inhibitor. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with CYP2D6 inhibitors, in patients with poor CYP2D6 metabolism, the mean exposure to gefitinib was 2-fold higher when compared to extensive metabolizers; the contribution of drugs that inhibit CYP2D6 on gefitinib exposure has not been evaluated. Additionally, at high concentrations, gefitinib is an inhibitor of CYP2D6, which is the primary isoenzyme responsible for the metabolism of paroxetine. In patients with solid tumors, exposure to metoprolol, another CYP2D6 substrate, was increased by 30% when given on day 15 of gefitinib dosing (500 mg daily); however, the effect of gefitinib on CYP2D6-dependent drugs is only likely to be clinically relevant when given with CYP2D6 substrates with a narrow therapeutic index or that are individually dose titrated.
    Granisetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering granisetron with other drugs that have serotonergic properties such as paroxetine. If serotonin syndrome is suspected, discontinue granisetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Guaifenesin; Hydrocodone: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as paroxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as paroxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Haloperidol: (Major) Haloperidol is metabolized by CYP2D6 and CYP3A4 and concurrent use with inhibitors of these isoenzymes may result in elevated haloperidol plasma concentrations and adverse effects including extrapyramidal symptoms or QT prolongation. Paroxetine is a potent CYP2D6 inhibitor. Because symptoms consistent with elevated haloperidol levels have been observed during co-administration of SSRIs and haloperidol, patients receiving these combinations should be monitored for adverse effects such as dizziness, sedation, impaired psychomotor performance, extrapyramidal symptoms, and adverse cardiac effects.
    Heparin: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving anticoagulants. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with an anticoagulant medication.
    Homatropine; Hydrocodone: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as paroxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Minor) Paroxetine impairs metabolism of the hepatic CYP2D6 isoenzyme pathway at therapeutic doses, resulting in substantial increases in concentrations of other drugs metabolized via the same pathway, including metoprolol. Clinicians should use paroxetine cautiously with metoprolol; downward dose adjustments of the beta-blocker may be required if paroxetine is initiated; alternatively an upward dose adjustment of the beta blocker may be needed if paroxetine is discontinued. Patients should be advised to report increased effects of these medications, including hypotension or increased dizziness to their health care professional.
    Hydrochlorothiazide, HCTZ; Propranolol: (Minor) Paroxetine impairs metabolism of the hepatic CYP2D6 isoenzyme pathway at therapeutic doses, resulting in substantial increases in concentrations of other drugs metabolized via the same pathway, including propranolol. Clinicians should use paroxetine cautiously with propranolol; downward dose adjustments of the beta-blocker may be required if paroxetine is initiated; alternatively an upward dose adjustment of the beta blocker may be needed if paroxetine is discontinued. Patients should be advised to report increased effects of these medications, including hypotension or increased dizziness to their health care professional.
    Hydrocodone: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as paroxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Hydrocodone; Ibuprofen: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as paroxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Hydrocodone; Phenylephrine: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as paroxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as paroxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as paroxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Hydrocodone; Pseudoephedrine: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as paroxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Severe) According to the manufacturer of paroxetine, treatment initiation with paroxetine 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 paroxetine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving paroxetine and requiring urgent treatment with IV methylene blue, paroxetine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Paroxetine may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving SSRIs, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case describes a patient receiving citalopram who experienced agitation, restlessness, pupil dilation with sluggish response to light, myoclonic movements of the lower limbs, and brisk reflexes following an infusion of methylene blue, while another patient receiving paroxetine developed tachycardia, agitation, dystonia and abnormal eye movements. During a retrospective study of 193 surgical patients who had received a methylene blue injection, it was found that all 12 of the patients who experienced postoperative neurological sequelae had been taking a serotonin reuptake inhibitor preoperatively. One of the 12 patients experienced cardiopulmonary arrest and died. Of the remaining 181 patients who did not experience neurological sequelae, 8.8% were taking a serotonin reuptake inhibitor. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin.
    Ibuprofen; Oxycodone: (Moderate) The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue the suspected drugs if serotonin syndrome is suspected and manage cliinically. There has been a case report of possible serotonin syndrome caused by the combination of oxycodone and selective serotonin reuptake inhbitors (SSRIs).
    Iloperidone: (Major) Paroxetine is a potent inhibitor of CYP2D6, which may result in decreased clearance of CYP2D6 substrates including iloperidone. Decreased metabolism of iloperidone may lead to clinically important adverse reactions, such as extrapyramidal symptoms. In addition, iloperidone is associated with a risk for QT prolongation and torsade de pointes (TdP), and should be used cautiously with potent CYP2D6 inhibitors such as paroxetine. The manufacturer of iloperidone recommends that the iloperidone dose be reduced by one-half during concurrent use of a potent CYP2D6 inhibitor. If paroxetine is subsequently withdrawn, the previous iloperidone dose should be resumed.
    Imatinib: (Moderate) Imatinib is a potent inhibitor of cytochrome P450 2D6, and may theoretically decrease paroxetine metabolism leading to increased adverse reactions.
    Imipramine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. 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, paroxetine is a potent CYP2D6 inhibitor and may decrease the metabolism of imipramine, a CYP2D6 substrate. Because there is a risk of QT prolongation and torsade de pointes (TdP) with tricyclics at elevated serum concentrations, coadministration should be approached with caution and close monitoring. Lastly, both paroxetine and imipramine may exhibit significant anticholinergic effects that may be additive during concurrent use.
    Isocarboxazid: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with selective serotonin reuptake inhibitors (SSRIs). MAOIs should not be used within 5 weeks of discontinuing treatment with fluoxetine or within 14 days of discontinuing treatment with other SSRIs. Conversely, SSRIs should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    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 therpay 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 therpay 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 therpay is necessary, patients should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Kava Kava, Piper methysticum: (Moderate) The German Commission E and other groups warn that any substances that act on the CNS, including SSRIs, may interact with the phytomedicinal kava kava, Piper methysticum. These interactions are probably pharmacodynamic in nature, or result from additive mechanisms of action.
    Levomilnacipran: (Major) Because of the potential risk and severity of serotonin syndrome, concurrent use of levomilnacipran with other drugs that have serotonergic properties, such as selective serotonin reuptake inhibitors (SSRIs), should generally be avoided. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
    Linezolid: (Severe) According to the manufacturer of paroxetine, treatment initiation with paroxetine is contraindicated in patients currently receiving linezolid due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than paroxetine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving paroxetine and requiring urgent treatment with linezolid, paroxetine should be discontinued immediately and linezolid therapy initiated only if acceptable alternatives are not available and the potential benefits of linezolid outweigh the risks. The patient should be monitored for serotonin syndrome for two weeks or until 24 hours after the last dose of linezolid, whichever comes first. Paroxetine 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 paroxetine can lead to serious reactions including serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Serotonin syndrome has been reported in patients receiving either citalopram, escitalopram, fluoxetine, or paroxetine in combination with linezolid.
    Lithium: (Major) Lithium is an effective augmenting agent to antidepressants in treatment-resistant depression; however, lithium has been reported to have central serotonin-enhancing effects and may interact pharmacodynamically with selective serotonin reuptake inhibitors (SSRIs) such as paroxetine to cause serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Patients should be informed of the possible increased risk of serotonin syndrome. If serotonin syndrome occurs, paroxetine and lithium should be discontinued and symptomatic treatment should be initiated. One case report suggests the possibility of serotonin syndrome in a patient receiving lithium and paroxetine at therapeutic doses of 400 mg/day and 30 mg/day, respectively, and paroxetine concentrations six times those usually observed in patients receiving this dosage. The symptoms resolved with a reduction in paroxetine dosage to 10 mg/day. One systematic review and meta-analysis of lithium augmentation of tricyclic and second generation antidepressants in major depression found no difference in discontinuation rate due to adverse events between the lithium and placebo groups. However, there are case reports of neurotoxicity (e.g., confusion, ataxia) as well as fever and seizures when SSRIs have been used with lithium. Neurotoxicity may be more likely to occur in the elderly.
    Loperamide: (Moderate) The plasma concentration of loperamide, a CYP2D6 substrate, may be increased when administered concurrently with paroxetine, a potent CYP2D6 inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Loperamide; Simethicone: (Moderate) The plasma concentration of loperamide, a CYP2D6 substrate, may be increased when administered concurrently with paroxetine, a potent CYP2D6 inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Lopinavir; Ritonavir: (Major) A dose reduction of paroxetine may be necessary during co-administration of ritonavir. Concurrent use of CYP2D6 substrates, such as paroxetine, with ritonavir could result in increases (up to 2-fold) in the AUC of paroxetine. Paroxetine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Lorcaserin: (Major) Based on the mechanism of action of lorcaserin and the theoretical potential for serotonin syndrome, use with extreme caution in combination with other drugs that may affect the serotonergic neurotransmitter systems, including, selective serotonin reuptake inhibitors (SSRIs). Patients receiving this combination should be monitored for the emergence of serotonin syndrome or Neuroleptic Malignant Syndrome (NMS) like signs and symptoms.
    Low Molecular Weight Heparins: (Major) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving low molecular weight heparins. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with molecular weight heparins.
    Magnesium Salicylate: (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation. A cohort study in > 26,000 patients found that SSRI use alone increased the risk for serious GI bleed by 3.6-fold; when an SSRI was combined with aspirin the risk was increased by > 5-fold. The absolute risk of GI bleed from concomitant therapy with aspirin and a SSRI was low (20/2640 patients) in this cohort study and the clinician may determine that the combined use of these drugs is appropriate.
    Maprotiline: (Major) Paroxetine is a potent inhibitor of CYP2D6, the primary isoenzyme responsible for the metabolism of maprotiline. In several cases, symptoms of toxicity, including seizures, have been reported when SSRIs and cyclic antidepressants have been used together. In addition, because maprotiline is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events. Patients receiving maprotiline should be monitored closely for toxicity if paroxetine is added.
    Meperidine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as meperidine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. A 42-year-old man became agitated, restless, diaphoretic, tachycardic, and hypertensive immediately after receipt of meperidine 50 mg intravenously. Two weeks before the incident, the patient had stopped a regimen of the SSRI, fluoxetine. Serotonin syndrome was suspected, as fluoxetine and norfluoxetine have long half-lives, and previous meperidine receipt during a time when the patient had not been taking fluoxetine was uneventful. If serotonin syndrome is suspected, the SSRI and concurrent serotonergic agents should be discontinued.
    Meperidine; Promethazine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as meperidine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. A 42-year-old man became agitated, restless, diaphoretic, tachycardic, and hypertensive immediately after receipt of meperidine 50 mg intravenously. Two weeks before the incident, the patient had stopped a regimen of the SSRI, fluoxetine. Serotonin syndrome was suspected, as fluoxetine and norfluoxetine have long half-lives, and previous meperidine receipt during a time when the patient had not been taking fluoxetine was uneventful. If serotonin syndrome is suspected, the SSRI and concurrent serotonergic agents should be discontinued. (Moderate) Promethazine is a substrate for CYP2D6 and paroxetine is a potent inhibitor of CYP2D6. Because promethazine is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events. In addition, both paroxetine and promethazine exhibit anticholinergic effects that may be additive during combined therapy. The risk of other adverse effects of promethazine may also be increased, including sedation and extrapyramidal symptoms.
    Mesoridazine: (Severe) The use of paroxetine with mesoridazine is essentially contraindicated. Paroxetine is a potent inhibitor of CYP2D6 and may result in increased serum mesoridazine concentrations, leading to a risk for QT prolongation and heart arrhythmia, or other phenothiazine-related side effects. Mesoridazine has a well-established risk for QT prolongation and torsade de pointes.
    Methadone: (Moderate) Paroxetine is a potent CYP2D6 inhibitor and can increase concentrations of drugs metabolized via the same pathway, including methadone. Increased opiate effects (e.g., dizziness, sedation, respiratory depression) are possible if these drugs are used concurrently. In addition, because methadone is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Severe) According to the manufacturer of paroxetine, treatment initiation with paroxetine 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 paroxetine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving paroxetine and requiring urgent treatment with IV methylene blue, paroxetine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Paroxetine 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.
    Methylene Blue: (Severe) According to the manufacturer of paroxetine, treatment initiation with paroxetine 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 paroxetine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving paroxetine and requiring urgent treatment with IV methylene blue, paroxetine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Paroxetine may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving SSRIs, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case describes a patient receiving citalopram who experienced agitation, restlessness, pupil dilation with sluggish response to light, myoclonic movements of the lower limbs, and brisk reflexes following an infusion of methylene blue, while another patient receiving paroxetine developed tachycardia, agitation, dystonia and abnormal eye movements. During a retrospective study of 193 surgical patients who had received a methylene blue injection, it was found that all 12 of the patients who experienced postoperative neurological sequelae had been taking a serotonin reuptake inhibitor preoperatively. One of the 12 patients experienced cardiopulmonary arrest and died. Of the remaining 181 patients who did not experience neurological sequelae, 8.8% were taking a serotonin reuptake inhibitor. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma.
    Methylergonovine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering SSRIs with other drugs that have serotonergic properties such as ergot alkaloids (e.g., ergotamine or dihydroergotamine). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, fluoxetine and fluvoxamine may reduce the metabolism of ergotamine, dihydroergotamine or methysergide via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects. Administration of fluoxetine or fluvoxamine with other ergot alkaloids, like ergonovine or methylergonovine, may also need to be approached with caution. Avoid coadministration of ergot alkaloids with fluoxetine or when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
    Methylphenidate: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate and selective serotonin reuptake inhibitors (SSRIs). There are rare reports of serotonin syndrome occurring during use of an SSRI and methylphenidate. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    Methysergide: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering SSRIs with other drugs that have serotonergic properties such as ergot alkaloids (e.g., ergotamine or dihydroergotamine). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, fluoxetine and fluvoxamine may reduce the metabolism of ergotamine, dihydroergotamine or methysergide via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects. Administration of fluoxetine or fluvoxamine with other ergot alkaloids, like ergonovine or methylergonovine, may also need to be approached with caution. Avoid coadministration of ergot alkaloids with fluoxetine or when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
    Metoclopramide: (Major) Metoclopramide is a substrate of CYP2D6 and paroxetine is a strong CYP2D6 inhibitor; due to the risk of increased metoclopramide plasma concentrations and extrapyramidal adverse reactions, dose adjustments of oral metoclopramide are recommended when administered in combination with strong CYP2D6 inhibitors. In addition, a few published case reports have documented possible interactions between metoclopramide and SSRIs that have resulted in either serotonin syndrome-type events and/or movement disorders (e.g., dystonia). The mechanism of the interactions is unknown but is thought to be a pharmacodynamic interaction; the interactions do not appear common. In patients with gastroesophageal reflux receiving a strong CYP2D6 inhibitor or who are known CYP2D6 poor metabolizers (PMs), the recommended dose of metoclopramide is 5 mg PO four times daily or 10 mg PO three times daily. In patients with diabetic gastroparesis receiving a strong CYP2D6 inhibitor or who are known CYP2D6 poor metabolizers (PMs), the recommended dose of metoclopramide is 5 mg PO four times daily times daily.
    Metoprolol: (Minor) Paroxetine impairs metabolism of the hepatic CYP2D6 isoenzyme pathway at therapeutic doses, resulting in substantial increases in concentrations of other drugs metabolized via the same pathway, including metoprolol. Clinicians should use paroxetine cautiously with metoprolol; downward dose adjustments of the beta-blocker may be required if paroxetine is initiated; alternatively an upward dose adjustment of the beta blocker may be needed if paroxetine is discontinued. Patients should be advised to report increased effects of these medications, including hypotension or increased dizziness to their health care professional.
    Mexiletine: (Moderate) Paroxetine impairs metabolism of the cytochrome P-450 isoenzyme CYP2D6 pathway at therapeutic doses. Although no clinical data are available, paroxetine should be used cautiously in patients receiving mexiletine since this antiarrhythmic is metabolized by this isozyme. Inhibition of CYP2D6 can result in increased concentrations of drugs metabolized via the same pathway, including mexiletine, which may increase the risk of side effects or proarrhythmia.
    Milnacipran: (Major) Because of the potential risk and severity of serotonin syndrome, concurrent use of milnacipran with other drugs that have serotonergic properties, such as the selective serotonin reuptake inhibitors (SSRIs), should generally be avoided. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, milnacipran and concurrent serotonergic agents should be discontinued.
    Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 substrate and inhibitor. Exposure of drugs metabolized by CYP2D6 such as paroxetine may be increased when co-administered with mirabegron. Paroxetine is a substrate and inhibitor of CYP2D6. Mirabegron exposure may also increase. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Mirtazapine: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering paroxetine with other drugs that have serotonergic properties such as mirtazapine. 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. Case reports suggest that serotonin syndrome is possible during concurrent use of mirtazapine and SSRIs. In addition, in vitro studies have identified mirtazapine as a substrate for several hepatic cytochrome CYP450 isoenzymes including CYP2D6, CYP1A2, and CYP3A4. Increased mirtazapine serum concentrations may occur following the addition of a potent CYP2D6 inhibitor such as paroxetine to a stable mirtazapine regimen. Patients receiving this combination should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
    Monoamine oxidase inhibitors: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with selective serotonin reuptake inhibitors (SSRIs). MAOIs should not be used within 5 weeks of discontinuing treatment with fluoxetine or within 14 days of discontinuing treatment with other SSRIs. Conversely, SSRIs should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Moricizine: (Major) Paroxetine impairs metabolism of the cytochrome P-450 isoenzyme CYP2D6 pathway at therapeutic doses. Although no clinical data are available, paroxetine should be used cautiously in patients receiving type IC antiarrhythmics and mexiletine since these antiarrhythmics are metabolized by this isozyme. Inhibition of CYP2D6 can result in increased concentrations of Class IC antiarrhythmics which may increase the risk of side effects or proarrhythmia.
    Morphine: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when administering selective serotonin reuptake inhibitors (SSRIs), such as paroxetine, with other drugs that have serotonergic properties such as morphine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and paroxetine should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Morphine; Naltrexone: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when administering selective serotonin reuptake inhibitors (SSRIs), such as paroxetine, with other drugs that have serotonergic properties such as morphine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and paroxetine should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Naproxen; Sumatriptan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., sumatriptan). Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome and can be life-threatening. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen.
    Naratriptan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., naratriptan). Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen.
    Nebivolol: (Major) Avoid the concomitant use of nebivolol and paroxetine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as paroxetine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect.
    Nebivolol; Valsartan: (Major) Avoid the concomitant use of nebivolol and paroxetine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as paroxetine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect.
    Nefazodone: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as nefazodone and paroxetine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. At least one case report of serotonin syndrome from the concurrent use of nefazodone and a selective serotonin reuptake inhibitor (i.e., paroxetine) has been published. Additionally, when a 200 mg dose of nefazodone was administered to subjects who had been receiving fluoxetine for 1 week, there was an increased incidence of transient serotonin-related adverse events. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Netupitant; Palonosetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as paroxetine. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Nilotinib: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of paroxetine. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as paroxetine.
    Nitroglycerin: (Minor) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as antidepressants. Patients should be monitored more closely for hypotension if nitroglycerin is used concurrently with antidepressants.
    Nonsteroidal antiinflammatory drugs: (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk of bleeding, including an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of NSAIDs. Additionally, NSAIDs impair the gastric mucosa defenses by inhibiting prostaglandin formation. A cohort study in more than 26,000 patients found that SSRI use alone increased the risk for serious GI bleed by 3.6-fold; when an SSRI was combined with NSAIDs, the risk was increased by more than 12.2-fold. The absolute risk of GI bleed from concomitant therapy with NSAIDs and a SSRI was low (17/4107 patients).
    Nortriptyline: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. 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, paroxetine is a potent CYP2D6 inhibitor and may decrease the metabolism of nortriptyline, a CYP2D6 substrate. Because there is a risk of QT prolongation and torsade de pointes (TdP) with tricyclics at elevated serum concentrations, coadministration should be approached with caution and close monitoring. Lastly, both paroxetine and nortriptyline may exhibit significant anticholinergic effects that may be additive during concurrent use.
    Olanzapine: (Major) Concurrent use of paroxetine and olanzapine may result in additive anticholinergic effects, such as urinary retention, constipation, blurred vision, and xerostomia. In addition, paroxetine is a potent inhibitor of CYP2D6, which is a minor isoenzyme pathway for the metabolism of olanzapine. Adverse effects of olanzapine that may become evident include fatigue, dizziness, weight gain, prolactin elevation, orthostatic hypotension, sedation, or extrapyramidal symptoms. In addition, olanzapine is associated with a possible risk of QT prolongation and should be used cautiously with strong CYP2D6 inhibitors such as paroxetine.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) A dose reduction of paroxetine may be necessary during co-administration of ritonavir. Concurrent use of CYP2D6 substrates, such as paroxetine, with ritonavir could result in increases (up to 2-fold) in the AUC of paroxetine. Paroxetine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Ondansetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering ondansetron with other drugs that have serotonergic properties such as paroxetine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, discontinue ondansetron and concurrent serotonergic agents and initiate appropriate medical treatment. In addition, because ondansetron is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events.
    Oritavancin: (Moderate) Paroxetine is metabolized by CYP2D6; oritavancin is a weak CYP2D6 inducer. Plasma concentrations and efficacy of paroxetine may be reduced if these drugs are administered concurrently.
    Oxycodone: (Moderate) The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue the suspected drugs if serotonin syndrome is suspected and manage cliinically. There has been a case report of possible serotonin syndrome caused by the combination of oxycodone and selective serotonin reuptake inhbitors (SSRIs).
    Paliperidone: (Major) Paroxetine is a potent inhibitor of CYP2D6, which may result in decreased clearance of CYP2D6 substrates such as paliperidone. Decreased metabolism of paliperidone may lead to clinically important adverse reactions such as extrapyramidal symptoms. In addition, paliperidone is associated with a risk for QT prolongation and torsade de pointes (TdP), and should be used cautiously with potent CYP2D6 inhibitors such as paroxetine. In one study of healthy subjects, paliperidone exposure was an average of 16% higher in extensive metabolizers of CYP2D6 who were receiving paroxetine 20 mg/day concurrently. The clinical significance of this interaction is unknown.
    Palonosetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as paroxetine. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Peginterferon Alfa-2b: (Moderate) Monitor for adverse effects associated with increased exposure to paroxetine if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP2D6 inhibitor, while paroxetine is a CYP2D6 substrate.
    Pentamidine: (Moderate) Pentamidine is a substrate of CYP2D6 and paroxetine is a potent inhibitor of CYP2D6. Because pentamidine is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events.
    Pentazocine: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions
    Pentazocine; Naloxone: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions
    Pentosan: (Major) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving anticoagulants, like pentosan. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with an anticoagulant medication.
    Pergolide: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering SSRIs with other drugs that have serotonergic properties such as ergot alkaloids (e.g., ergotamine or dihydroergotamine). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, fluoxetine and fluvoxamine may reduce the metabolism of ergotamine, dihydroergotamine or methysergide via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects. Administration of fluoxetine or fluvoxamine with other ergot alkaloids, like ergonovine or methylergonovine, may also need to be approached with caution. Avoid coadministration of ergot alkaloids with fluoxetine or when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
    Perphenazine: (Moderate) Substantial increases in concentrations of phenothiazines, such as perphenazine, may occur due to CYP2D6 inhibition by paroxetine, which may increase the risk of adverse effects such as extrapyramidal symptoms. In addition, because perphenazine is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events. Additive anticholinergic effects are also possible.
    Perphenazine; Amitriptyline: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. In addition, paroxetine is a potent CYP2D6 inhibitor and may decrease the metabolism of amitriptyline, a CYP2D6 substrate. Because there is a risk of QT prolongation and torsade de pointes (TdP) with tricyclics at elevated serum concentrations, coadministration should be approached with caution and close monitoring. Lastly, both paroxetine and amitriptyline may exhibit significant anticholinergic effects that may be additive during concurrent use. (Moderate) Substantial increases in concentrations of phenothiazines, such as perphenazine, may occur due to CYP2D6 inhibition by paroxetine, which may increase the risk of adverse effects such as extrapyramidal symptoms. In addition, because perphenazine is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events. Additive anticholinergic effects are also possible.
    Phenelzine: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with selective serotonin reuptake inhibitors (SSRIs). MAOIs should not be used within 5 weeks of discontinuing treatment with fluoxetine or within 14 days of discontinuing treatment with other SSRIs. Conversely, SSRIs should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Phentermine: (Moderate) Use phentermine and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) together with caution; use together may be safe and efficacious for some patients based on available data, provided the patient is on a stable antidepressant regimen and receives close clinical monitoring. Regular appointments to assess the efficacy of the weight loss treatment, the emergence of adverse events, and blood pressure monitoring are recommended. Watch for excessive serotonergic effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome or cardiovascular or pulmonary effects when combined with serotonergic agents. One case report has been received of adverse reactions with phentermine and fluoxetine. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses, and that phentermine does not additionally increase plasma serotonin levels when combined with other serotonergic agents. In large controlled clinical studies, patients were allowed to start therapy with phentermine or phentermine; topiramate extended-release for obesity along with their antidepressants (e.g., SSRIs or SNRIs, but not MAOIs or TCAs) as long as the antidepressant dose had been stable for at least 3 months prior to the initiation of phentermine, and the patient did not have suicidal ideation or more than 1 episode of major depression documented. In analyses of the results, therapy was generally well tolerated, especially at lower phentermine doses, based on discontinuation rates and reported adverse events. Because depression and obesity often coexist, the study data may be important to providing optimal co-therapies.
    Phentermine; Topiramate: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as selective serotonin reuptake inhibitors (SSRIs) like paroxetine may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation. (Moderate) Use phentermine and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) together with caution; use together may be safe and efficacious for some patients based on available data, provided the patient is on a stable antidepressant regimen and receives close clinical monitoring. Regular appointments to assess the efficacy of the weight loss treatment, the emergence of adverse events, and blood pressure monitoring are recommended. Watch for excessive serotonergic effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome or cardiovascular or pulmonary effects when combined with serotonergic agents. One case report has been received of adverse reactions with phentermine and fluoxetine. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses, and that phentermine does not additionally increase plasma serotonin levels when combined with other serotonergic agents. In large controlled clinical studies, patients were allowed to start therapy with phentermine or phentermine; topiramate extended-release for obesity along with their antidepressants (e.g., SSRIs or SNRIs, but not MAOIs or TCAs) as long as the antidepressant dose had been stable for at least 3 months prior to the initiation of phentermine, and the patient did not have suicidal ideation or more than 1 episode of major depression documented. In analyses of the results, therapy was generally well tolerated, especially at lower phentermine doses, based on discontinuation rates and reported adverse events. Because depression and obesity often coexist, the study data may be important to providing optimal co-therapies.
    Phenylephrine; Promethazine: (Moderate) Promethazine is a substrate for CYP2D6 and paroxetine is a potent inhibitor of CYP2D6. Because promethazine is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events. In addition, both paroxetine and promethazine exhibit anticholinergic effects that may be additive during combined therapy. The risk of other adverse effects of promethazine may also be increased, including sedation and extrapyramidal symptoms.
    Phenytoin: (Moderate) Paroxetine is a potent inhibitor of cytochrome 2D6, one pathway by which elevations in some anticonvulsant serum concentrations may occur. Monitoring of phenytoin concentrations and the clinical status of the patient during concomitant therapy is recommended. The dose of phenytoin should be adjusted if necessary.
    Pimozide: (Severe) Pimozide is contraindicated for use with selective serotonin reuptake inhibitors (SSRIs). Pimozide is thought to be primarily metabolized through CYP3A4, and to a lesser extent, CYP1A2 and CYP2D6. Elevated plasma concentrations of pimozide occurring through inhibition of one or more of these isoenzymes can lead to QT prolongation, ventricular arrhythmias, and sudden death. Concurrent use of pimozide and CYP3A4 inhibitors or potent CYP2D6 inhibitors is contraindicated by the manufacturer of pimozide. Because citalopram is associated with a dose-dependent QT prolongation and pimozide has an established association with QT prolongation and torsade de pointes (TdP), concurrent use of pimozide and citalopram is contraindicated. In a controlled study, the mean QTc values increased about 10 msec in the group receiving a combination of a single dose of pimozide 2 mg and citalopram 40 mg daily for 11 days compared to the pimozide monotherapy group. The mean AUC and Cmax of pimozide were not altered. Concurrent use of pimozide with fluvoxamine, a CYP1A2 and CYP3A4 inhibitor, or fluoxetine, a CYP2D6 and CYP3A4 inhibitor, may result in elevated pimozide concentrations. Sertraline, a CYP2D6 inhibitor, has been noted to increase the AUC of pimozide by roughly 40%. Paroxetine, a potent CYP2D6 inhibitor, has been associated with mean increases in pimozide AUC of 151% and increases in pimozide Cmax of 62%. The modest CYP2D6 inhibitory effects of escitalopram may result in increased concentrations of drugs metabolized via the same pathway such as pimozide.
    Pirfenidone: (Moderate) Pirfenidone is primarily metabolized by CYP1A2 with minor contributions from other CYP isoenzymes including CYP2D6. Paroxetine is a potent inhibitor of CYP2D6. Because pirfenidone is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events and should be approached with caution.
    Prasugrel: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving prasugrel. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Procarbazine: (Major) Procarbazine is a weak monoamine oxidase inhibitor (MAOI). Although procarbazine appears to be less likely than other MAOIs to produce serious drug interactions, clinicians should avoid the use of selective serotonin reuptake inhibitors (SSRIs) in patients receiving MAOIs. Fatalities have been reported when fluoxetine was administered to patients receiving MAOIs. Confusion, seizures, severe hypertension, and other, less severe symptoms have also been reported with this drug combination. Non-selective MAOIs inhibit both MAO types A and B. Since serotonin is metabolized by MAO type A, it is thought that this drug interaction may lead to serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. At least 2 weeks should elapse between the discontinuation of MAOI therapy and the start of therapy with an SSRI except fluoxetine. At least 5 weeks should elapse between the discontinuation of fluoxetine therapy and commencement of MAOI therapy. This 5-week period is needed because of the long half-lives of fluoxetine and its principle metabolite norfluoxetine.
    Prochlorperazine: (Moderate) Substantial increases in concentrations of phenothiazines may occur due to CYP2D6 inhibition by paroxetine. which may increase the risk of adverse effects, including extrapyramidal symptoms or QT prolongation. Phenothiazines with a possible risk of QT prolongation include prochlorperazine.
    Promethazine: (Moderate) Promethazine is a substrate for CYP2D6 and paroxetine is a potent inhibitor of CYP2D6. Because promethazine is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events. In addition, both paroxetine and promethazine exhibit anticholinergic effects that may be additive during combined therapy. The risk of other adverse effects of promethazine may also be increased, including sedation and extrapyramidal symptoms.
    Propafenone: (Major) Paroxetine impairs metabolism of the cytochrome P-450 isoenzyme CYP2D6 pathway at therapeutic doses. Although no clinical data are available, paroxetine should be used cautiously in patients receiving type IC antiarrhythmics and mexiletine since these antiarrhythmics are metabolized by this isozyme. Inhibition of CYP2D6 can result in increased concentrations of Class IC antiarrhythmics which may increase the risk of side effects or proarrhythmia.
    Propranolol: (Minor) Paroxetine impairs metabolism of the hepatic CYP2D6 isoenzyme pathway at therapeutic doses, resulting in substantial increases in concentrations of other drugs metabolized via the same pathway, including propranolol. Clinicians should use paroxetine cautiously with propranolol; downward dose adjustments of the beta-blocker may be required if paroxetine is initiated; alternatively an upward dose adjustment of the beta blocker may be needed if paroxetine is discontinued. Patients should be advised to report increased effects of these medications, including hypotension or increased dizziness to their health care professional.
    Protriptyline: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. 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, paroxetine is a potent CYP2D6 inhibitor and may decrease the metabolism of protriptyline, a CYP2D6 substrate. Because there is a risk of QT prolongation and torsade de pointes (TdP) with tricyclics at elevated serum concentrations, coadministration should be approached with caution and close monitoring. Lastly, both paroxetine and protriptyline may exhibit significant anticholinergic effects that may be additive during concurrent use.
    Quetiapine: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with drugs that are dopamine antagonists such as quetiapine. 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 quetiapine and an SSRI should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
    Quinidine: (Moderate) Quinidine inhibits CYP2D6 and may theoretically increase concentrations of other drugs metabolized by this enzyme. Caution is recommended when administering quinidine with CYP2D6 substrates, including paroxetine.
    Quinine: (Major) Both paroxetine and quinine are substrates of CYP2D6. In addition, quinine is a moderate inhibitor of CYP2D and paroxetine is a potent inhibitor of CYP2D6. One or both medications may inhibit the metabolism of the other. Patients should be monitored for an increase in adverse effects of paroxetine (e.g., serotonin syndrome, anticholinergic effects) or quinine (e.g., QT prolongation) during concurrent therapy. In addition, because quinine is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events.
    Ranolazine: (Moderate) Monitor for adverse effects of paroxetine (e.g., serotonin syndrome) and ranolazine (e.g., QT prolongation) during coadministration. In theory, ranolazine may reduce the metabolism of paroxetine, and paroxetine may reduce the metabolism of ranolazine, increasing the risk for adverse effects associated with either drug. Both ranolazine and paroxetine are substrates of CYP2D6. Ranolazine is a moderate inhibitor of CYP2D6 and paroxetine is a potent inhibitor of CYP2D6. Because ranolazine is primarily metabolized by CYP3A4, inhibition of a single enzyme, such as CYP2D6, may not significantly decrease ranolazine clearance.
    Rasagiline: (Major) It is recommended to avoid concurrent use of rasagiline and antidepressants, including selective serotonin reuptake inhibitors (SSRIs). Severe CNS toxicity with hyperpyrexia has been reported during concurrent use of antidepressants and selective or non-selective MAOIs. During post-marketing use of rasagiline, non-fatal cases of serotonin syndrome have been reported during concomitant antidepressant administration. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. At least 2 weeks should elapse between stopping rasagiline treatment and beginning therapy with any SSRI. Conversely, when discontinuing an SSRI, it is advisable to wait the length of 4 to 5 half-lives of the individual agent being discontinued prior to initiation with rasagiline. At least 5 weeks should elapse between the discontinuation of fluoxetine therapy and initiation of rasagiline; this 5-week period is needed because of the long half-lives of fluoxetine and its active metabolite norfluoxetine. Fluvoxamine is a strong CYP1A2 inhibitor, and rasagiline plasma concentrations may increase up to 2-fold during concurrent use, resulting in the potential for increased adverse events from rasagiline.
    Remifentanil: (Moderate) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected.
    Reteplase, r-PA: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SSRI.
    Risperidone: (Major) Risperidone is associated with a risk for QT prolongation and torsade de pointes, and should be used cautiously with potent CYP2D6 inhibitors such as paroxetine. Paroxetine may decrease the clearance of CYP2D6 substrates such as risperidone. When oral risperidone is given with a CYP2D6 inhibitor, the dose of risperidone should be reduced; do not exceed 8 mg/day PO in adults. When initiating therapy, titrate risperidone slowly. Upon discontinuation of the CYP2D6 inhibitor, the risperidone dose should be re-evaluated and increased if necessary. For the long-acting injection, the current adult dosage should be re-evaluated when a CYP2D6 inhibitor is initiated or discontinued. When initiation of a CYP2D6 inhibitor is considered, patients may be placed on a lower dose of injectable risperidone 2 to 4 weeks prior to initiation to adjust for the expected increase in risperidone plasma concentrations. For patients receiving a 25 mg dose, it is recommended to maintain the 25 mg dose upon initiation of the CYP2D6 inhibitor unless clinical judgment warrants lowering the dose to 12.5 mg or interrupting risperidone therapy. The efficacy of the 12.5 mg dose has not been evaluated in clinical trials. When injectable risperidone is initiated in patients already receiving a CYP2D6 inhibitor, a starting dose of 12.5 mg can be considered. Poor metabolizers of CYP2D6 may also be at greater risk for risperidone-induced adverse events. Decreased metabolism of risperidone may lead to clinically important adverse reactions that are associated with antipsychotic use, such as extrapyramidal symptoms. Daily dosing of paroxetine 20 mg PO in patients stabilized on risperidone (4 to 8 mg/day) increased mean plasma concentrations of risperidone roughly 4-fold, decreased 9-hydroxyrisperidone concentrations approximately 10%, and increased concentrations of the active moiety (the sum of risperidone plus 9-hydroxyrisperidone) approximately 1.4-fold. Other data suggest that daily administration of paroxetine increases plasma concentrations of risperidone 3- to 9-fold.
    Ritonavir: (Major) A dose reduction of paroxetine may be necessary during co-administration of ritonavir. Concurrent use of CYP2D6 substrates, such as paroxetine, with ritonavir could result in increases (up to 2-fold) in the AUC of paroxetine. Paroxetine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Rivaroxaban: (Major) Selective serotonin reuptake inhibitors (SSRIs) can inhibit serotonin uptake by platelets, thus causing platelet dysfunction and increasing the risk for bleeding with rivaroxaban; however, the absolute risk is not known. If these drugs are administered together, instruct patients to monitor for signs and symptoms of bleeding, and to promptly report any bleeding events to their practitioner.
    Rizatriptan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., rizatriptan). Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen.
    Rolapitant: (Major) Use caution if paroxetine and rolapitant are used concurrently, and monitor for paroxetine-related adverse effects. Paroxetine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant lasts for at least 7 days, and may last longer after single dose administration. The Cmax and AUC of another CYP2D6 substrate, dextromethorphan, were increased by 120% and 160%, respectively, on day 1 with rolapitant, and by 180% and 230%, respectively, on day 8 after rolapitant administration.
    Safinamide: (Major) The concurrent use of selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs) is generally avoided; however, the manufacturer of safinamide recommends monitoring for serotonin syndrome and using the lowest effective dose of the SSRI during concurrent use. During clinical trial evaluation of safinamide, one case of serotonin syndrome occurred during co-administration with an SSRI. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Salsalate: (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation. A cohort study in > 26,000 patients found that SSRI use alone increased the risk for serious GI bleed by 3.6-fold; when an SSRI was combined with aspirin the risk was increased by > 5-fold. The absolute risk of GI bleed from concomitant therapy with aspirin and a SSRI was low (20/2640 patients) in this cohort study and the clinician may determine that the combined use of these drugs is appropriate.
    Selegiline: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with selective serotonin reuptake inhibitors (SSRIs). MAOIs should not be used within 5 weeks of discontinuing treatment with fluoxetine or within 14 days of discontinuing treatment with other SSRIs. Conversely, SSRIs should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Sertraline: (Severe) Due to the similarity in pharmacology of sertraline and paroxetine and the potential for serious adverse reactions, including serotonin syndrome, selective serotonin reuptake inhibitors (SSRIs) should not be administered together. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. In addition, because sertraline is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SSRI to another SSRI.
    Sibutramine: (Major) Sibutramine is a serotonin reuptake inhibitor. Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering sibutramine with other drugs that have serotonergic properties such as selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, in vitro studies indicate that metabolism of sibutramine is mediated through CYP3A4. Theoretically, the metabolism of sibutramine may be decreased as a result of CYP3A4 inhibition by fluoxetine or fluvoxamine. Patients receiving sibutramine in combination with an SSRI should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
    Sodium picosulfate; Magnesium oxide; Anhydrous citric acid: (Moderate) Use caution when prescribing sodium picosulfate; magnesium oxide; anhydrous citric acid in patients taking concomitant medications that are known to induce Antidiuretic Hormone Secretion (SIADH), such as tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), antipsychotics and carbamazepine, as these drugs may increase the risk of water retention and/or electrolyte imbalance.
    St. John's Wort, Hypericum perforatum: (Major) Due to possible additive effects on serotonin concentrations, it is advisable to avoid combinations of St. John's wort, Hypericum perforatum with selective serotonin reuptake inhibitors (SSRIs). Interactions between SSRIs and serotonergic agents can lead to serious reactions including serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Several cases of serotonin syndrome reactions have been documented when SSRIs were used concurrently with St. John's wort. A single case report is noted of a 50 year old woman with depression who experienced excessive sedation after ingesting paroxetine with St. John's wort. After discontinuing her conventional paroxetine treatment for 10 days, she started St. John's wort powder at a dose of 600 mg per day. The woman experienced no adverse events related to the change in therapy. She decided to take paroxetine 20 mg one evening due to an episode of insomnia. The next day she was found in an arousable but lethargic and incoherent state. After 2 hours, she complained of weakness, fatigue, and nausea. The patient recovered completely within 48 hours.
    Streptokinase: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SSRI.
    Sumatriptan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., sumatriptan). Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome and can be life-threatening. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen.
    Tamoxifen: (Major) Tamoxifen is converted to endoxifen and other active metabolites by cytochrome P450 (CYP) enzymes (e.g., 2D6, 3A4). Paroxetine is considered a moderate to potent inhibitor of CYP2D6; reduced tamoxifen efficacy is possible with concomitant use. If treatment with an antidepressant and tamoxifen is necessary, it may be preferable to use an agent that exhibits mild inhibition of CYP2D6.
    Tamsulosin: (Moderate) Use caution when administering tamsulosin with a strong CYP2D6 inhibitor such as paroxetine. Tamsulosin is extensively metabolized by CYP2D6 hepatic enzymes. In clinical evaluation, concomitant treatment with paroxetine resulted in an increase in the Cmax and AUC of tamsulosin by a factor of 1.3 and 1.6, respectively. If concomitant use in necessary, monitor patient closely for increased side effects.
    Tapentadol: (Major) Caution is advised when tapentadol is coadministered with selective serotonin reuptake inhibitors (SSRIs) as this combination may increase the potential for serotonin syndrome development. If concomitant treatment is clinically warranted, careful observation of the patient is advised, especially during initiation of the second therapy and after dosage adjustments (increases) of either agent.
    Tedizolid: (Minor) Caution is warranted with the concurrent use of tedizolid and selective serotonin reuptake inhibitors (SSRIs) due to the theoretical risk of serotonin syndrome. Animal studies did not predict serotonergic effects; however, patients on concurrent SSRIs were excluded from clinical trials. Addtionally, tedizolid is an antibiotic that is also a weak reversible, non-selective MAO inhibitor and monoamine oxidase type A deaminates serotonin; therefore, coadministration theoretically could lead to serious reactions including serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome has been reported in patients receiving either citalopram, escitalopram, fluoxetine, or paroxetine in combination with linezolid, which is structurally similar to tedizolid.
    Tenecteplase, TNK-tPA: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SSRI.
    Terbinafine: (Moderate) Systemic terbinafine inhibits hepatic isoenzyme CYP2D6, and thus may inhibit the clearance of drugs metabolized by this isoenzyme, such as selective serotonin reuptake inhibitors (SSRIs). The clinical relevance of the interaction is not known. Topical forms of terbinafine do not interact.
    Tetrabenazine: (Major) The primary metabolites of tetrabenazine, alpha-dihydrotetrabenzaine (alpha-HTBZ) and beta-dihydrotetrabenazine (beta-HTBZ), are substrates for CYP2D6. Coadministration of 50 mg of tetrabenazine following 10 days of 20 mg of paroxetine, a potent CYP2D6 inhibitor, resulted in an increase in Cmax of approximately 30% and a 3-fold increase in AUC for alpha-HTBZ. The Cmax and AUC for beta-HTBZ increased 2.4-fold and 9-fold, respectively. The elimination half-life of alpha-HTBZ and beta-HTBZ was approximately 14 hours when tetrabenazine was given with paroxetine. When tetrabenazine is given with a strong inhibitor of CYP2D6 such as paroxetine, the maximum single dose of tetrabenazine should not exceed 25 mg and the daily dose should not exceed 50 mg. In addition, because tetrabenazine is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events. During use of this combination, monitor for adverse effects associated with tetrabenazine such as QT prolongation, excess sedation, and extrapyramidal symptoms.
    Theophylline, Aminophylline: (Major) Paroxetine has been reported to cause elevations of theophylline serum concentrations. Monitor aminophylline serum concentrations when paroxetine is given concurrently with aminophylline. Observe patients for signs or symptoms of aminophylline toxicity. (Major) Paroxetine has been reported to cause elevations of theophylline serum concentrations. The interaction has not been formally studied. It is recommended that theophylline serum concentrations be monitored when paroxetine is given concurrently with theophylline or aminophylline. Observe patients for signs or symptoms of theophylline toxicity.
    Thioridazine: (Severe) Thioridazine is contraindicated for use with paroxetine. Serum concentrations of thioridazine and its two active metabolites, mesoridazine and sulforidazine, may increase by up to three-fold through potent inhibition of CYP2D6 by paroxetine. Substantial increases in serum thioridazine concentrations may lead to QT prolongation, which is associated with serious ventricular arrhythmias, such as torsade de pointe and sudden death. In addition, the risk of extrapyramidal symptoms and anticholinergic effects is increased.
    Thrombin Inhibitors: (Major) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombin inhibitors. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with an anticoagulant medication.
    Thrombolytic Agents: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SSRI.
    Ticagrelor: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving prasugrel. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Ticlopidine: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Timolol: (Moderate) Timolol is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as paroxetine, could theoretically impair timolol metabolism; the clinical significance of such interactions is unknown.
    Tinzaparin: (Major) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving low molecular weight heparins. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with molecular weight heparins.
    Tipranavir: (Moderate) Use caution when coadministering tipranavir and ritonavir with SSRIs, as increased SSRI concentrations may be seen. Patients should be monitored for increased SSRI adverse effects and the SSRI dose should be adjusted if necessary.
    Tirofiban: (Moderate) Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding.
    Tolterodine: (Moderate) Paroxetine, a potent CYP2D6 inhibitor, may inhibit the metabolism of tolterodine, a CYP2D6 substrate. In a study assessing another potent CYP2D6 inhibitor (fluoxetine) and tolterodine, the metabolism of tolterodine immediate release was significantly decreased in CYP2D6 extensive metabolizers, resulting in a 4.8-fold increase in tolterodine AUC. There was a 52% decrease in Cmax and a 20% decrease in AUC of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of tolterodine. The sums of unbound serum concentrations of tolterodine and 5-HMT were only 25% higher during the interaction. Although the manufacturer requires no dose adjustment during concurrent use of tolterodine and fluoxetine, the kinetic and clinical effects of paroxetine use are unknown. Both drugs exhibit anticholinergic effects that may be additive. In addition, because tolterodine is a primary substrate of CYP2D6 and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events.
    Topiramate: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as selective serotonin reuptake inhibitors (SSRIs) like paroxetine may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Tramadol: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as tramadol. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Several cases of serotonin syndrome have been reported after the administration of tramadol with a SSRI. Concomitant use of tramadol also increases the seizure risk in patients taking selective serotonin reuptake inhibitors (SSRIs). Post-marketing reports implicate the concurrent use of SSRIs with tramadol in some cases of seizures. Lastly, SSRIs such as paroxetine 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.
    Tranylcypromine: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with selective serotonin reuptake inhibitors (SSRIs). MAOIs should not be used within 5 weeks of discontinuing treatment with fluoxetine or within 14 days of discontinuing treatment with other SSRIs. Conversely, SSRIs should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Trazodone: (Major) Due to the risk of serotonin syndrome, concurrent use of trazodone and other serotonergic medications, such as selective serotonin reuptake inhibitors (SSRIs), should be avoided if possible. If concomitant use is clinically warranted, patients should be informed of the increased risk of serotonin syndrome, particularly during treatment initiation and during dose increases. 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. Treatment with trazodone and any concomitant serotonergic agents should be discontinued immediately if signs and symptoms of serotonin syndrome occur, and supportive symptomatic treatment should be initiated.
    Trifluoperazine: (Moderate) Substantial increases in concentrations of phenothiazines may occur due to CYP2D6 inhibition by paroxetine. which may increase the risk of adverse effects, including extrapyramidal symptoms or QT prolongation. Phenothiazines with a possible risk of QT prolongation include trifluoperazine.
    Trimipramine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. 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, paroxetine is a potent CYP2D6 inhibitor and may decrease the metabolism of trimipramine, a CYP2D6 substrate. Because there is a risk of QT prolongation and torsade de pointes (TdP) with tricyclics at elevated serum concentrations, coadministration should be approached with caution and close monitoring. Lastly, both paroxetine and trimipramine may exhibit significant anticholinergic effects that may be additive during concurrent use.
    Urokinase: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SSRI.
    Valbenazine: (Major) Consider reducing the dose of valbenazine, based on tolerability, during co-administration with a strong CYP2D6 inhibitor, such as paroxetine. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, concentrations of the active metabolite of valbenazine may be higher in patients taking a strong CYP2D6 inhibitor and QT prolongation may become clinically significant.
    Valerian, Valeriana officinalis: (Moderate) Substances that act on the CNS, including psychoactive drugs, may theoretically interact with valerian, Valeriana officinalis. These interactions are probably pharmacodynamic in nature, or result from additive mechanisms of action. Persons taking medications such as SSRIs should discuss the use of herbal supplements with their health care professional prior to consuming these herbs. Patients should not abruptly stop taking their prescribed psychoactive medication.
    Vemurafenib: (Moderate) Concomitant use of vemurafenib and paroxetine may result in increased paroxetine concentrations. Paroxetine is metabolized by CYP2D6 and vemurafenib is a weak CYP2D6 inhibitor. Monitor patients for toxicity.
    Venlafaxine: (Major) Due to similarity of pharmacology and the potential for serotonin syndrome, selective serotonin reuptake inhibitors (SSRIs) should generally not be administered with serotonin norepinephrine reuptake inhibitors like venlafaxine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, venlafaxine, paroxetine, and concurrent serotonergic agents should be discontinued. In addition, because venlafaxine is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events.
    Vilazodone: (Major) Due to possible additive effects on serotonin concentrations, it is advisable to avoid combining selective serotonin reuptake inhibitors (SSRIs) such as paroxetine with vilazodone. Interactions between vilazodone and serotonergic agents can lead to serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Patients receiving vilazodone and paroxetine should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. Vilazodone and paroxetine should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Vorapaxar: (Moderate) Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as selective serotonin reuptake inhibitors (SSRIs). Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion. In addition, fluoxetine and fluvoxamine are CYP3A4 inhibitors and coadministration with vorapaxar, a CYP3A4 substrate, may result in increased serum concentrations of vorapaxar. Increased exposure to vorapaxar may increase the risk of bleeding complications. Patients should be instructed to monitor for signs and symptoms of bleeding while taking a SSRI with vorapaxar and to promptly report any bleeding events.
    Vortioxetine: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, vortioxetine should generally not be co-administered with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Monitor for serotonin syndrome during a transition from vortioxetine to an SSRI. If coadministration is necessary, the manufacturer recommends a reduction in the vortioxetine dose by one-half when strong inhibitors of CYP2D6 such as paroxetine are used since CYP2D6 is the primary isoenzyme responsible for the metabolism of vortioxetine to its inactive metabolite. The vortioxetine dose should be increased to the original level when the CYP2D6 inhibitor is discontinued.
    Warfarin: (Major) Caution is advised during concurrent use of warfarin with paroxetine. If these drugs are administered together, instruct patients to monitor for signs and symptoms of bleeding, and to promptly report any bleeding events to their practitioner. It would be prudent for clinicians to monitor the INR and patient's clinical status closely if paroxetine is added to or removed from the regimen of a patient stabilized on warfarin. In one study of healthy volunteers, the mean hypoprothrombinemic response to warfarin was not affected by paroxetine, but several subjects had clinically significant bleeding after several days of concomitant therapy. The mechanism of this interaction is uncertain. Pharmacokinetic studies did not find any displacement of warfarin from protein binding sites by the highly protein bound paroxetine. SSRIs like paroxetine can inhibit serotonin uptake by platelets, thus causing platelet dysfunction and increasing the risk for bleeding; however, the absolute risk is not known.
    Ziprasidone: (Major) 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 drugs that are dopamine antagonists such as ziprasidone. 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 ziprasidone and an SSRI should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
    Zolmitriptan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., zolmatriptan). Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome and can be life-threatening. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen.
    Zolpidem: (Moderate) Disorientation, delusions, or hallucinations have been reported rarely during co-administration of zolpidem and SSRIs (e.g., fluoxetine, sertraline, fluvoxamine). The duration of the visual hallucinations has ranged from 30 minutes to 7 hours. Data from a clinical study in which SSRI-treated patients were given immediate-release zolpidem revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n = 95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction. The mechanism for the interaction is thought to be pharmacodynamic in nature; therefore, a similar reaction is possible with other SSRIs such as paroxetine.

    PREGNANCY AND LACTATION

    Pregnancy

    All formulations of paroxetine may cause fetal harm during human pregnancy; the Brisdelle (brand for menopause) is contraindicated for use during pregnancy because menopausal vasomotor symptoms do not occur during pregnancy and paroxetine can cause fetal harm. Unless other treatment options are not available, do not initiate paroxetine during the first trimester of pregnancy or in women who plan to become pregnant in the near future. The FDA is evaluating data to better characterize the risk of congenital malformations resulting from infant exposure to paroxetine during pregnancy. Exposure in the first trimester may increase the risk for congenital malformations, particularly cardiac malformations. A retrospective, epidemiologic study derived from the Swedish National Registry, comprised of 6896 women prescribed antidepressants in early pregnancy (5,123 of these women exposed to SSRIs; 815 to paroxetine) suggests an increased risk of cardiovascular malformations, primarily ventricular (VSDs) and atrial (ASDs) septal defects in those with exposure to paroxetine. This increased risk was seen compared to the entire registry population (OR 1.8; 95% CI 1.1 to 2.8). The rate of cardiovascular malformations following paroxetine exposure was 2% vs. 1% in the entire registry population; however, there was no increase in the overall risk for congenital malformations in either group. In another retrospective, cohort study (a US health insurance claims database), evaluating infant outcomes in those whose mothers received antidepressants in the first trimester (n = 5,956 total ; 815 for paroxetine), a 1.5-fold elevated risk for cardiac malformations and a 1.8-fold elevated risk for overall congenital malformations was seen in the paroxetine group compared to the group that received other antidepressants in the first trimester (OR 1.5; 95% CI 0.8 to 2.9). The prevalence of cardiac malformations when drug was received in the first trimester was 1.5% for paroxetine and 1% for other antidepressants. Nine out of 12 newborns with cardiac malformations whose mothers received paroxetine in the first trimester had VSDs. Unlike the first study, there was an increased risk of overall major congenital malformations (inclusive of the cardiovascular defects) for paroxetine compared to other antidepressants (OR 1.8; 95% CI 1.2 to 2.8). The prevalence of all congenital malformations following first trimester exposure was 4% for paroxetine vs. 2% for other antidepressants. Results from 2 large case-control studies (each with more than 9,000 birth defect cases and more than 4,000 controls) showed a 2- to 3-fold increased risk of right ventricular outflow tract obstructions from infant exposures to paroxetine in utero during the first trimester of pregnancy, with 7 exposed in one study (OR 2.5; 95% CI, 1 to 6), and 6 exposed in the other study (OR 3.3; 95% CI 1.3 to 8.8). All of these studies were limited to first trimester exposure only, therefore the risk of fetal exposure to paroxetine in the second and third trimesters is not known. A prospective, cohort study was conducted to evaluate the outcome of newborns born to 267 women who took an SSRI during pregnancy (of whom 97 took paroxetine). Compared with a neonatal control group, SSRI-exposed neonates had similar rates of major malformation, spontaneous and elective abortion, and stillbirth. Mean birth weight and gestational age were similar among the two groups of neonates. In animal studies, SSRIs appear to downregulate serotonin receptors in the fetal cortex; the changes are present for a period of time after birth but the effect on neurological development is uncertain; the applicability of these findings to humans is also unknown. A neonatal abstinence syndrome has been reported at birth following in utero paroxetine exposure; exposed neonates may need to be monitored for associated symptoms. A cohort study of 55 women revealed that 22% (12 of 55) of neonates exposed to paroxetine in the third trimester had complications requiring treatment or extended hospitalization vs. 6% in comparison groups. Post-marketing reports indicate that premature births have occurred in pregnant women receiving paroxetine or other SSRIs. Additionally, epidemiologic reports suggest a possible association between maternal use of SSRIs after 20 weeks gestation and the development of persistent pulmonary hypertension (PPHN) of the newborn. More recent retrospective studies have not shown an increased risk of PPHN with SSRI exposure. In December 2011, the FDA issued a safety announcement stating that based on conflicting data, an increased risk of PPHN from SSRI exposure cannot be determined. The FDA advises that healthcare professionals should not alter their current practice of treating depression in pregnancy at this time. Increasing evidence suggests an association between antidepressant use during pregnancy and a subsequent diagnosis of autism spectrum disorder (ASD) in the offspring. In two separate population based case-control studies, an approximate 2-fold increased risk of autism spectrum disorder was observed. One study found the increased risk was associated only with SSRI use, while the other study found an increased risk associated with use of SSRIs and tricyclic antidepressants. Providers should inform women receiving paroxetine to the potential fetal risk if they should become pregnant or are currently in their first trimester. Discontinuing paroxetine and switching to another antidepressant should be considered when possible for these patients. Women who are pregnant, or are planning a pregnancy, and currently taking paroxetine should consult with their physician about whether to continue taking it. A prospective study of pregnant women receiving antidepressant treatment found that only 26% of those maintained on their antidepressant had relapsed versus 68% of those who had discontinued their medication. In individual cases, the benefits of continuing paroxetine may outweigh the potential risk to the fetus. The effect of SSRIs on labor and delivery in humans is unknown. The National Pregnancy Registry for Psychiatric Medications is dedicated to evaluating the safety of psychiatric medications that may be taken by women during pregnancy to treat a wide range of mood, anxiety, or psychiatric disorders. The primary goal of this Registry is to determine the frequency of major malformations, such as heart defects, cleft lip, or neural tube defects, in babies exposed to various psychiatric drugs during pregnancy. While the research concentrates on atypical antipsychotics and antidepressant use, pregnant women using other psychiatric medications are encouraged to register. For more information, contact the registry at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry or by phone 1-866-961-2388.

    MECHANISM OF ACTION

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

    PHARMACOKINETICS

    Paroxetine formulations are administered orally. The drug is widely distributed, including into the CNS, with only 1% of paroxetine remaining in the plasma. Paroxetine is 93—95% bound to plasma protein; however, the drug does not displace other highly protein-bound drugs.
     
    Based on pharmacokinetic studies, the steady-state paroxetine exposure based on AUC is several fold higher than with a single dose. The excess accumulation is a consequence of a saturable metabolic pathway. Paroxetine is extensively metabolized via oxidation, methylation and conjugation to several metabolites, none of which shows any appreciable pharmacological activity. Conjugates with glucuronic acid and sulfate predominate. Metabolism is partly achieved by cytochrome P-450 isoenzymes, predominantly CYP2D6. Due to saturation of CYP2D6 by paroxetine, the relationship between pharmacokinetics and dosage or duration of treatment is nonlinear. At steady-state, when the CYP2D6 is essentially saturated, paroxetine clearance becomes governed by alternative CYP450 isozymes like CYP3A4, which, unlike CYP2D6, do not show evidence of saturation. Excretion is mainly renal (about 62%), mostly as metabolites and about 2% as unchanged drug. Roughly 36% is excreted in the feces, mainly via the bile as metabolites. The mean elimination half-life of the immediate-release paroxetine is approximately 21 hours while the elimination half-life for the controlled-release product is 15—20 hours.
     
    Affected cytochrome P450 isoenzymes:
    Paroxetine is a substrate and potent inhibitor of CYP2D6. In > 90% of patients, the CYP2D6 isoenzyme is saturated early in dosing with paroxetine (in roughly 10—14 days). Due to saturation of CYP2D6 by paroxetine, the relationship between pharmacokinetics and dosage or duration of treatment is nonlinear. At steady-state, when the CYP2D6 is essentially saturated, paroxetine clearance becomes governed by alternative CYP450 isozymes like CYP3A4, which, unlike CYP2D6, do not show evidence of saturation. Paroxetine does not appear to inhibit other CYP isoenzymes, including CYP3A4, to any clinically significant degree.

    Oral Route

    Paroxetine is absorbed completely after oral administration. Paroxetine immediate-release tablets and oral suspension are bioequivalent. Paxil CR controlled-release tablets are enteric coated to delay the start of drug release until the tablets have left the stomach; they are also designed via the Geomatrix polymeric matrix to allow for a 4—5 hour dissolution rate, with a Tmax occurring roughly 6—10 hours after dosing. The bioavailability of paroxetine, regardless of dosage form, is not affected by food. There appears to be individual patient variation in response, but steady-state concentrations are achieved in about 10—14 days with either the immediate-release or controlled-release formulations. The onset of action, however, may require 1—4 weeks of therapy.