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PARoxetine

Medically reviewed by Drugs.com. Last updated on Jul 1, 2020.

Pronunciation

(pa ROKS e teen)

Index Terms

  • Paroxetine HCl
  • Paroxetine Hydrochloride
  • Paroxetine Mesylate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule, Oral, as mesylate [strength expressed as base]:

Brisdelle: 7.5 mg [contains fd&c red #40, fd&c yellow #6 (sunset yellow)]

Generic: 7.5 mg

Suspension, Oral, as hydrochloride [strength expressed as base]:

Paxil: 10 mg/5 mL (250 mL) [contains fd&c yellow #6 aluminum lake, methylparaben, propylene glycol, propylparaben, saccharin sodium; orange flavor]

Tablet, Oral, as hydrochloride [strength expressed as base]:

Paxil: 10 mg [scored]

Paxil: 10 mg [scored; contains fd&c blue #2 aluminum lake, fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake]

Paxil: 20 mg [scored]

Paxil: 20 mg [scored; contains fd&c blue #2 aluminum lake, fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake]

Paxil: 30 mg

Paxil: 30 mg [contains fd&c blue #2 aluminum lake, fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake]

Paxil: 40 mg

Paxil: 40 mg [contains fd&c blue #2 aluminum lake, fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake]

Generic: 10 mg, 20 mg, 30 mg, 40 mg

Tablet, Oral, as mesylate [strength expressed as base]:

Pexeva: 10 mg, 20 mg

Pexeva: 20 mg [DSC] [scored]

Pexeva: 30 mg, 40 mg

Tablet Extended Release 24 Hour, Oral, as hydrochloride [strength expressed as base]:

Paxil CR: 12.5 mg [contains fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake]

Paxil CR: 25 mg

Paxil CR: 25 mg [contains fd&c blue #2 aluminum lake, fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake]

Paxil CR: 37.5 mg [contains fd&c blue #2 aluminum lake]

Paxil CR: 37.5 mg [contains fd&c blue #2 aluminum lake, fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake]

Generic: 12.5 mg, 25 mg, 37.5 mg

Brand Names: U.S.

  • Brisdelle
  • Paxil
  • Paxil CR
  • Pexeva

Pharmacologic Category

  • Antidepressant, Selective Serotonin Reuptake Inhibitor

Pharmacology

Paroxetine is a selective serotonin reuptake inhibitor, chemically unrelated to tricyclic, tetracyclic, or other antidepressants; presumably, the inhibition of serotonin reuptake from brain synapse stimulated serotonin activity in the brain

Absorption

Completely absorbed following oral administration

Distribution

Vd: 8.7 L/kg (3 to 28 L/kg)

Metabolism

Extensively hepatic via CYP2D6 enzymes; primary metabolites are formed via oxidation and methylation of parent drug, with subsequent glucuronide/sulfate conjugation; nonlinear pharmacokinetics (via 2D6 saturation) may be seen with higher doses and longer duration of therapy. Metabolites exhibit ~2% potency of parent compound. Cmin concentrations are 70% to 80% greater in the elderly compared to nonelderly patients; clearance is also decreased.

Excretion

Urine (64%, 2% as unchanged drug); feces (36% primarily via bile, <1% as unchanged drug)

Onset of Action

Anxiety disorders (generalized anxiety, obsessive-compulsive, panic, and posttraumatic stress disorder): Initial effects may be observed within 2 weeks of treatment, with continued improvements through 4 to 6 weeks (Issari 2016; Varigonda 2016; WFSBP [Bandelow 2012]); some experts suggest up to 12 weeks of treatment may be necessary for response, particularly in patients with obsessive-compulsive disorder and posttraumatic stress disorder (BAP [Baldwin 2014]; Katzman 2014; WFSBP [Bandelow 2012]).

Body dysmorphic disorder: Initial effects may be observed within 2 weeks; some experts suggest up to 12 to 16 weeks of treatment may be necessary for response in some patients (Phillips 2008).

Depression: Initial effects may be observed within 1 to 2 weeks of treatment, with continued improvements through 4 to 6 weeks (Papakostas 2006; Posternak 2005; Szegedi 2009; Taylor 2006).

Premenstrual dysphoric disorder: Initial effects may be observed within the first few days of treatment, with response at the first menstrual cycle of treatment (ISPMD [Nevatte 2013]).

Time to Peak

Capsules: Median: 6 hours (range: 3 to 8 hours)

Tablets, oral suspension: Immediate release: Mean: 5.2 to 8.1 hours

Tablets: Controlled release: 6 to 10 hours

Half-Life Elimination

Paxil: 21 hours; Paxil CR: 15 to 20 hours; Pexeva: 33.2 hours

Protein Binding

93% to 95%

Special Populations: Renal Function Impairment

Mean plasma concentrations increased approximately 4 times, with CrCl <30 mL/minute. Plasma concentrations increased 2-fold with CrCl 30 to 60 mL/minute.

Special Populations: Hepatic Function Impairment

2-fold increase in plasma concentrations and AUC after 14 days of daily administration in patients with alcohol-related cirrhosis (Dalhoff 1991).

Special Populations: Elderly

Minimum concentrations were 70% to 80% greater than in younger patients. Reduce initial dosage; no dosage adjustment is necessary with Brisdelle.

Use: Labeled Indications

Generalized anxiety disorder (immediate release): Treatment of generalized anxiety disorder.

Major depressive disorder (unipolar) (immediate and extended release): Treatment of unipolar major depressive disorder.

Obsessive-compulsive disorder (immediate release): Treatment of obsessions and compulsions in patients with obsessive-compulsive disorder.

Panic disorder (immediate and extended release): Treatment of panic disorder, with or without agoraphobia.

Posttraumatic stress disorder (immediate release): Treatment of posttraumatic stress disorder.

Premenstrual dysphoric disorder (extended release): Treatment of premenstrual dysphoric disorder.

Social anxiety disorder (immediate and extended release): Treatment of social anxiety disorder, also known as social phobia.

Vasomotor symptoms of menopause (immediate release; 7.5 mg capsule): Treatment of moderate to severe vasomotor symptoms associated with menopause.

Off Label Uses

Body dysmorphic disorder

Based on the National Institute for Health and Care Excellence (NICE) guidelines for the treatment of obsessive-compulsive disorder and body dysmorphic disorder, selective serotonin reuptake inhibitors given as monotherapy or in combination with cognitive behavior therapy are recommended in the management of body dysmorphic disorder in adults with moderate or severe functional impairment, respectively.

Premature ejaculation

Data from a meta-analysis of 35 clinical trials involving the use of serotonergic antidepressants, 9 of which were double-blind or open-label clinical trials using paroxetine, support the use of daily paroxetine in the treatment of premature ejaculation [Waldinger 2004]. Two single-blind trials also support on-demand dosing regimens [Abu El-Hamd 2018], [McMahon 1999].

According to the International Society for Sexual Medicine guidelines, daily or on-demand dosing of paroxetine is effective and recommended in the management of premature ejaculation. On-demand dosing regimens were less efficacious than daily dosing in most studies; however, on-demand dosing may be combined with either an initial trial of daily treatment or concomitant low-dose daily treatment.

Contraindications

Hypersensitivity (eg, anaphylaxis, angioedema, Stevens-Johnson syndrome) to paroxetine or any component of the formulation; concurrent use with or within 14 days of monoamine oxidase inhibitors (including linezolid or methylene blue IV); concomitant use with pimozide or thioridazine; pregnancy (Brisdelle only).

Dosing: Adult

Note: Dose: In patients sensitive to side effects, some experts suggest a lower starting dose of 5 to 10 mg once daily (immediate release [IR]) or 12.5 mg once daily (extended release [ER]) and gradual titration in increments of no more than 10 mg (immediate release) or 12.5 mg (extended release), particularly in patients with anxiety who are generally more sensitive to overstimulation effects (eg, anxiety, insomnia) with antidepressants (Hirsch 2019c; Siris 2019; Stein 2019b; WFSBP [Bandelow 2012]). Dosage forms: Paroxetine is available as IR and ER formulations; both formulations are dosed once daily but are not interchangeable on a mg to mg basis. Where dosing for the ER formulation is not provided for an indication, may convert between formulations using equivalence shown in Dosing conversions section below.

Body dysmorphic disorder (off-label use): Dosing recommendations based on expert opinion: Immediate release: Oral: Initial: 20 mg once daily; may increase dose gradually based on response and tolerability in increments of 20 mg/day at intervals of every 2 to 3 weeks to a usual dose of 60 mg/day; doses up to 100 mg/day may be necessary in some patients for optimal response, typically under specialist care. Note: An adequate trial for assessment of effect in body dysmorphic disorder is 12 to 16 weeks, including maximum tolerated doses for at least 3 to 4 of those weeks (Phillips 2019).

Generalized anxiety disorder: Immediate release: Oral: Initial: 10 mg once daily; may increase dose based on response and tolerability in increments of 10 mg/day at intervals ≥1 week up to 50 mg/day (Pollack 2001; WFSBP [Bandelow 2012]).

Major depressive disorder (unipolar):

Immediate release: Oral: Initial: 20 mg once daily; may increase dose based on response and tolerability in increments of 10 to 20 mg/day at intervals ≥1 week to a maximum of 50 mg/day (Hirsch 2019b).

Extended release: Oral: Initial: 25 mg once daily; may increase dose based on response and tolerability in increments of 12.5 mg/day at intervals ≥1 week to a maximum of 62.5 mg/day.

Obsessive-compulsive disorder: Immediate release: Oral: Initial: 20 mg once daily; may increase dose based on response and tolerability in increments of 10 mg/day at intervals ≥1 week up to a recommended dose of 40 to 60 mg/day; maximum dose: 60 mg/day (APA [Koran 2007]). Note: An adequate trial for assessment of effect in obsessive-compulsive disorder is considered ≥6 weeks at the maximum tolerated dose (Issari 2016).

Panic disorder:

Immediate release: Oral: Initial: 10 mg once daily for 3 to 7 days; may increase dose based on response and tolerability in increments of 10 mg/day at intervals ≥1 week up to a usual dose of 20 to 40 mg/day (APA [Stein 2009]); maximum dose: 60 mg/day.

Extended release: Oral: Initial: 12.5 mg once daily; may increase dose based on response and tolerability in increments of 12.5 mg/day at intervals ≥1 week up to a maximum of 75 mg/day.

Posttraumatic stress disorder: Immediate release: Oral: Initial: 20 mg once daily; may increase dose based on response and tolerability in increments of 10 to 20 mg/day at intervals ≥1 week up to 60 mg/day (Marshall 2007; Stein 2019a).

Premature ejaculation (off-label use): Immediate release: Oral: Initial: 10 mg once daily; may increase dose based on response and tolerability in increments of 10 mg/day at intervals ≥1 week to a usual dosage of 20 mg/day (Waldinger 2001). Some patients may require up to 40 mg/day for optimal response (ISSM [Althof 2014]; Waldinger 1997); some experts suggest 3- to 4-week titration intervals (Khera 2020).

Premenstrual dysphoric disorder: Note: Some experts prefer selective serotonin reuptake inhibitors (SSRIs) other than paroxetine for this use (Casper 2020).

Continuous daily dosing regimen:

Immediate release (off-label): Oral: Initial: 10 mg once daily; increase to usual effective dose of 20 mg once daily over the first month; in a subsequent menstrual cycle, a further increase to 40 mg/day may be necessary in some patients for optimal response (Casper 2020).

Extended release: Oral: Initial: 12.5 mg once daily; increase to usual effective dose of 25 mg once daily over the first month; in a subsequent menstrual cycle, a further increase to 50 mg/day (based on equivalent IR dose) may be necessary in some patients for optimal response (Casper 2020).

Intermittent regimens:

Luteal phase dosing regimen:

Immediate release (off-label): Oral: Initial: 10 mg once daily during the luteal phase of menstrual cycle only (ie, beginning therapy 14 days before anticipated onset of menstruation and continued to the onset of menses); over the first month, may increase to usual effective dose of 20 mg once daily during the luteal phase; in a subsequent menstrual cycle, a further increase to 30 mg/day during the luteal phase may be necessary in some patients for optimal response (Casper 2020).

Extended release: Oral: Initial: 12.5 mg once daily during the luteal phase of menstrual cycle only (ie, beginning therapy 14 days before anticipated onset of menstruation and continued to the onset of menses); over the first month, may increase to usual effective dose of 25 mg once daily during the luteal phase; in a subsequent menstrual cycle, a further increase to 37.5 mg/day (based on equivalent IR dose) during the luteal phase may be necessary in some patients for optimal response (Casper 2020).

Symptom-onset dosing regimen (off-label): Immediate release: Oral: Initial: 10 mg once daily from the day of symptom onset until a few days after the start of menses; over the first month, may increase dose based on response and tolerability up to 20 mg/day; in a subsequent menstrual cycle, a further increase to 30 mg/day may be necessary in some patients for optimal response (Casper 2020).

Social anxiety disorder:

Immediate release: Oral: Initial: 10 mg once daily; may increase dose based on response and tolerability in increments of 10 mg/day at intervals ≥1 week to a maximum of 60 mg/day (Baldwin 1999; Liebowitz 2002; Mancini 1996; Stein 1998).

Extended release: Oral: Initial: 12.5 mg once daily; may increase dose based on response and tolerability in increments of 12.5 mg/day at intervals ≥1 week up to a maximum of 37.5 mg/day (manufacturer's labeling). Note: Doses up to 75 mg/day (based on equivalent IR dose) may be necessary in some patients for optimal response (Liebowitz 2002).

Vasomotor symptoms of menopause (alternative agent): Note: Nonhormonal alternative in patients unable or unwilling to take estrogen (AACE [Goodman 2011]).

Immediate release:

Capsule: Oral: 7.5 mg once daily at bedtime.

Tablet (off-label): Oral: 10 to 20 mg once daily at bedtime (Stearns 2005; Slaton 2015).

Extended release (off-label): Oral: 12.5 to 25 mg once daily at bedtime (Stearns 2003; Slaton 2015).

Dosing conversions: Immediate release 10 mg is equivalent to extended release 12.5 mg (DeVane 2003).

Discontinuation of therapy: When discontinuing antidepressant treatment that has lasted for >3 weeks, gradually taper the dose (eg, over 2 to 4 weeks) to minimize withdrawal symptoms and detect reemerging symptoms (APA 2010; WFSBP [Bauer 2015]). Reasons for a slower taper (eg, over 4 weeks) include use of a drug with a half-life <24 hours (eg, paroxetine, venlafaxine), prior history of antidepressant withdrawal symptoms, or high doses of antidepressants (APA 2010; Hirsch 2019a). If intolerable withdrawal symptoms occur, resume the previously prescribed dose and/or decrease dose at a more gradual rate (Shelton 2001). Select patients (eg, those with a history of discontinuation syndrome) on long-term treatment (>6 months) may benefit from tapering over >3 months (WFSBP [Bauer 2015]). Evidence supporting ideal taper rates is limited (Shelton 2001; WFSBP [Bauer 2015]).

Switching antidepressants: Evidence for ideal antidepressant switching strategies is limited; strategies include cross-titration (gradually discontinuing the first antidepressant while at the same time gradually increasing the new antidepressant) and direct switch (abruptly discontinuing the first antidepressant and then starting the new antidepressant at an equivalent dose or lower dose and increasing it gradually). Cross-titration (eg, over 1 to 4 weeks depending upon sensitivity to discontinuation symptoms and adverse effects) is standard for most switches, but is contraindicated when switching to or from an MAOI. A direct switch may be an appropriate approach when switching to another agent in the same or similar class (eg, when switching between two SSRIs), when the antidepressant to be discontinued has been used for <1 week, or when the discontinuation is for adverse effects. When choosing the switch strategy, consider the risk of discontinuation symptoms, potential for drug interactions, other antidepressant properties (eg, half-life, adverse effects, pharmacodynamics), and the degree of symptom control desired (Hirsch 2019b; Ogle 2013; WFSBP [Bauer 2013]).

Switching to or from an MAOI:

Allow 14 days to elapse between discontinuing an MAOI and initiation of paroxetine.

Allow 14 days to elapse between discontinuing paroxetine and initiation of an MAOI.

Dosing: Geriatric

Major depressive disorder (unipolar), obsessive-compulsive disorder, panic disorder, social anxiety disorder:

Immediate release: Oral: Initial: 10 mg/day; may increase dose based on response and tolerability in increments of 10 mg/day at intervals ≥1 week to a maximum of 40 mg/day.

Extended release: Oral: Initial: 12.5 mg/day; may increase dose based on response and tolerability in increments of 12.5 mg/day at intervals ≥1 week to a maximum of 37.5 mg/day (social anxiety disorder) or 50 mg/day (major depressive disorder, panic disorder).

Note: An adequate trial for assessment of effect in obsessive-compulsive disorder is considered to be ≥6 weeks at the maximum tolerated dose (Issari 2016).

Dosing conversions: Refer to adult dosing.

Discontinuation of therapy: Refer to adult dosing.

Switching antidepressants: Refer to adult dosing.

Dosing: Pediatric

Note: Immediate-release paroxetine is available in two salts, hydrochloride (eg, Paxil) and mesylate (eg, Brisdelle, Pexeva); use extra precaution to ensure product selection. Paroxetine is available as immediate-release and extended-release formulations; both formulations are dosed once daily but are not interchangeable on a mg to mg basis; based on adult bioavailability data, immediate-release 10 mg is equivalent to extended-release 12.5 mg (DeVane 2003).

Obsessive-compulsive disorder (OCD): Limited data available: Children and Adolescents 7 to 17 years: Oral: Immediate release (hydrochloride salt): Initial: 10 mg once daily; titrate every 7 to 14 days in 10 mg/day increments; maximum daily dose: 60 mg/day. Dosing based on two trials. The first was a 12-week open-label trial of paroxetine in 20 outpatients 8 to 17 years of age that demonstrated the potential clinical usefulness in pediatric OCD (Rosenberg 1999). The second trial demonstrated efficacy of paroxetine in a 10-week, randomized, double-blind, placebo-controlled trial conducted in 207 pediatric patients (aged 7 to 17 years) with OCD; the overall mean dose was 20.3 mg/day for children and 26.8 mg/day for adolescents (Geller 2004).

Social anxiety disorder: Limited data available: Children and Adolescents 8 to 17 years: Oral: Immediate release (hydrochloride salt): Initial: 10 mg once daily; titrate at intervals of at least 7 days in 10 mg/day increments; maximum daily dose: 50 mg/day. Dosing based on a 16-week multicenter, randomized, double-blind, placebo-controlled trial that reported the efficacy of paroxetine in pediatric patients (aged 8 to 17 years) with social anxiety disorder; 163 patients were randomized to receive paroxetine; the overall mean dose was 21.7 mg/day for children and 26.1 mg/day for adolescents (Wagner 2004).

Discontinuation of OCD therapy: Consider planning discontinuation of therapy during lower-stress times, recognizing non-illness-related factors could cause stress or anxiety and be misattributed to OCD treatment discontinuation (Hathaway 2018). To discontinue therapy, gradually taper the dose to minimize the incidence of discontinuation syndromes (withdrawal) and allow for the detection of reemerging disease state symptoms (eg, relapse). Evidence supporting ideal taper rates after illness remission is sparse, particularly in pediatric patients; however, a general consensus is to taper over several weeks to months and to resume the previous OCD therapy if symptoms worsen; a plan for continued psychotherapy during serotonergic medication discontinuation is recommended (Boisseau 2018; Fenske 2015). A unified taper protocol has been reported in adults with OCD in which serotonin reuptake inhibitor monotherapy was tapered over 12 weeks with biweekly psychiatrist visits (Boisseau 2018). For the treatment of depression, experts suggest tapering therapy over at least several weeks with consideration to the half-life of the antidepressant; agents with a shorter half-life may need to be tapered more conservatively and if intolerable discontinuation symptoms occur following a dose reduction, consider resuming the previously prescribed dose and/or decrease dose at a more gradual rate; similar principles may also be applicable to OCD therapy discontinuation (APA 2010; Bauer 2002; Fenske 2009; Haddad 2001; NCCMH 2010; Schatzberg 2006; Shelton 2001; Warner 2006).

Monoamine oxidase (MAO) inhibitor recommendations:

Switching to or from an MAO inhibitor intended to treat psychiatric disorders:

Allow 14 days to elapse between discontinuing an MAO inhibitor intended to treat psychiatric disorders and initiation of paroxetine.

Allow 14 days to elapse between discontinuing paroxetine and initiation of an MAO inhibitor intended to treat psychiatric disorders.

Administration

Oral: May be administered without regard to meals. Administer preferably in the morning; when used for vasomotor symptoms of menopause, administer at bedtime. Do not crush, break, or chew ER or IR film-coated tablets.

Bariatric surgery: Tablet, extended release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. ER tablets should be swallowed whole. IR tablet, capsule, and oral suspension formulations are available. If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery.

Storage

Capsules: Store between 20°C and 25°C (68°F and 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). Protect from light and humidity.

Tablets: Store between 20°C and 25°C (68°F and 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F).

Suspension: Store at or below 25°C (77°F).

Drug Interactions

Acalabrutinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the antiplatelet effect of other Agents with Antiplatelet Properties. Monitor therapy

Agents with Blood Glucose Lowering Effects: Selective Serotonin Reuptake Inhibitors may enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Monitor therapy

Ajmaline: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Ajmaline: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Ajmaline. Monitor therapy

Alcohol (Ethyl): May enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Management: Patients receiving selective serotonin reuptake inhibitors should be advised to avoid alcohol. Monitor for increased psychomotor impairment in patients who consume alcohol during treatment with selective serotonin reuptake inhibitors. Consider therapy modification

Almotriptan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Alosetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Amphetamines: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors). This could result in serotonin syndrome. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may increase the serum concentration of Amphetamines. Management: Monitor for amphetamine toxicities, including serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability). Initiate amphetamines at lower doses, monitor frequently, and adjust dose as needed. Monitor therapy

Anticoagulants: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants. Exceptions: Bemiparin; Enoxaparin; Heparin. Monitor therapy

Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Exceptions: Alosetron; Ondansetron; Ramosetron. Monitor therapy

Antipsychotic Agents: Serotonergic Agents (High Risk) may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonergic agents may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Monitor therapy

Apixaban: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Apixaban. Specifically, the risk for bleeding may be increased. Management: Carefully consider risks and benefits of this combination and monitor closely. Monitor therapy

Aprepitant: PARoxetine may decrease the serum concentration of Aprepitant. Aprepitant may decrease the serum concentration of PARoxetine. Monitor therapy

ARIPiprazole: CYP2D6 Inhibitors (Strong) may increase the serum concentration of ARIPiprazole. Management: Aripiprazole dose reductions are required for indications other than major depressive disorder. Dose reductions vary based on formulation, initial starting dose, and the additional use of CYP3A4 inhibitors. See full interaction monograph for details. Consider therapy modification

ARIPiprazole Lauroxil: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil. Management: Decrease aripiprazole lauroxil dose to next lower strength if used with strong CYP2D6 inhibitors for over 14 days. No dose adjustment needed if using the lowest dose (441 mg) or if a CYP2D6 PM. Max dose is 441 mg if also taking strong CYP3A4 inhibitors. Consider therapy modification

Asenapine: May increase the serum concentration of PARoxetine. Management: Decrease the paroxetine dose by half when used concomitantly with asenapine. Monitor patients receiving this combination closely for signs and symptoms of increased paroxetine toxicity. Consider therapy modification

Aspirin: Selective Serotonin Reuptake Inhibitors may enhance the antiplatelet effect of Aspirin. Monitor therapy

AtoMOXetine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of AtoMOXetine. Management: Initiate atomoxetine at a reduced dose (patients who weigh up to 70 kg: 0.5 mg/kg/day; adults or patients who weigh 70 kg or more: 40 mg/day) in patients receiving a strong CYP2D6 inhibitor. Increase to usual target dose after 4 weeks if needed. Consider therapy modification

Bemiparin: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Bemiparin. Management: Avoid concomitant use of bemiparin with antiplatelet agents. If concomitant use is unavoidable, monitor closely for signs and symptoms of bleeding. Consider therapy modification

Brexanolone: Selective Serotonin Reuptake Inhibitors may enhance the CNS depressant effect of Brexanolone. Monitor therapy

Brexpiprazole: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Brexpiprazole. Management: Reduce brexpiprazole dose to 50% of usual with strong CYP2D6 inhibitors, reduce to 25% of usual if used with both a strong CYP2D6 inhibitor and a strong or moderate CYP3A4 inhibitor; these recommendations do not apply if treating major depressive disorder Consider therapy modification

Bromopride: May enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Avoid combination

BuPROPion: May enhance the adverse/toxic effect of PARoxetine. Monitor therapy

BusPIRone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Carvedilol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Carvedilol. Monitor therapy

Cephalothin: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Cephalothin. Specifically, the risk for bleeding may be increased. Monitor therapy

Chlorpheniramine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Chlorpheniramine. Monitor therapy

Cimetidine: May increase the serum concentration of PARoxetine. Monitor therapy

Citalopram: May enhance the antiplatelet effect of Selective Serotonin Reuptake Inhibitors. Citalopram may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, mental status changes) when these agents are combined. In addition, monitor for signs and symptoms of bleeding. Monitor therapy

Clarithromycin: May enhance the adverse/toxic effect of PARoxetine. Clarithromycin may enhance the QTc-prolonging effect of PARoxetine. Monitor therapy

CloZAPine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of CloZAPine. Monitor therapy

Cobicistat: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Collagenase (Systemic): Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Monitor therapy

Cyclobenzaprine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

CYP2D6 Inhibitors (Moderate): May increase the serum concentration of PARoxetine. Exceptions: Darunavir; DULoxetine; Lorcaserin (Withdrawn From US Market); Perhexiline; Thioridazine. Monitor therapy

CYP2D6 Inhibitors (Strong): May increase the serum concentration of PARoxetine. Exceptions: BuPROPion; FLUoxetine. Monitor therapy

Cyproheptadine: May diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. Monitor therapy

Dabigatran Etexilate: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Dabigatran Etexilate. Agents with Antiplatelet Properties may increase the serum concentration of Dabigatran Etexilate. This mechanism applies specifically to clopidogrel. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Monitor therapy

Dapoxetine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Do not use serotonergic agents (high risk) with dapoxetine or within 7 days of serotonergic agent discontinuation. Do not use dapoxetine within 14 days of monoamine oxidase inhibitor use. Dapoxetine labeling lists this combination as contraindicated. Avoid combination

Darunavir: May decrease the serum concentration of PARoxetine. Monitor therapy

Dasatinib: May enhance the anticoagulant effect of Agents with Antiplatelet Properties. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy

Deoxycholic Acid: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Monitor therapy

Desmopressin: Selective Serotonin Reuptake Inhibitors may enhance the adverse/toxic effect of Desmopressin. Monitor therapy

Deutetrabenazine: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Deutetrabenazine. Management: The total daily dose of deutetrabenazine should not exceed 36 mg, and the maximum single dose of deutetrabenazine should not exceed 18 mg, with concurrent use of a strong CYP2D6 inhibitor. Consider therapy modification

Dexmethylphenidate-Methylphenidate: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Dextromethorphan: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors). This could result in serotonin syndrome. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may increase the serum concentration of Dextromethorphan. Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes). Consider therapy modification

DOXOrubicin (Conventional): CYP2D6 Inhibitors (Strong) may increase the serum concentration of DOXOrubicin (Conventional). Avoid combination

DULoxetine: May enhance the antiplatelet effect of Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors). DULoxetine may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors). This could result in serotonin syndrome. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may increase the serum concentration of DULoxetine. Management: Monitor for increased duloxetine effects/toxicities and signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperthermia, tremor, mental status changes) when these agents are combined. In addition, monitor for signs and symptoms of bleeding. Monitor therapy

Edoxaban: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased. Monitor therapy

Eletriptan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Eliglustat: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Eliglustat. Management: Eliglustat dose is 84 mg daily with CYP2D6 inhibitors. Use is contraindicated (COI) when also combined with strong CYP3A4 inhibitors. When also combined with a moderate CYP3A4 inhibitor, use is COI in CYP2D6 EMs or IMs and should be avoided in CYP2D6 PMs. Consider therapy modification

Enoxaparin: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Enoxaparin. Management: Discontinue antiplatelet agents prior to initiating enoxaparin whenever possible. If concomitant administration is unavoidable, monitor closely for signs and symptoms of bleeding. Consider therapy modification

Ergot Derivatives: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Exceptions: Lisuride; Nicergoline. Monitor therapy

Fat Emulsion (Fish Oil Based): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Monitor therapy

Fenfluramine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Monitor therapy

Fesoterodine: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Fesoterodine. Monitor therapy

Flecainide: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Flecainide. Monitor therapy

FLUoxetine: May enhance the antiplatelet effect of PARoxetine. FLUoxetine may enhance the serotonergic effect of PARoxetine. This could result in serotonin syndrome. FLUoxetine may increase the serum concentration of PARoxetine. PARoxetine may increase the serum concentration of FLUoxetine. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, mental status changes), bleeding, and increased SSRI toxicities when these agents are combined. Monitor therapy

FluPHENAZine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of FluPHENAZine. Monitor therapy

Fosamprenavir: May decrease the serum concentration of PARoxetine. The active metabolite amprenavir is likely responsible for this effect. Monitor therapy

Fosaprepitant: PARoxetine may decrease serum concentrations of the active metabolite(s) of Fosaprepitant. Fosaprepitant may decrease the serum concentration of PARoxetine. Monitor therapy

Galantamine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Galantamine. Monitor therapy

Gefitinib: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Gefitinib. Monitor therapy

Gilteritinib: May diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. Management: Avoid use of this combination if possible. If the combination cannot be avoided, monitor closely for evidence of reduced response to the selective serotonin reuptake inhibitor. Consider therapy modification

Glucosamine: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Haloperidol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Haloperidol. Monitor therapy

Heparin: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Heparin. Management: Decrease the dose of heparin or agents with antiplatelet properties if coadministration is required. Consider therapy modification

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Management: Avoid combination when possible. If used, monitor more closely for evidence of bleeding. Discontinue herbal products with anticoagulant or antiplatelet actions 2 weeks prior to surgical, dental, or invasive procedures. Consider therapy modification

Ibritumomab Tiuxetan: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Monitor therapy

Ibrutinib: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Monitor therapy

Iloperidone: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Iloperidone. Specifically, concentrations of the metabolite P88 may be increased. CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Iloperidone. Specifically, concentrations of the metabolite P95 may be decreased. CYP2D6 Inhibitors (Strong) may increase the serum concentration of Iloperidone. Management: Reduce iloperidone dose by half when administered with a strong CYP2D6 inhibitor and monitor for increased iloperidone toxicities, including QTc interval prolongation and arrhythmias. Consider therapy modification

Indoramin: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Indoramin. Monitor therapy

Inotersen: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Ioflupane I 123: Selective Serotonin Reuptake Inhibitors may diminish the diagnostic effect of Ioflupane I 123. Monitor therapy

Lasmiditan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Levomethadone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Limaprost: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Linezolid: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This could result in serotonin syndrome. Avoid combination

Lofexidine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Lofexidine. Monitor therapy

Lorcaserin (Withdrawn From US Market): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Lumefantrine: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Maprotiline: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Maprotiline. Monitor therapy

Mequitazine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Mequitazine. Avoid combination

Metaxalone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Methadone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Methylene Blue: Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Avoid combination

Metoclopramide: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Metoclopramide. Management: For gastroparesis: reduce metoclopramide dose to 5mg 4 times/day and limit to 20mg/day; nasal spray not recommended. For GERD: reduce metoclopramide dose to 5mg 4 times/day or to 10mg 3 times/day and limit to 30mg/day. Monitor for EPS when combined. Consider therapy modification

Metoprolol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Metoprolol. Monitor therapy

MetyroSINE: May enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Monitor therapy

Mexiletine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Mexiletine. Monitor therapy

Monoamine Oxidase Inhibitors (Antidepressant): Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect of Monoamine Oxidase Inhibitors (Antidepressant). This could result in serotonin syndrome. Avoid combination

Multivitamins/Fluoride (with ADE): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Multivitamins/Minerals (with AE, No Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Nebivolol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Nebivolol. Monitor therapy

Nefazodone: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Nicergoline: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Nicergoline. Specifically, concentrations of the MMDL metabolite may be increased. CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Nicergoline. Specifically, concentrations of the MDL metabolite may be decreased. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): Selective Serotonin Reuptake Inhibitors may enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective). Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective) may diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents (Nonselective): Selective Serotonin Reuptake Inhibitors may enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Nonsteroidal Anti-Inflammatory Agents (Nonselective) may diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. Management: Consider alternatives to NSAIDs. Monitor for evidence of bleeding and diminished antidepressant effects. It is unclear whether COX-2-selective NSAIDs reduce risk. Consider therapy modification

Nonsteroidal Anti-Inflammatory Agents (Topical): May enhance the antiplatelet effect of Selective Serotonin Reuptake Inhibitors. Monitor therapy

Obinutuzumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Monitor therapy

Oliceridine: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors). This could result in serotonin syndrome. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may increase the serum concentration of Oliceridine. Management: Monitor for increased opioid effects (eg, respiratory depression, sedation) and for serotonin syndrome/serotonin toxicity when these agents are combined. Monitor therapy

Olmutinib: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Olmutinib. Monitor therapy

Omega-3 Fatty Acids: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Ondansetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Opioid Agonists: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Exceptions: Alfentanil; Benzhydrocodone; Buprenorphine; Butorphanol; Codeine; Dihydrocodeine; FentaNYL; HYDROcodone; Levomethadone; Meperidine; Methadone; Oliceridine; OxyCODONE; SUFentanil; TraMADol. Monitor therapy

Opioid Agonists (metabolized by CYP3A4 and CYP2D6): May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors). This could result in serotonin syndrome. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may diminish the therapeutic effect of Opioid Agonists (metabolized by CYP3A4 and CYP2D6). Management: Monitor for decreased therapeutic response (eg, analgesia) and opioid withdrawal when coadministered with SSRIs that strongly inhibit CYP2D6. Additionally, monitor for serotonin syndrome/serotonin toxicity if these drugs are combined. Exceptions: Oliceridine. Monitor therapy

Opioid Agonists (metabolized by CYP3A4): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Exceptions: Levomethadone; Methadone. Monitor therapy

Oxitriptan: Serotonergic Agents (High Risk) may enhance the serotonergic effect of Oxitriptan. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Ozanimod: May enhance the adverse/toxic effect of Serotonergic Agents (High Risk). Management: Concomitant use of ozanimod with serotonergic agents is not recommended. If combined, monitor patients closely for the development of hypertension, including hypertensive crises. Consider therapy modification

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Specifically, the risk of bleeding may be increased by concurrent use of these agents. Monitor therapy

Pentoxifylline: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Perhexiline: PARoxetine may increase the serum concentration of Perhexiline. Perhexiline may increase the serum concentration of PARoxetine. Monitor therapy

Perphenazine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Perphenazine. Monitor therapy

Pimozide: Selective Serotonin Reuptake Inhibitors may enhance the adverse/toxic effect of Pimozide. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs as appropriate. Avoid combination

Pitolisant: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Pitolisant. Management: Reduce the pitolisant dose by 50% if a strong CYP2D6 inhibitor is initiated. For patients receiving strong CYP2D6 inhibitors, initiate pitolisant at 8.9 mg once daily and increase after 7 days to a maximum of 17.8 mg once daily. Consider therapy modification

Pravastatin: May enhance the adverse/toxic effect of PARoxetine. Specifically, blood glucose elevations may occur with the combination. Monitor therapy

Primaquine: CYP2D6 Inhibitors (Strong) may diminish the therapeutic effect of Primaquine. CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Primaquine. Monitor therapy

Propafenone: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Propafenone. Monitor therapy

Propranolol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Propranolol. Monitor therapy

Prostacyclin Analogues: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Ramosetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Rasagiline: Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect of Rasagiline. This could result in serotonin syndrome. Avoid combination

RisperiDONE: CYP2D6 Inhibitors (Strong) may increase the serum concentration of RisperiDONE. Management: Careful monitoring for risperidone toxicities and possible dose adjustment are recommended when combined with strong CYP2D6 inhibitors. See full interaction monograph for details. Consider therapy modification

Rivaroxaban: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Rivaroxaban. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Monitor therapy

Safinamide: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This could result in serotonin syndrome. Management: Use the lowest effective dose of SSRIs in patients treated with safinamide and monitor for signs and symptoms of serotonin syndrome/serotonin toxicity. Consider therapy modification

Salicylates: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the antiplatelet effect of other Selective Serotonin Reuptake Inhibitors. Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect of other Selective Serotonin Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, mental status changes) when these agents are combined. In addition, monitor for signs and symptoms of bleeding. Exceptions: Citalopram; Dapoxetine; Vortioxetine. Monitor therapy

Selegiline: Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect of Selegiline. This could result in serotonin syndrome. Avoid combination

Selumetinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Serotonergic Agents (High Risk, Miscellaneous): May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Serotonergic Non-Opioid CNS Depressants: Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect of Serotonergic Non-Opioid CNS Depressants. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Serotonergic Opioids (High Risk): May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) if these agents are combined. Exceptions: TraMADol. Monitor therapy

Serotonin 5-HT1D Receptor Agonists (Triptans): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Exceptions: Almotriptan; Eletriptan. Monitor therapy

Serotonin/Norepinephrine Reuptake Inhibitors: Selective Serotonin Reuptake Inhibitors may enhance the antiplatelet effect of Serotonin/Norepinephrine Reuptake Inhibitors. Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, mental status changes) when these agents are combined. In addition, monitor for signs and symptoms of bleeding. Exceptions: DULoxetine. Monitor therapy

St John's Wort: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. St John's Wort may decrease the serum concentration of Serotonergic Agents (High Risk). Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Syrian Rue: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Tamoxifen: CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Tamoxifen. Specifically, strong CYP2D6 inhibitors may decrease the metabolic formation of highly potent active metabolites. Management: Avoid concurrent use of strong CYP2D6 inhibitors with tamoxifen when possible, as the combination may be associated with a reduced clinical effectiveness of tamoxifen. Consider therapy modification

Tamsulosin: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Tamsulosin. Monitor therapy

Tetrabenazine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Tetrabenazine. Specifically, concentrations of the active alpha- and beta-dihydrotetrabenazine metabolites may be increased. Management: Limit the tetrabenazine dose to 50 mg per day (25 mg per single dose) in patients taking strong CYP2D6 inhibitors. Consider therapy modification

Thiazide and Thiazide-Like Diuretics: Selective Serotonin Reuptake Inhibitors may enhance the hyponatremic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Thioridazine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Thioridazine. Avoid combination

Thrombolytic Agents: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents. Monitor therapy

Thyroid Products: Selective Serotonin Reuptake Inhibitors may diminish the therapeutic effect of Thyroid Products. Thyroid product dose requirements may be increased. Monitor therapy

Timolol (Ophthalmic): CYP2D6 Inhibitors (Strong) may increase the serum concentration of Timolol (Ophthalmic). Monitor therapy

Timolol (Systemic): CYP2D6 Inhibitors (Strong) may increase the serum concentration of Timolol (Systemic). Monitor therapy

Tipranavir: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Tolterodine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Tolterodine. Monitor therapy

TraMADol: Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may enhance the adverse/toxic effect of TraMADol. Specifically, the risk for serotonin syndrome/serotonin toxicity and seizures may be increased. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may diminish the therapeutic effect of TraMADol. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes), seizures, and decreased tramadol efficacy when these agents are combined. Monitor therapy

Tricyclic Antidepressants: PARoxetine may enhance the serotonergic effect of Tricyclic Antidepressants. PARoxetine may increase the serum concentration of Tricyclic Antidepressants. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and increased TCA concentrations/effects if these agents are combined. Consider therapy modification

Tropisetron: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Tropisetron. Monitor therapy

Urokinase: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Urokinase. Avoid combination

Valbenazine: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Valbenazine. Management: Reduce valbenazine dose to 40 mg once daily when combined with a strong CYP2D6 inhibitor. Monitor for increased valbenazine effects/toxicities. Consider therapy modification

Vitamin E (Systemic): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Selective Serotonin Reuptake Inhibitors may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Vortioxetine: Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may enhance the antiplatelet effect of Vortioxetine. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may enhance the serotonergic effect of Vortioxetine. This could result in serotonin syndrome. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may increase the serum concentration of Vortioxetine. Management: Consider alternatives to this drug combination. If combined, reduce the vortioxetine dose by half and monitor for signs and symptoms of bleeding and serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, autonomic instability). Consider therapy modification

Zanubrutinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Zuclopenthixol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Zuclopenthixol. Monitor therapy

Adverse Reactions

Incidence varies by dose and indication. Adverse reactions reported as a composite of all indications.

>10%:

Dermatologic: Diaphoresis (5% to 14%)

Endocrine & metabolic: Decreased libido (3% to 15% [placebo: 0% to 5%])

Gastrointestinal: Constipation (2% to 16%), decreased appetite (1% to 12%), diarrhea (6% to 18%), dyspepsia (2% to 13%), nausea (17% to 26%), xerostomia (3% to 18%)

Genitourinary: Ejaculatory disorder (13% to 28% [placebo: 0% to 2%])

Nervous system: Dizziness (6% to 14%), drowsiness (3% to 24%; less frequent in children and adolescents) (Safer 2006), headache (6% to 27%), insomnia (7% to 24%)

Neuromuscular & skeletal: Asthenia (12% to 22%), tremor (4% to 11%)

1% to 10%:

Cardiovascular: Chest pain (3%), hypertension (≥1%), palpitations (2% to 3%), tachycardia (≥1%), vasodilation (2% to 4%)

Dermatologic: Pruritus (≥1%), skin rash (2% to 3%)

Endocrine & metabolic: Weight gain (≥1%)

Gastrointestinal: Abdominal pain (4% to 7%), dysgeusia (2%), flatulence (4% to 6%), increased appetite (2% to 4%), nausea and vomiting (4%), vomiting (2% to 3%; more frequent in children [two- to threefold] and adolescents) (Safer 2006)

Genitourinary: Difficulty in micturition (3%), dysmenorrhea (5%), female genital tract disease (2% to 10% [placebo: 0% to 1%]), impotence (2% to 10% [placebo: 0% to 3%]), male genital disease (10% [placebo: 0%]), orgasm disturbance (2% to 10% [placebo: 0% to 1%]), urinary frequency (2% to 3%), urinary tract infection (2%), urination disorder (3%)

Infection: Infection (5% to 6%)

Nervous system: Abnormal dreams (3% to 4%), agitation (3% to 5%), amnesia (2%), anxiety (2% to 5%), chills (2%), confusion (1%), depersonalization (3%), drugged feeling (2%), emotional lability (≥1%), fatigue (5%), lack of concentration (3% to 4%), manic reaction (1% to 2%), myasthenia (1%), myoclonus (2% to 3%), nervousness (4% to 9%), paresthesia (4%), vertigo (≥1%), yawning (2% to 5%)

Neuromuscular & skeletal: Arthralgia (≥1%), back pain (3% to 5%), myalgia (2% to 5%), myopathy (2%)

Ophthalmic: Blurred vision (4%), visual disturbance (2% to 5%)

Otic: Tinnitus (≥1%)

Respiratory: Pharyngeal edema (2%), pharyngitis (4%), respiratory system disorder (7%), rhinitis (3%), sinusitis (≤8%)

Miscellaneous: Trauma (3% to 6%)

<1%:

Cardiovascular: Acute myocardial infarction, angina pectoris, bradycardia, bundle branch block, cardiac failure, cerebral ischemia, cerebrovascular accident, eclampsia, hypotension, ischemic heart disease, low cardiac output, phlebitis, pulmonary embolism, syncope, thrombophlebitis, thrombosis, torsades de pointes, vasculitis (Welsh 2006; Margolese 2001), ventricular arrhythmia

Dermatologic: Cellulitis, ecchymoses, erythema of skin, exfoliative dermatitis, fungal dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis (Ahmed 2008)

Endocrine & metabolic: Dehydration, diabetes mellitus, goiter, hypercholesterolemia, hyperglycemia, hyperthyroidism, hypoglycemia, hypothyroidism, increased lactate dehydrogenase, ketosis

Gastrointestinal: Aphthous stomatitis, bloody diarrhea, cholelithiasis, colitis, dysphagia, esophageal achalasia, fecal impaction, gastroenteritis, hematemesis, intestinal obstruction, pancreatitis, peptic ulcer, peritonitis

Hematologic & oncologic: Anemia, hematoma, hemorrhage, hypergammaglobulinemia, lymphadenopathy, pancytopenia, prolonged bleeding time, quantitative disorders of platelets

Hepatic: Abnormal hepatic function tests, hepatic necrosis, hepatitis (Colakoglu 2005), hyperbilirubinemia, increased serum alkaline phosphatase, jaundice

Hypersensitivity: Anaphylaxis, angioedema (Mithani 1996), hypersensitivity reaction (Mera 2006), tongue edema (Mithani 1996)

Infection: Sepsis

Nervous system: Adrenergic syndrome, aphasia, behavioral problems, bulimia nervosa, delirium, drug dependence, dystonia, extrapyramidal reaction, Guillain-Barre syndrome, hallucination, meningitis, migraine, neuroleptic malignant syndrome (with drug interactions) (Tanii 2006; Uguz 2013), neuropathy, seizure, serotonin syndrome (Hudd 2020; Velez 2004), status epilepticus, suicidal ideation (Hammad 2006), suicidal tendencies (Hammad 2006)

Neuromuscular & skeletal: Akinesia, dyskinesia, increased creatine phosphokinase in blood specimen, myelitis, osteoarthritis, osteoporosis, tetany

Ophthalmic: Cataract

Otic: Deafness

Renal: Acute renal failure, increased blood urea nitrogen

Respiratory: Asthma, bronchitis, dyspnea, hemoptysis, pneumonia, pulmonary edema, pulmonary emphysema, pulmonary fibrosis, pulmonary hypertension

Postmarketing:

Cardiovascular: Atrial fibrillation, atrioventricular nodal arrhythmia (Kopp 2001), edema (Uguz 2014), orthostatic hypotension (Andrews 1998), ventricular fibrillation (Lee 2018), ventricular tachycardia

Dermatologic: Acute generalized exanthematous pustulosis (Mameli 2013), erythema multiforme (Rodriguez-Pazos 2011), hyperhidrosis, urticaria (Welsh 2006)

Endocrine & metabolic: Galactorrhea not associated with childbirth (Gonzales 2000; Morrison 2001), hyperprolactinemia (Evrensel 2016), hyponatremia (Gandhi 2017), porphyria, SIADH (Gandhi 2017), uncontrolled diabetes mellitus

Gastrointestinal: Acute pancreatitis, hemorrhagic pancreatitis, stomatitis (angular) (Verma 2012)

Genitourinary: Priapism (Ahmad 1995), urinary incontinence (Votolato 2000), urinary retention

Hematologic & oncologic: Abnormal erythrocytes, agranulocytosis, aplastic anemia, bone marrow aplasia, eosinophilia (Yasui-Furukori 2012), hemolytic anemia, Henoch-Schonlein purpura, immune thrombocytopenia, thrombocytopenia (Ono 2013)

Hepatic: Hepatic failure, hepatotoxicity (Azaz-Livshits 2002; Benbow 1997)

Hypersensitivity: Nonimmune anaphylaxis

Nervous system: Aggressive behavior (Nishida 2008; Sharma 2016), akathisia (Baldassano 1996), depression, disorientation (Wakeno 2007), homicidal ideation (Moore 2010), hyperactive behavior (agitation, hyperactivation, hyperkinesis, restlessness; more frequent in children [two- to threefold] and adolescents) (Safer 2006), hypertonia, malaise, restless leg syndrome (Rottach 2008; Sanz-Fuentenebro 1996), restlessness (Naslund 2017), tremor (Lai 2005), trismus, withdrawal syndrome (Fava 2015)

Ophthalmic: Acute angle-closure glaucoma (Eke 1997; Kirwan 1997; Lewis 1997), mydriasis (dose-dependent) (Nielsen 2010), optic neuritis

Respiratory: Hypersensitivity pneumonitis (Maia 2015), laryngismus

ALERT: U.S. Boxed Warning

Suicidal thoughts and behaviors:

Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening and for emergence of suicidal thoughts and behaviors. Paroxetine is not approved for use in pediatric patients.

Warnings/Precautions

Major psychiatric warnings:

• Suicidal thoughts/behavior: [US Boxed Warning]: Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening and for emergence of suicidal thoughts and behaviors. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥65 years of age. Closely monitor patients for clinical worsening, suicidality, or unusual changes in behavior, particularly during the initial 1 to 2 months of therapy or during periods of dosage adjustments (increases or decreases); the patient's family or caregiver should be instructed to closely observe the patient and communicate condition with health care provider. A medication guide concerning the use of antidepressants should be dispensed with each prescription. Paroxetine is not FDA approved for use in children.

- The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy.

- Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their healthcare provider if any of these symptoms or worsening depression or psychosis occur.

Concerns related to adverse effects:

• Akathisia: Inability to remain still due to feelings of agitation or restlessness has been observed with paroxetine and other selective serotonin reuptake inhibitors (SSRIs). Usually occurs within the first few weeks of therapy.

• Anticholinergic effects: Has low potential for sedation and anticholinergic effects relative to cyclic antidepressants; however, among the SSRI class these effects are relatively higher.

• Bleeding risk: May impair platelet aggregation resulting in increased risk of bleeding events, particularly if used concomitantly with aspirin, nonsteroidal anti-inflammatory drugs, warfarin or other anticoagulants. Bleeding related to SSRI use has been reported to range from relatively minor bruising and epistaxis to life-threatening hemorrhage.

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).

• Fractures: Bone fractures have been associated with antidepressant treatment. Consider the possibility of a fragility fracture if an antidepressant-treated patient presents with unexplained bone pain, point tenderness, swelling, or bruising (Rabenda 2013; Rizzoli, 2012).

• Ocular effects: May cause mild pupillary dilation, which can lead to an episode of narrow-angle glaucoma in susceptible individuals. Consider evaluating patients who have not had an iridectomy for narrow-angle glaucoma risk factors.

• Serotonin syndrome: Potentially life-threatening serotonin syndrome (SS) has occurred with serotonergic agents (eg, SSRIs, serotonin-norepinephrine reuptake inhibitors [SNRIs]), particularly when used in combination with other serotonergic agents (eg, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, St John's wort, tryptophan) or agents that impair metabolism of serotonin (eg, monoamine oxidase [MAO] inhibitors intended to treat psychiatric disorders, other MAO inhibitors [ie, linezolid and intravenous methylene blue]). Monitor patients closely for signs of SS such as mental status changes (eg, agitation, hallucinations, delirium, coma); autonomic instability (eg, tachycardia, labile blood pressure, diaphoresis); neuromuscular changes (eg, tremor, rigidity, myoclonus); GI symptoms (eg, nausea, vomiting, diarrhea); and/or seizures. Discontinue treatment (and any concomitant serotonergic agent) immediately if signs/symptoms arise.

• Sexual dysfunction: May cause or exacerbate sexual dysfunction.

• Syndrome of inappropriate antidiuretic hormone secretion and hyponatremia: SSRIs and SNRIs have been associated with the development of syndrome of inappropriate antidiuretic hormone secretion (SIADH); hyponatremia has been reported rarely (including severe cases with serum sodium <110 mmol/L), predominately in the elderly. Volume depletion and/or concurrent use of diuretics likely increases risk.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with cardiovascular disease; paroxetine has not been systemically evaluated in patients with a recent history of myocardial infarction or unstable heart disease.

• Hepatic impairment: Use with caution in patients with hepatic impairment; clearance is decreased and plasma concentrations are increased; a lower dosage may be needed. However, selective serotonin reuptake inhibitors such as paroxetine are considered the safest antidepressants to use in chronic liver disease because of their relative lack of side effects and high therapeutic index (Mullish 2014).

• Mania/hypomania: May precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Combination therapy with an antidepressant and a mood stabilizer may be effective for acute treatment of bipolar major depressive episodes, but should be avoided in acute mania or mixed episodes, as well as maintenance treatment in bipolar disorder due to the mood-destabilizing effects of antidepressants (CANMAT [Yatham 2018]; WFSBP [Grunze 2018]). Patients presenting with depressive symptoms should be screened for bipolar disorder. Paroxetine is not FDA approved for the treatment of bipolar depression.

• Renal impairment: Use with caution in patients with renal impairment; clearance is decreased and plasma concentrations are increased; a lower dosage may be needed.

• Seizure disorder: Use with caution in patients with a previous seizure disorder or condition predisposing to seizures such as brain damage or alcoholism.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Brisdelle: Brisdelle contains a lower dose than what is required for the treatment of psychiatric conditions. Patients who require paroxetine for the treatment of psychiatric conditions should discontinue Brisdelle and begin treatment with a paroxetine-containing medication which provides an adequate dosage.

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley, 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.

Other warnings/precautions:

• Discontinuation syndrome: Abrupt discontinuation or interruption of antidepressant therapy has been associated with a discontinuation syndrome. Symptoms arising may vary with antidepressant however commonly include nausea, vomiting, diarrhea, headaches, lightheadedness, dizziness, diminished appetite, sweating, chills, tremors, paresthesias, fatigue, somnolence, and sleep disturbances (eg, vivid dreams, insomnia). Less common symptoms include electric shock-like sensations, cardiac arrhythmias (more common with tricyclic antidepressants), myalgias, parkinsonism, arthralgias, and balance difficulties. Psychological symptoms may also emerge such as agitation, anxiety, akathisia, panic attacks, irritability, aggressiveness, worsening of mood, dysphoria, mood lability, hyperactivity, mania/hypomania, depersonalization, decreased concentration, slowed thinking, confusion, and memory or concentration difficulties. Greater risks for developing a discontinuation syndrome have been associated with antidepressants with shorter half-lives, longer durations of treatment, and abrupt discontinuation. For antidepressants of short or intermediate half-lives, symptoms may emerge within 2 to 5 days after treatment discontinuation and last 7 to 14 days (APA 2010; Fava 2006; Haddad 2001; Shelton 2001; Warner 2006).

• Electroconvulsive therapy: May increase the risks associated with electroconvulsive therapy; consider discontinuing, when possible, prior to ECT treatment.

Monitoring Parameters

Liver and renal function tests (baseline; as clinically indicated); serum sodium in at-risk populations (as clinically indicated); CBC (as clinically indicated); evaluate for suicidal ideation (baseline and with dose changes).

Pregnancy Risk Factor

D/X (product specific)

Pregnancy Considerations

Paroxetine crosses the placenta (Hendrick 2003). An increased risk of teratogenic effects, including cardiovascular defects, may be associated with maternal use of paroxetine or other SSRIs; however, available information is conflicting. Nonteratogenic effects in the newborn following SSRI/SNRI exposure late in the third trimester include respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypo- or hypertonia, hyper-reflexia, jitteriness, irritability, constant crying, and tremor. Symptoms may be due to the toxicity of the SSRIs/SNRIs or a discontinuation syndrome and may be consistent with serotonin syndrome associated with SSRI treatment. Persistent pulmonary hypertension of the newborn (PPHN) has also been reported with SSRI exposure. The long-term effects of in utero SSRI exposure on infant development and behavior are not known.

Due to pregnancy-induced physiologic changes, some pharmacokinetic parameters of paroxetine may be altered. The maternal CYP2D6 genotype also influences paroxetine plasma concentrations during pregnancy (Hostetter 2000; Ververs 2009).

The manufacturer suggests discontinuing paroxetine or switching to another antidepressant unless the benefits of therapy justify continuing treatment during pregnancy; consider other treatment options for women who are planning to become pregnant. The ACOG recommends that therapy with SSRIs or SNRIs during pregnancy be individualized; treatment of depression during pregnancy should incorporate the clinical expertise of the mental health clinician, obstetrician, primary health care provider, and pediatrician. The ACOG also recommends that therapy with paroxetine be avoided during pregnancy if possible and that fetuses exposed in early pregnancy be assessed with a fetal echocardiography (ACOG 2008). Other guidelines note that treatment with paroxetine should not be initiated in pregnant women (Bauer 2013). According to the American Psychiatric Association (APA), the risks of medication treatment should be weighed against other treatment options and untreated depression. The use of paroxetine is not recommended as first line therapy during pregnancy. For women who discontinue antidepressant medications during pregnancy and who may be at high risk for postpartum depression, the medications can be restarted following delivery (APA 2010). Treatment algorithms have been developed by the ACOG and the APA for the management of depression in women prior to conception and during pregnancy (Yonkers 2009).

Menopausal vasomotor symptoms do not occur during pregnancy; therefore, the use of paroxetine for the treatment of menopausal vasomotor symptoms is contraindicated in pregnant women.

Pregnant women exposed to antidepressants during pregnancy are encouraged to enroll in the National Pregnancy Registry for Antidepressants (NPRAD). Women 18 to 45 years of age or their health care providers may contact the registry by calling 844-405-6185. Enrollment should be done as early in pregnancy as possible.

Patient Education

What is this drug used for?

• It is used to treat low mood (depression).

• It is used to treat obsessive-compulsive problems.

• It is used to treat panic attacks.

• It is used to treat anxiety.

• It is used to treat post-traumatic stress.

• It is used to treat mood problems caused by monthly periods.

• It is used to treat hot flashes caused by menopause.

• It may be given for other reasons.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Fatigue

• Anxiety

• Headache

• Nausea

• Vomiting

• Constipation

• Abdominal pain

• Passing gas

• Back pain

• Anxiety

• Diarrhea

• Passing gas

• Dry mouth

• Back pain

• Trouble sleeping

• Loss of strength and energy

• Tremors

• Lack of appetite

• Yawning

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Depression like thoughts of suicide, anxiety, emotional instability, agitation, irritability, panic attacks, mood changes, behavioral changes, or confusion

• Serotonin syndrome like dizziness, severe headache, agitation, sensing things that seem real but are not, fast heartbeat, abnormal heartbeat, flushing, tremors, sweating a lot, change in balance, severe nausea, severe diarrhea

• Low sodium like headache, trouble focusing, trouble with memory, confusion, weakness, seizures, or change in balance

• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding

• Seizures

• Restlessness

• Vision changes

• Eye pain

• Severe eye irritation

• Confusion

• Change in balance

• Agitation

• Twitching

• Sweating

• Stiff muscles

• Abnormal heartbeat

• Sensing things that seem real but are not

• Severe dizziness

• Passing out

• Bone pain

• Excessive weight loss

• Burning or numbness feeling

• Sexual dysfunction

• Erection that lasts more than 4 hours

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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