Contact Us    Contact Us     |     Feedback
MOBILE VIEW  | 

PAROXETINE

Export To Excel

Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Paroxetine is a selective serotonin reuptake inhibitor (SSRI) which is not structurally related to the other selective serotonin reuptake inhibitors, tricyclic or tetracyclic antidepressants.

Specific Substances

    1) Paroxetine hydrochloride
    2) (-)trans-4R-(4'-fluorophenyl)-3S-[(3',4'-methylenedioxyphenoxy)methyl] piperidine hydrochloride hemihydrate
    3) Molecular Formula: C19-H20-FNO3.HCl.1/2H20
    4) CAS 78246-49-8 (paroxetine hydrochloride)
    1.2.1) MOLECULAR FORMULA
    1) PAROXETINE HYDROCHLORIDE: C19H20FNO3 x HCl x 1/2H2O
    2) PAROXETINE MESYLATE: C19H20FNO3 x CH3SO3H

Available Forms Sources

    A) FORMS
    1) Paroxetine hydrochloride is available as 10 mg, 20 mg, 30 mg, and 40 mg tablets and 12.5 mg, 35 mg, and 37.5 mg oral extended-release tablets, and 10 mg/5 mL oral suspension (Prod Info PAXIL(R) oral tablets, oral suspension, 2014; Prod Info PAXIL CR(R) controlled-release oral tablets, 2010a). Paroxetine mesylate is available as 10 mg, 20 mg, 30 mg, and 40 mg tablets and 7.5 mg oral capsules (Prod Info BRISDELLE(TM) oral capsules, 2013; Prod Info PEXEVA(R) oral tablets, 2014).
    B) USES
    1) Paroxetine hydrochloride is used to treat major depression, obsessive compulsive disorder, panic disorder, generalized anxiety disorder, posttraumatic stress disorder, social phobia, and premenstrual dysphoric disorder (Prod Info PAXIL(R) oral tablets, oral suspension, 2014; Prod Info PAXIL CR(R) controlled-release oral tablets, 2010a).
    2) Paroxetine mesylate is used to treat major depression, obsessive-compulsive disorder, panic disorder, generalized anxiety disorder and moderate to severe abnormal vasomotor function associated with menopause (Prod Info BRISDELLE(TM) oral capsules, 2013; Prod Info PEXEVA(R) oral tablets, 2014).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: paroxetine is a selective serotonin reuptake inhibitor (SSRI) used commonly to treat major depression, obsessive compulsive disorder, panic disorder, and social anxiety disorder. It has also been used off-label to treat adult night terrors.
    B) PHARMACOLOGY: Paroxetine is an SSRI that is NOT structurally related to other SSRIs, tricyclic antidepressants, or tetracyclic antidepressants. It inhibits reuptake of serotonin in presynaptic nerve terminals in the central nervous system. It has weak antimuscarinic effects but no significant effect on norepinephrine or dopamine reuptake and no significant peripheral alpha-adrenergic agonism.
    C) TOXICOLOGY: Toxic effects of paroxetine occur as an extension of its therapeutic effects causing increased serotonin in the CNS, leading to serotonergic toxicity and serotonin syndrome (more likely when combined with other serotonergic agents). Paroxetine may inhibit serotonin uptake into platelets leading to abnormalities in platelet aggregation, which is a serotonin-mediated process.
    D) EPIDEMIOLOGY: Paroxetine overdoses are common; however, severe toxicity from isolated ingestion is relatively rare. A majority of patients will have only mild symptoms.
    E) WITH THERAPEUTIC USE
    1) COMMON: Mild adverse effects with therapeutic paroxetine use include fatigue, difficulty concentrating, insomnia and sleep disturbances, nausea, vomiting, diarrhea, constipation, anorexia, weight loss, blurred vision, orthostatic dizziness, a mild decrease in systolic blood pressure, and minimal QRS prolongation (by average of 0.004 seconds compared to baseline).
    2) LESS FREQUENT: Less frequent adverse effects include spontaneous ecchymosis, syncope, premature ventricular contractions (PVCs), tremor, headache, extrapyramidal reactions, akathisia, orolingual movements, and bruxism.
    3) RARE: Rare adverse effects of therapeutic use include acute and angle closure glaucoma (thought to be mediated via direct effect on the iris or ciliary body muscle), hyponatremia due to SIADH, hepatotoxicity with jaundice, priapism, and upper gastrointestinal bleeding.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Most patients ingesting single-agent paroxetine in overdose will have only mild toxicity. Signs and symptoms after overdose commonly include nausea, mild CNS depression, vomiting, tremors, sinus tachycardia, and anxiety.
    2) SEVERE TOXICITY: In cases of severe toxicity, patients who overdose on paroxetine may rarely develop serotonin syndrome (more common in combination with other serotonergic agents although it has been described in one case with paroxetine only), characterized by altered mental status, autonomic nervous systemic dysfunction including hyperthermia and abnormal neuromuscular activity with marked hyperreflexia and clonus greater in the lower extremities than the upper extremities. Other rare severe toxicity includes hyponatremia due to SIADH, marked altered mental status with coma, and rhabdomyolysis. QT prolongation has also been reported in 2 patients after paroxetine overdose.
    0.2.20) REPRODUCTIVE
    A) Brisdelle(TM) is contraindicated during pregnancy. Discontinue therapy with Paxil(R) or change to another antidepressant if a woman becomes pregnant while taking paroxetine, unless the benefits of the drug to the mother justify continuing treatment. For women intending to become pregnant, or those already in their first trimester, initiate paroxetine only after other treatment options have been given thorough consideration. Human studies of paroxetine use during pregnancy showed an increased risk of major congenital and cardiac malformations and an increased risk of pulmonary hypertension of the newborn (PPHN), especially with use during the first trimester of pregnancy. An increased risk for social-behavioral abnormalities at 2 to 6 years of age was reported in children exposed to SSRIs or serotonin–norepinephrine reuptake inhibitors (SNRIs) in utero who developed neonatal abstinence syndrome (NAS) at birth. Paroxetine is excreted in human breast milk, although there have been no observable adverse effects reported in nursing infants.

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) Paroxetine levels are not widely available or clinically useful.
    C) Serum electrolytes, renal function, and creatine kinase (CK) should be evaluated in patients with evidence of toxicity.
    D) Patients with toxicity should receive an EKG and cardiac monitoring.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Patients who develop severe toxicity with SEROTONIN SYNDROME should be managed primarily with benzodiazepines to control agitation and muscle activity. Patients who become hyperthermic should be externally cooled with evaporative cooling and fanning. Patients whose hyperthermia does not resolve with benzodiazepines and external cooling should be intubated and paralyzed with non-depolarizing agents. Cyproheptadine, a non-specific 5-HT antagonist, has been shown to block development of serotonin syndrome in animals and can be used in patients with severe serotonin syndrome (although there are no controlled human trials to show efficacy). Bromocriptine and dantrolene are NOT recommended for treatment of serotonin syndrome as their use may lead to worse outcomes. HYPOTENSION should be treated initially with normal saline boluses. In patients with persistent hypotension, a direct-acting vasopressor such as norepinephrine should be used as a next agent. Dopamine carries a theoretical risk of worsened serotonin syndrome and should NOT be used as a first-line agent.
    C) DECONTAMINATION
    1) PREHOSPITAL: If the ingestion has occurred within 1 hour, consider administering charcoal (50 to 100 g in adults; 25 to 50 g in children). However, charcoal should be avoided in any patient with altered mental status and concern for inability to protect their airway.
    2) HOSPITAL: If the ingestion has occurred within 1 hour, consider administering charcoal (50 to 100 g in adults; 25 to 50 g in children). However, charcoal should be avoided in any patient with altered mental status and concern for inability to protect their airway.
    D) AIRWAY MANAGEMENT
    1) Rarely, patients with marked CNS depression may need intubation for respiratory support.
    E) ANTIDOTE
    1) There is no specific antidote for treatment of paroxetine overdose.
    F) HYPOTENSIVE EPISODE
    1) IV 0.9% NaCl 10 to 20 ml/kg, add norepinephrine if hypotension persists.
    G) SEIZURE
    1) Administer IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    H) SEROTONIN SYNDROME
    1) Initial treatment should be intravenous benzodiazepines to control agitation and muscle activity. Titrate dose to achieve mild sedation. Treat hyperthermia by controlling agitation and evaporative cooling with water to the skin and fans. Ice water immersion may be necessary in severe cases. Patients with severe muscle activity and hyperthermia may require aggressive sedation, neuromuscular paralysis with a non-depolarizing agent, and endotracheal intubation with mechanical ventilation. Cyproheptadine, a nonspecific 5-HT antagonist, may be considered for treatment of serotonin syndrome if not responsive to benzodiazepines and cooling measures. Animal studies have shown an ability to reverse serotonin syndrome; however, there have been no human controlled trials showing efficacy. Cyproheptadine is only available in oral formulation. Adult dosing is 12 mg once followed by 2 mg every 2 hours if symptoms persist up to a maximum of 32 mg in 24 hours. Once control is achieved, a maintenance dose of 8 mg should be given every 6 hours. Pediatric dosing is 0.25 mg/kg/day divided every 6 hours.
    I) ENHANCED ELIMINATION
    1) Hemodialysis would NOT be expected to be useful in paroxetine overdose due to the large volume of distribution and high degree of protein binding of the drug.
    J) PATIENT DISPOSITION
    1) HOME CRITERIA: Children and adults with mild symptoms (eg, vomiting, mydriasis, diaphoresis, mild somnolence) following an inadvertent ingestion of up to 100 mg paroxetine can be managed at home with instructions to call the poison center, if symptoms develop. For patients already on paroxetine, those with inadvertent ingestions of up to 5 times their own single therapeutic dose can be observed at home with instructions to call the poison center back, if symptoms develop.
    2) OBSERVATION CRITERIA: Any patient with an intentional ingestion or who develops more than mild symptoms should be sent to a healthcare facility for evaluation and treatment. For paroxetine naive patients with ingestion of more than 100 mg paroxetine and for patients on chronic paroxetine therapy with an ingestion of more than 5 times that patient's single therapeutic dose, prompt referral to a healthcare facility is necessary for evaluation and treatment. Patients should be observed for 6 to 8 hours for regular-release and 12 to 18 hours for controlled-release formulations (Tmax at therapeutic doses is 6 to 10 hours).
    3) ADMISSION CRITERIA: Patients who develop clinical signs and symptoms of paroxetine toxicity, such as tachycardia or altered mental status, should be admitted to the hospital. Patients who develop evidence of severe toxicity with signs of serotonin syndrome may need to be admitted to an ICU setting.
    4) CONSULT CRITERIA: Consult a medical toxicologist or poison center for any patient with severe toxicity, suspected serotonin syndrome, or in whom the diagnosis is unclear.
    K) PITFALLS
    1) The possibility of multidrug involvement should be considered. Patients ingesting controlled release paroxetine may have delayed onset and prolonged duration of toxic effects.
    L) DIFFERENTIAL DIAGNOSIS
    1) Severe toxicity with serotonin syndrome may appear similar to neuroleptic malignant syndrome, sympathomimetic toxicity, sedative-hypnotic withdrawal, alcohol withdrawal, anticholinergic toxicity, malignant hyperthermia, or sepsis.
    M) PHARMACOKINETICS
    1) Paroxetine is absorbed slowly but is highly bioavailable. Regular-release reaches peak absorption within 5.2 to 6.4 hours, while controlled-release reaches peak absorption within 6 to 10 hours. The volume of distribution is large (12 to 16 L/kg) and paroxetine is 95% protein bound. The elimination half-life is 12 to 21 hours; this can be prolonged with higher doses, repeat dosing, in elderly patients (10 to 44 hours), in those with renal insufficiency (11 to 55 hours), or with cirrhosis (17 to 312 hours). Paroxetine undergoes extensive first-pass metabolism. It undergoes hepatic metabolism via CYP2D6, oxidation, methylation, glucuronidation, and sulfation. Tmax for immediate release formulations is 6.4 hours and for extended release 6 to 10 hours.

Range Of Toxicity

    A) TOXICITY: In a series of 35 patients, ingestion of 10 to 1000 mg resulted in no toxicity. In 16 children under the age of 5 years, overdoses between 10 to 120 mg resulted in no symptoms. Overdoses between 100 to 800 mg in adolescents age 12 to 17 years had no symptoms in most cases. In 2 cases, an overdose of 3600 mg and of 180 mg, paroxetine alone resulted in serotonin syndrome. In one case of overdose in an elderly patient, ingestion of 360 mg resulted in profuse vomiting and hyponatremia with SIADH. The largest reported overdose ingestion survived and recovered from is 2000 mg.
    B) THERAPEUTIC DOSE: ADULTS: For paroxetine hydrochloride, the adult dose for immediate-release formulation is 10 to 60 mg/day. For controlled-release the dose is 12.5 to 75 mg/day. For paroxetine mesylate, the adult dose is 10 to 60 mg/day. There is no specific data available on pediatric dosing; safety and efficacy have not been established in pediatric patients. PEDIATRIC: There is no specific data available on pediatric dosing; safety and efficacy have not been established in pediatric patients.

Clinical Effects

Summary Of Exposure

    A) USES: paroxetine is a selective serotonin reuptake inhibitor (SSRI) used commonly to treat major depression, obsessive compulsive disorder, panic disorder, and social anxiety disorder. It has also been used off-label to treat adult night terrors.
    B) PHARMACOLOGY: Paroxetine is an SSRI that is NOT structurally related to other SSRIs, tricyclic antidepressants, or tetracyclic antidepressants. It inhibits reuptake of serotonin in presynaptic nerve terminals in the central nervous system. It has weak antimuscarinic effects but no significant effect on norepinephrine or dopamine reuptake and no significant peripheral alpha-adrenergic agonism.
    C) TOXICOLOGY: Toxic effects of paroxetine occur as an extension of its therapeutic effects causing increased serotonin in the CNS, leading to serotonergic toxicity and serotonin syndrome (more likely when combined with other serotonergic agents). Paroxetine may inhibit serotonin uptake into platelets leading to abnormalities in platelet aggregation, which is a serotonin-mediated process.
    D) EPIDEMIOLOGY: Paroxetine overdoses are common; however, severe toxicity from isolated ingestion is relatively rare. A majority of patients will have only mild symptoms.
    E) WITH THERAPEUTIC USE
    1) COMMON: Mild adverse effects with therapeutic paroxetine use include fatigue, difficulty concentrating, insomnia and sleep disturbances, nausea, vomiting, diarrhea, constipation, anorexia, weight loss, blurred vision, orthostatic dizziness, a mild decrease in systolic blood pressure, and minimal QRS prolongation (by average of 0.004 seconds compared to baseline).
    2) LESS FREQUENT: Less frequent adverse effects include spontaneous ecchymosis, syncope, premature ventricular contractions (PVCs), tremor, headache, extrapyramidal reactions, akathisia, orolingual movements, and bruxism.
    3) RARE: Rare adverse effects of therapeutic use include acute and angle closure glaucoma (thought to be mediated via direct effect on the iris or ciliary body muscle), hyponatremia due to SIADH, hepatotoxicity with jaundice, priapism, and upper gastrointestinal bleeding.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Most patients ingesting single-agent paroxetine in overdose will have only mild toxicity. Signs and symptoms after overdose commonly include nausea, mild CNS depression, vomiting, tremors, sinus tachycardia, and anxiety.
    2) SEVERE TOXICITY: In cases of severe toxicity, patients who overdose on paroxetine may rarely develop serotonin syndrome (more common in combination with other serotonergic agents although it has been described in one case with paroxetine only), characterized by altered mental status, autonomic nervous systemic dysfunction including hyperthermia and abnormal neuromuscular activity with marked hyperreflexia and clonus greater in the lower extremities than the upper extremities. Other rare severe toxicity includes hyponatremia due to SIADH, marked altered mental status with coma, and rhabdomyolysis. QT prolongation has also been reported in 2 patients after paroxetine overdose.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) BLURRED VISION has been reported at therapeutic doses (Ohrberg et al, 1992).
    2) ANISOCORIA has been reported in a patient taking paroxetine 50 mg daily (Barrett, 1994).
    3) ACUTE ANGLE GLAUCOMA has been associated with therapeutic use of paroxetine. A direct effect on the iris or ciliary body muscle through serotoninergic or anticholinergic mechanisms is suggested (Eke & Bates, 1997).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYARRHYTHMIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: An 18-year-old woman treated with paroxetine 20 mg/day for major depressive disorder for 1 week presented to the emergency department 10 hours after intentionally ingesting an additional 180 mg of the medication. Examination at admission showed tachycardia (110 beats/minute), hypertension (150/80), tachypenea, elevated temperature, and hyperreflexia. She was discharged without complication on day 2 after receiving treatment for serotonin syndrome and discontinuing paroxetine (Canan et al, 2008).
    b) CASE REPORT: Sinus tachycardia developed in one case of overdose (Boyer & Blumhardt, 1992).
    B) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) An asymptomatic decrease in systolic blood pressure was noted in patients taking therapeutic doses of paroxetine after 4 weeks on therapy (Battegay et al, 1985).
    b) Orthostatic dizziness was reported in 6 of 19 patients taking therapeutic doses (Laurson et al, 1985).
    c) In worldwide clinical trials, dizziness occurred among 5% or greater of patients treated with paroxetine hydrochloride, which was at least twice the incidence reported among patients receiving placebo (Prod Info PAXIL(R) oral tablets, oral suspension, 2012).
    d) CASE REPORT: Syncope associated with a sudden fall in blood pressure and pulse developed in a 71 year-old-woman taking therapeutic doses (Lundmark et al, 1989).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Hypotension (110/68) and sinus bradycardia confirmed by ECG were reported in an 18-year-old woman who intentionally ingested 560 mg paroxetine. She recovered fully (Gupta et al, 2005).
    C) ECTOPIC BEATS
    1) WITH THERAPEUTIC USE
    a) Multiple premature ventricular contractions (PVCs) without associated symptoms developed on one patient taking therapeutic doses of paroxetine (Battegay et al, 1985).
    D) ELECTROCARDIOGRAM ABNORMAL
    1) WITH THERAPEUTIC USE
    a) After 4 weeks at therapeutic doses QRS was prolonged by 0.004 seconds compared to baseline (Edwards et al, 1989).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 55-year-old man being treated with paroxetine, atomoxetine, and bupropion developed QT prolongation after intentionally ingesting approximately 4.5 g of controlled-release paroxetine in addition to an unknown quantity of immediate-release paroxetine. His QTc interval at admission, 16 hours after ingestion, was 475 msec; by day 7 it was 540 msec. Despite treatment for serotonin syndrome, enoxaparin prophylaxis, and treatment of complications, he died 9 days after admission when he suffered a massive pulmonary embolism (Muzyk et al, 2010).
    b) CASE REPORT: QT prolongation of 0.48 msec developed in a 63-year-old woman after she intentionally ingested 2 g of paroxetine. The prolongation resolved over 1 month without treatment and she recovered fully (Hilleret et al, 2002).
    E) UNEXPECTED THERAPEUTIC EFFECT
    1) WITH THERAPEUTIC USE
    a) Results of a case-control study (653 cases of first myocardial infarction (MI) and 2990 control subjects) indicated that SSRIs, including paroxetine, may confer a protective effect against MI, possibly attributable to an inhibitory effect on serotonin-mediated platelet activation or amelioration of other factors associated with increased risk for MI in depression (Sauer et al, 2001).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH THERAPEUTIC USE
    a) Tiredness, somnolence, lethargy, difficulty concentrating are commonly reported adverse effects (Feighner et al, 1993; Dunbar et al, 1993) Calghorn et al, 1992; (Rickels et al, 1989) Laurson et al, 1985).
    b) In pooled results from 3 clinical trials involving 1276 women with severe vasomotor symptoms associated with menopause (VMS), 31 out of 635 (4.9%) women treated with paroxetine mesylate 7.5 mg once daily developed fatigue, malaise, or lethargy compared with 18 out of 641 (2.8%) women treated with placebo (Prod Info BRISDELLE(TM) oral capsules, 2013).
    c) In worldwide clinical trials, asthenia or somnolence occurred among 5% or greater of patients treated with paroxetine hydrochloride, which was at least twice the incidence reported among patients receiving placebo (Prod Info PAXIL(R) oral tablets, oral suspension, 2012).
    d) CASE REPORT: Profound psychomotor retardation developed in a mentally retarded 67-year-old woman taking paroxetine 20 mg/day (Lewis et al, 1993).
    2) WITH POISONING/EXPOSURE
    a) CNS depression, with stupor, somnolence and coma, has been reported in acute overdoses involving paroxetine alone or with other substances (Prod Info Paxil(R), paroxetine hydrochloride, 2001; Myers et al, 1994).
    b) CASE REPORT: Sedation and indolence were observed in a 63-year-old woman 7 hours after she intentionally ingested 2 g of paroxetine. She recovered fully (Hilleret et al, 2002).
    B) RESTLESS LEGS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 48-year-old woman with a history of major depressive disorder developed restless legs syndrome (RLS) immediately after discontinuing clomipramine 60 mg daily (taken for 5 years) and beginning paroxetine 20 mg daily (Nader et al, 2007).
    C) TREMOR
    1) WITH THERAPEUTIC USE
    a) Tremor is a commonly reported side effect (Dunbar et al, 1993; Feighner et al, 1993; Ohrberg et al, 1992; Claghorn et al, 1992; Dunbar, 1989) Laurson et al, 1985).
    b) In worldwide clinical trials, tremors and nervousness occurred among 5% or greater of patients treated with paroxetine hydrochloride, which was at least twice the incidence reported among patients receiving placebo (Prod Info PAXIL(R) oral tablets, oral suspension, 2012).
    2) WITH POISONING/EXPOSURE
    a) CASE SERIES: Tremor developed in 2 of 13 patients with paroxetine only overdose in one study (Myers et al, 1994).
    D) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache is reported at therapeutic doses (Ohrberg et al, 1992; Dunbar, 1989; Mertens & Pintens, 1988; Laursen et al, 1985). In pooled results from 3 clinical trials involving 1276 women with severe vasomotor symptoms associated with menopause (VMS), 40 out of 635 (6.3%) women treated with paroxetine mesylate 7.5 mg once daily developed headaches compared with 31 out of 641 (4.8%) women treated with placebo (Prod Info BRISDELLE(TM) oral capsules, 2013).
    E) SLEEP DISORDER
    1) WITH THERAPEUTIC USE
    a) Sleep disturbance is common at therapeutic doses (Ohrberg et al, 1992; Claghorn et al, 1992; Laursen et al, 1985).
    b) In worldwide clinical trials, insomnia occurred among 5% or greater of patients treated with paroxetine hydrochloride, which was at least twice the incidence reported among patients receiving placebo (Prod Info PAXIL(R) oral tablets, oral suspension, 2012).
    c) In 12 volunteers paroxetine increased the time required to achieve REM sleep, decreased the proportion of sleep spent as REM sleep, increased the number of awakenings and reduced total sleep (Oswald & Adam, 1986).
    F) EXTRAPYRAMIDAL DISEASE
    1) WITH THERAPEUTIC USE
    a) Extrapyramidal reactions, particularly dystonic reactions involving the face or mouth, appear to occur more frequently with paroxetine than with other serotonin reuptake inhibitors (Anon, 1993; Gerber & Lynd, 1998).
    b) CASE REPORT: A 35-year-old woman with early-onset parkinsonism developed worsening symptoms (tremor, rigidity, postural instability) after taking paroxetine 20 mg/day (Jimenez-Jimenez et al, 1994). Symptoms returned to baseline after discontinuing paroxetine.
    G) ELECTROENCEPHALOGRAM ABNORMAL
    1) WITH THERAPEUTIC USE
    a) At therapeutic doses paroxetine induces a decrease in delta and theta activity, and in increase in beta activity (McClelland & Raptopoulos, 1984).
    H) AKATHISIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Akathisia developed in a 63-year-old man treated with paroxetine 20 mg/day (Adler & Angrist, 1995). The Adverse Drug Reactions Advisory Committee has received several reports of akathisia (restlessness, constant need to pace), including one case which began 5 months after starting paroxetine and resolved on discontinuation of the drug (Anon, 1996).
    I) DROWSY
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 38-year-old woman developed narcolepsy 4 weeks after beginning paroxetine 20 mg/day (Owley & Flaherty, 1994). Symptoms resolved after paroxetine was discontinued and returned when it was resumed at 10 mg/day.
    J) DYSKINESIA
    1) WITH THERAPEUTIC USE
    a) Orolingual movements (intermittent facial movements, initially involving the tongue and lips) have been described as an adverse effect of SSRIs, including paroxetine (Gerber & Lynd, 1998; Anon, 1996). Bruxism has also been described as an adverse effect of paroxetine (Gerber & Lynd, 1998; Romanelli et al, 1996).
    K) SEROTONIN SYNDROME
    1) WITH POISONING/EXPOSURE
    a) Serotonin syndrome has been reported following overdose and therapeutic use of SSRIs, particularly when more than one has been ingested concomitantly (Velez et al, 2004; Johnson et al, 2001; Prod Info Paxil(R), paroxetine hydrochloride, 2001). Diagnostic criteria for serotonin syndrome include at least three of the following features: mental status changes (confusion, hypomania), agitation, myoclonus, hyperreflexia, diaphoresis, shivering, tremor, diarrhea, incoordination, and fever.
    b) CASE REPORTS
    1) FATALITY: A 55-year-old man with a history of ADHD, depression, and anxiety being treated with paroxetine, atomoxetine, and bupropion suffered a massive pulmonary embolism and died 9 days after intentionally ingesting approximately 4.5 g of controlled-release paroxetine in addition to an unknown quantity of immediate-release paroxetine. He presented to the emergency department 16 hours after ingestion with symptoms consistent with mild serotonin syndrome and normal vital signs; however, his symptoms were worsening. Laboratory analysis was unremarkable and ECG showed a mildly prolonged QT interval . He was transferred to a medicine-psychiatry unit and treated with IV hydration, lorazepam, and cyproheptadine. His symptoms persisted, including prolonged QT interval. The cyproheptadine was increased and he was started on enoxaparin prophylaxis. On day 4 of admission, he spiked a fever of 101 degrees F and his creatine kinase (CK) peaked at 4052 U/L (normal range: 30 to 220 U/L). He was transferred to the medical ICU and treated for aspiration pneumonia. He was ventilated for 2 days with an elevated WBC. His condition started to improved and he was extubated but died 9 days after admission when he suffered a massive pulmonary embolism (Muzyk et al, 2010).
    2) An 18-year-old woman being treated with paroxetine 20 mg/day for major depressive disorder for 1 week presented to the emergency department 10 hours after intentionally ingesting an additional 180 mg of the medication. She presented with agitation, confusion, and disorientation. Physical examination revealed tachycardia at 110 beats/minute, a respiratory rate of 22 breaths/minute, temperature of 38.1 degrees C, and blood pressure of 150/80. Neurologic examination was positive for hyperreflexia (primarily to the lower extremities). Laboratory analysis and head CT were normal. Decontamination with charcoal administration was administered after gastric lavage failed to remove pill fragments. She was treated with IV hydration and 1 dose of oral alprazolam. The paroxetine was discontinued and she was started on cyproheptadine 18 mg/day. Her mental status improved within 24 hours and she was discharged without complications on the second day of admission (Canan et al, 2008).
    3) CASE REPORT: One day after ingesting 3600 mg of paroxetine (no other coingestants), a 57-year-old man presented to the emergency department (ED) with hypertension, tachycardia, mydriasis, profuse diaphoresis, myoclonic jerks and tremors, hyperreflexia and hypertonicity. Serotonin syndrome was suspected. Serum paroxetine levels 27.5 hours post ingestion were 1800 ng/mL. Symptoms resolved over 6 days (Velez et al, 2004; Johnson et al, 2001).
    4) CASE REPORT: An 18-year-old woman treated with paroxetine 20 mg/day for major depressive disorder for 1 week presented to the emergency department 10 hours after intentionally ingesting an additional 180 mg of the medication. She presented with agitation, confusion, disorientation, and hyperreflexia (primarily to the lower extremities). She was discharged without complication on day 2 after receiving treatment for serotonin syndrome and discontinuing paroxetine (Canan et al, 2008).
    5) CASE REPORT: An 18-year-old woman being treated with paroxetine 20 mg/day and clonazepam 0.25 mg/day for depression presented at the emergency department with restlessness and incoherent speech after intentionally ingesting an additional 560 mg of paroxetine. Examination revealed hypotension and ECG showed sinus bradycardia. She was treated with IV hydration only and within 48 hours her vital signs improved. Within 3 days she was stable (Gupta et al, 2005).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) SEROTONIN SYNDROME
    a) RATS: Single dose (180-300 mg/kg orally) toxicity studies in rats resulted in serotonin syndrome, which was well demonstrated on day 8 to 15 following a dose, indicating prolonged serotoninergic changes (Ryan et al, 2001).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) In pooled results from 3 clinical trials involving 1276 women with severe vasomotor symptoms associated with menopause (VMS), 27 out of 635 (4.3%) women treated with paroxetine mesylate 7.5 mg once daily developed nausea and/or vomiting compared with 15 out of 641 (2.3%) women treated with placebo (Prod Info BRISDELLE(TM) oral capsules, 2013).
    b) In worldwide clinical trials, nausea occurred among 5% or greater of patients treated with paroxetine hydrochloride, which was at least twice the incidence reported among patients receiving placebo (Prod Info PAXIL(R) oral tablets, oral suspension, 2012).
    2) WITH POISONING/EXPOSURE
    a) Spontaneous vomiting developed in one of 13 patients with paroxetine only overdose (Myers et al, 1994). Severe vomiting has rarely been reported (Johnsen & Hoejlyng, 1998). Nausea and vomiting are commonly reported side effects (Dunbar, 1989) Martins & Pintens, 1988; (Rickels et al, 1989; Dunbar et al, 1993; De Wilde et al, 1993; Bascara, 1989).
    b) CASE REPORT: Episodes of vomiting were reported 3 hours and 6 hours after an 18-year-old woman being treated with paroxetine 20 mg/day and clonazepam 0.25 mg/day for depression intentionally ingested an additional 560 mg of paroxetine. Upon examination at the emergency department she was diaphoretic and her extremities were cold. She was restless, her speech was incoherent, and she was hypotensive. ECG showed sinus bradycardia. She was treated with IV hydration only and her vital signs improved with 48 hours. Within 3 days she was stable (Gupta et al, 2005).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea is reported at therapeutic doses (Claghorn et al, 1992).
    b) Paroxetine increases gastrointestinal motility and reduces orocecal transit time at therapeutic doses (Gorard et al, 1994).
    C) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation is a commonly reported side effect (Dunbar et al, 1993; Claghorn et al, 1992; Rickels et al, 1989).
    D) APTYALISM
    1) WITH THERAPEUTIC USE
    a) Dry mouth occurs at therapeutic doses (Miller et al, 1989; Battegay et al, 1985).
    E) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) Anorexia and weight loss are reported at therapeutic doses (Feighner et al, 1993; Ohrberg et al, 1992)
    b) In worldwide clinical trials decreased appetite occurred among 5% or greater of patients treated with paroxetine hydrochloride, which was at least twice the incidence reported among patients receiving placebo (Prod Info PAXIL(R) oral tablets, oral suspension, 2012).
    F) GASTRIC HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) CASE SERIES: In a retrospective cohort study of 317,824 elderly patients, it was reported that high inhibition of serotonin reuptake increased the risk of upper gastrointestinal (GI) bleeding. An overall risk of 7.3 per 1000 person years was reported. Elderly patients and those with previous GI bleeding were at increased risk (Van Walraven et al, 2001).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER DAMAGE
    1) WITH THERAPEUTIC USE
    a) Rare cases of severe hepatotoxicity with jaundice associated with paroxetine therapy have been reported. Hepatotoxicity has been of the hepatocellular type or hepatocellular and cholestatic mixed type. Liver damage is generally reversible on discontinuation of the drug. Liver damage is most likely idiosyncratic (Odeh et al, 2001).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) DYSURIA
    1) WITH THERAPEUTIC USE
    a) Both urinary frequency and difficulty urinating have been reported as side effects (Feighner et al, 1993; Ohrberg et al, 1992).
    B) ABNORMAL EJACULATION
    1) WITH THERAPEUTIC USE
    a) Abnormal ejaculation and impotence occur more frequently than with other serotonin reuptake inhibitors (Feighner et al, 1993; Anon, 1993; Claghorn et al, 1992).
    b) In worldwide clinical trials, ejaculatory disturbance and other male genital disorders including impotence occurred among 5% or greater of men treated with paroxetine hydrochloride, which was at least twice the incidence reported among men receiving placebo (Prod Info PAXIL(R) oral tablets, oral suspension, 2012).
    C) PRIAPISM
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 58-year-old man developed priapism following treatment with paroxetine 20 mg/day (Ahmad, 1995).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) PLATELET AGGREGATION
    1) WITH THERAPEUTIC USE
    a) Spontaneous ecchymosis has been reported in 2 patients taking therapeutic doses (Ottervanger et al, 1994). Routine coagulation studies were normal in these patients, but in one patient there was no spontaneous platelet aggregation. Spontaneous ecchymoses due to therapeutic paroxetine occurred in a 47-year-old patient. Discontinuation of paroxetine resulted in resolution of ecchymoses (Cooper et al, 1998).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) EXCESSIVE SWEATING
    1) WITH THERAPEUTIC USE
    a) Increased sweating is reported as a side effect (Claghorn et al, 1992; Rickels et al, 1989; Laursen et al, 1985).
    b) In worldwide clinical trials, sweating occurred among 5% or greater of patients treated with paroxetine hydrochloride, which was at least twice the incidence reported among patients receiving placebo (Prod Info PAXIL(R) oral tablets, oral suspension, 2012).
    B) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Rashes have developed during therapeutic use (Dunbar et al, 1993; Claghorn et al, 1992).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) RHABDOMYOLYSIS
    1) WITH POISONING/EXPOSURE
    a) Rhabdomyolysis has been reported following acute overdoses involving paroxetine alone or with other substances (Prod Info Paxil(R), paroxetine hydrochloride, 2001).

Reproductive

    3.20.1) SUMMARY
    A) Brisdelle(TM) is contraindicated during pregnancy. Discontinue therapy with Paxil(R) or change to another antidepressant if a woman becomes pregnant while taking paroxetine, unless the benefits of the drug to the mother justify continuing treatment. For women intending to become pregnant, or those already in their first trimester, initiate paroxetine only after other treatment options have been given thorough consideration. Human studies of paroxetine use during pregnancy showed an increased risk of major congenital and cardiac malformations and an increased risk of pulmonary hypertension of the newborn (PPHN), especially with use during the first trimester of pregnancy. An increased risk for social-behavioral abnormalities at 2 to 6 years of age was reported in children exposed to SSRIs or serotonin–norepinephrine reuptake inhibitors (SNRIs) in utero who developed neonatal abstinence syndrome (NAS) at birth. Paroxetine is excreted in human breast milk, although there have been no observable adverse effects reported in nursing infants.
    3.20.2) TERATOGENICITY
    A) CONGENITAL MALFORMATIONS
    1) Epidemiological studies found that paroxetine was linked with a 1% to 2% increased risk of cardiac malformations in infants exposed during the first trimester. These malformations usually manifested in the atrial or ventricular septum. In addition, 2- to 3-fold increased risk of right ventricular outflow tract obstructions was found in 2 case-control studies; the defect developed in 7 paroxetine-exposed infants (n= greater than 9000) and 6 controls (n= greater than 4000). No overall increase in congenital malformations in other studies was observed with first-trimester paroxetine exposure (Prod Info BRISDELLE(TM) oral capsules, 2013).
    2) First-trimester paroxetine exposure is not associated with an increase in infant cardiovascular defects, according to an international retrospective epidemiological study. In unpublished studies, cardiovascular malformations were reported in 0.7% of 1174 infants exposed to paroxetine and in 0.7% of 1174 infants with no exposure to antidepressants or teratogenic agents. In an analysis of 5 published database studies including 2061 cases, the rate of cardiovascular malformations in paroxetine-exposed infants was 1.5%. When combined, the mean cardiovascular malformation rate in paroxetine-exposed infants was 1.2% (Einarson et al, 2008).
    3) Epidemiological studies have demonstrated that infants exposed in utero to paroxetine during the first trimester had an increased risk of cardiovascular malformations, primarily ventricular and atrial septal defects (Prod Info PAXIL(R) oral tablets, suspension, 2008; Prod Info PAXIL CR(R) controlled-release oral tablets, 2008).
    4) A retrospective cohort study, evaluating 5956 infants of mothers who were given either paroxetine (n=815) or other antidepressants during the first trimester, showed that the prevalence of cardiovascular malformations was 1.5% for the paroxetine group, compared with 1% for the other antidepressants. This study also demonstrated that the prevalence of all congenital malformations following first trimester exposure was 4% for paroxetine, compared with 2% for other antidepressants (Prod Info PAXIL(R) oral tablets, suspension, 2008; Prod Info PAXIL CR(R) controlled-release oral tablets, 2008).
    5) Data from the case-controlled National Birth Defects Prevention Study (NBDPS), indicated that early maternal exposure (defined as treatment with any SSRI from 1 month before to 3 months after conception) to SSRIs was associated with a significant 2.4 times increased risk of anencephaly, which occurred in 9 exposed infants out of 214, a significant 2.5 times increased risk of craniosynostosis, which occurred in 24 exposed infants out of 432 , and a significant 2.8 times increased risk of omphalocele, which occurred in 11 exposed infants out of 181. However, early exposure did not significantly increase the risks of congenital heart defects or most other birth defects. The most commonly used SSRIs reported by control mothers were sertraline, fluoxetine, paroxetine, and citalopram (Alwan et al, 2007). Using an expanded data-set from this study, a follow-up analysis confirmed associations between early maternal exposure to paroxetine and anencephaly, with a significant 3.2 times increased risk, and omphalocele, with a significant 3.5 times increased risk. For paroxetine treatment, significant associations were also seen for atrial septal defects (1.8 times increased risk), right ventricular outflow tract obstruction defects (2.4 times increased risk), and gastroschisis (2.5 times increased risk) in this analysis (Reefhuis et al, 2015).
    6) Paroxetine doses above 25 mg/day are associated with major congenital and cardiac malformations in infants exposed during the first trimester of pregnancy, according to a population-based registry analysis including 1403 women. Based on results from 2 nested case-control studies of 101 infants with major congenital malformations (including 24 with cardiac malformations), exposure to paroxetine or other SSRIs did not increase the risk of malformations compared to non-SSRI antidepressants when given at doses less than 25 mg/day. Adjusted analysis showed that infants exposed to paroxetine during the first trimester at doses greater than 25 mg/day had a 3-fold greater risk of major cardiac malformations and more than 2-fold greater risk of major congenital malformations (Berard et al, 2007).
    7) Fetal exposure to paroxetine during the first trimester resulted in a higher incidence of malformations compared with exposure to other antidepressants, according to a population-based cohort study including 815 infants among 791 women exposed to paroxetine monotherapy, 1020 infants among 989 women exposed to paroxetine mono- or polytherapy, 4198 infants among 4072 women exposed to other antidepressant monotherapy, and 4936 infants among 4767 women exposed to other antidepressant mono- or polytherapy. A significantly increased risk of all congenital malformations and a nonsignificantly increased risk of cardiovascular malformations were observed in infants exposed to paroxetine compared with other antidepressants in monotherapy (89% and 46%, respectively) and mono- or polytherapy groups (76% and 68%, respectively) (Cole et al, 2007).
    8) SSRI administration lasting more than 30 days during the second or third lunar month of pregnancy was associated with a significant 80% increased risk of clubfoot occurrence in infants. Escitalopram administration had a significant 190% increased risk, paroxetine administration had a nonsignificant 820% increased risk, sertraline administration had a non-significant 60% increased risk, fluoxetine administration had a nonsignificant 30% increased risk, and citalopram administration had a non-significant 10% decreased risk. Because of small numbers of subjects exposed to these SSRIs, the estimated odds ratios were unstable for these agents, especially for paroxetine (Yazdy et al, 2014).
    B) ANIMAL STUDIES
    1) LACK OF EFFECT
    a) No teratogenic effects were seen in animals administered approximately 65 and 16 times the maximum recommended human dose of paroxetine for menopause-related vasomotor symptoms during organ formation (Prod Info BRISDELLE(TM) oral capsules, 2013).
    b) Following prenatal exposure to a clinically relevant paroxetine dose in animals, no major behavioral alterations were noted; however, heightened performance on select anxiety testing in infant offspring and aggressive behavior in adult males were noted (Coleman et al, 1999).
    3.20.3) EFFECTS IN PREGNANCY
    A) CLINICAL CONSIDERATIONS
    1) Brisdelle(TM) is contraindicated during pregnancy (Prod Info BRISDELLE(TM) oral capsules, 2013). Discontinue therapy with Paxil(R) or change to another antidepressant if a woman becomes pregnant while taking paroxetine, unless the benefits of the drug to the mother justify continuing treatment. For women intending to become pregnant, or those already in their first trimester, initiate paroxetine only after other treatment options have been given thorough consideration (Prod Info PAXIL CR(R) oral controlled-release tablets, 2014; Prod Info PAXIL(R) oral tablets, suspension, 2011).
    B) AUTISM SPECTRUM DISORDER
    1) A cohort study of prospectively collected data demonstrated an increased risk of autism spectrum disorder (ASD) in children whose mothers used antidepressants during the second or third trimesters of pregnancy; the risk was even greater with second or third trimester exposure to SSRIs. Thirty-one infants who were exposed to antidepressants during the second or third trimester were diagnosed with ASD. After adjusting for potential confounders, second or third trimester exposure to antidepressants was associated with a significant 87% increased risk of ASD, while first trimester exposure or use of antidepressants in the year before pregnancy was not associated with any such risk. Use of SSRIs during the second or third trimester was associated with a significant more than 2-fold increased risk of ASD (22 exposed infants), while other classes of antidepressants were not associated with an increased risk. Even after restricting the sample size to those children whose mothers had a history of depression and used antidepressants during the second or third trimester, the risk of ASD still persisted. In addition, use of more than 1 class of antidepressants during the second or third trimester was associated with a significant more than 4-fold increased risk of ASD (Boukhris et al, 2016).
    C) LONG TERM NEURODEVELOPMENT
    1) In a prospective, single-blind, cohort study, full-term infants who developed neonatal abstinence syndrome (NAS) at birth had similar cognitive abilities compared with full term infants without NAS at birth when reevaluated at 2 to 6 years of age. However, infants with NAS at birth were at an increased risk for social-behavioral abnormalities at 2 to 6 years of age. The study was designed to assess the long-term neurodevelopment of children exposed in utero to fluoxetine, paroxetine, citalopram, sertraline, fluvoxamine, or venlafaxine. Children with NAS at birth (n=30; Finnegan score of 4 or greater) were compared to children without NAS (n=52; Finnegan score 0 to 3); both groups were similar in mean cognitive ability (106.9 +/- 14 versus 100.5 +/- 14.6, respectively) and developmental scores (98.9 +/- 11.4 versus 95.7 +/- 9.9, respectively). Cognitive ability was based on scores from the Wechsler Preschool and Primary Scale of Intelligence II, the Stanford-Binet Intelligence Scales, or the Bayley Scale of Infant Development II. The NAS infants had a significant 3-fold increased risk of social-behavior abnormalities based on the Denver Developmental Screening Test II (DDST-II) (Klinger et al, 2011).
    D) SPONTANEOUS ABORTION
    1) A nested case-controlled study showed an increased risk of spontaneous abortion with SSRI use, and notably, paroxetine or venlafaxine use alone, during pregnancy. Data collected from the Quebec Pregnancy Registry between January 1998 and December 2003 on women who filled at least 1 antidepressant prescription during pregnancy and had a clinically detected spontaneous abortion by the twentieth week of gestation (n=284) showed a significant 68% increased risk of spontaneous abortion when compared with randomly selected registry controls (4 matched controls per case) without antidepressant use. Tracked antidepressant categories included SSRIs, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, combined use of 2 or more antidepressant classes, or others. Paroxetine use alone was associated with a significant 75% higher risk of spontaneous abortion. The highest daily doses of paroxetine or venlafaxine during pregnancy were associated with the greatest spontaneous abortion risk; of the women taking paroxetine (n=84) or venlafaxine (n=33) who spontaneously aborted, an adjusted analysis showed 25.5% averaged daily doses of more than 25 mg of paroxetine and 50% averaged daily doses greater than 150 mg of venlafaxine. Use of sertraline, fluoxetine, citalopram, fluvoxamine, or combined use of 2 or more SSRIs during pregnancy did not correspond with a significant increase in risk of spontaneous abortion (Nakhai-Pour et al, 2010).
    E) WITHDRAWAL SYNDROME
    1) Paroxetine exposure in utero, with maternal doses ranging from 20 to 120 mg/day, has resulted in a neonatal syndrome with effects including jitteriness, vomiting, irritability, hypoglycemia, and necrotizing enterocolitis. It was speculated that paroxetine, which causes inhibition of muscarinic-type cholinergic receptors, when withdrawn may result in cholinergic rebound in neonates (Stiskal et al, 2001). It has been suggested that the neonates experienced a serotonin syndrome, due to time course and symptoms, as opposed to neonatal paroxetine withdrawal syndrome.(Isbister et al, 2001).
    2) CASE REPORT: A term (40+ weeks) male infant exposed in utero to paroxetine (15 mg daily) since 28 weeks gestation was born with hypotonia, flaccidity and nasal flaring. Physical exam also included labored breathing, pallor, and irregular heartbeat. A pneumomediastinum was found on x-ray and intubation was required 3 hours after birth. A thoracentesis was also performed for a pneumothorax found postintubation. Once intubated the hypotonia resolved, and the infant became hypertonic. Arching and hypertonicity continued until 24 hours of age and corresponded to serum paroxetine levels of greater than 125 nmol/L (range 125 to 400 nmol/L); abnormalities in tone resolved when the paroxetine level fell below 125 nmol/L. The authors reported that the usual adult range for paroxetine in their institution was 12 to 155 nmol/L (Knoppert et al, 2006).
    3) CASE REPORT: Within 12 hours of birth, a neonate (39 weeks gestation) whose mother took paroxetine 30 mg once daily and chlorpromazine 50 mg twice daily throughout the pregnancy, developed respiratory distress (tachypnea with respiratory rate 90/min and intercostal recession) and an intermittent fever (up to 38 degrees C). She also developed jitteriness (rhythmical jerking of the left arm and leg), tremor, generalized hypertonia, an opisthotonus posturing, hyperreflexia and a hyperactive Moro reflex at 60 hours of age. Laboratory results excluded infective or metabolic causes. On day 6 postpartum, paroxetine level in serum was undetectable (limit of detection for assay: 5 mcg/L). A midazolam infusion at 60 mcg/kg/hr was started. Within 24 hours, the seizures improved; however, an abnormal posture with neck retraction and generalized hypertonia persisted until day 8. Following supportive care, she improved and was discharged on day 11. It is not clear if this represented serotonin toxicity or a withdrawal phenomenon (Haddad et al, 2005).
    4) Third-trimester paroxetine exposure is associated with neonatal distress, according to a prospective, controlled cohort study including 55 neonates. The pregnant women studied were taking between 10 mg and 60 mg of paroxetine daily. Data showed that 12 of 55 neonates exposed to paroxetine in late gestation had complications necessitating intensive treatment and prolonged hospitalization. A comparison group of 27 women treated with paroxetine (10 mg to 40 mg/day) in their first or second trimester and 27 women exposed to nonteratogenic agents (eg, acetaminophen or dental x-rays) were matched for maternal age, gravity, parity, social drug use, and nonteratogenic drug use. Of the 12 infants experiencing complications, 9 had respiratory distress, 2 had hypoglycemia, and 1 had jaundice. Only 3 infants in the comparison group experienced complications, 2 with respiratory distress and 1 with jaundice (Costei et al, 2002).
    F) QT PROLONGATION
    1) A study of prospectively collected data suggests antenatal use of SSRI antidepressants is associated with QTc interval prolongation in exposed neonates. Between January 2000 and December 2005, researchers compared 52 neonates exposed to SSRI antidepressants (paroxetine (n=25), citalopram (n=13), fluoxetine (n=12), fluvoxamine (n=1), and venlafaxine (n=1)) in the immediate antenatal period to 52 matched neonates with no exposure. Prolonged QTc is defined as an interval of greater than 460 milliseconds (msec) (the widely used upper limit cited by authorities in both pediatric cardiology and neonatology). A pediatric cardiologist, blinded to drug exposure, interpreted all electrocardiograms (ECGs) using standard statistical analyses. ECG recordings revealed markedly prolonged mean QTc intervals in exposed neonates compared to unexposed neonates (mean; 409 +/- 42 msec versus 392 +/- 29 msec). The mean uncorrected QT interval was 7.5% longer among exposed neonates (mean; 280 +/- 31 msec versus 261 +/- 25 msec). Ten percent (n=5) of exposed neonates had a notable increase in QTc interval prolongation (greater than 460 msec) compared to none of the unexposed neonates. The longest QTc interval observed was 543 msec (Dubnov-Raz et al, 2008).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Paroxetine is excreted in breast milk (Prod Info PAXIL(R) oral tablets, suspension, 2008; Prod Info PAXIL CR(R) controlled-release oral tablets, 2008) at concentrations similar to those found in plasma (Misri et al, 2000; Kaye et al, 1989). In 16 mother and infant serum pairs, no detectable paroxetine was found in the serum of nursing infants (Stowe et al, 2000). Nondetectable breast-milk levels were evident over a 24-hour collection from a mother taking chronic paroxetine; the infant's paroxetine serum level was nondetectable (Hendrick et al, 2000).
    2) In 1 study, serum levels were not detected in breastfed infants (n=6) of paroxetine-treated mothers. Serum drug level was still undetectable in an infant of a paroxetine-treated mother with CYP2C19 poor metabolizer status (Berle et al, 2004).
    3) A mean milk/serum concentration ratio of 0.69 was measured with a maternal dose of 20 mg/day and 0.72 with a dose of 40 mg/day. Estimated relative doses to the infant were 1% and 2%, respectively (Ohman et al, 1999). Similar results were reported in other studies (Misri et al, 2000; Begg et al, 1999).
    4) According to a meta-analysis including studies of SRI use in lactating women, paroxetine and sertraline had better safety profiles than other SRIs. A daily dose of paroxetine ranged from 5 to 60 mg resulted in a relative infant dose ranging from 0.34% to 3% (below the recommended safety limit of 10%). Detectable serum levels in infants were only found in 3 studies (0.95 to 188 ng/mL), and detected milk concentrations ranged from 2 to 776 ng/mL. Short-term adverse effects were reported in 2 out of 228 cases. Because paroxetine has a better safety profile compared to other SSRIs, it should be considered when treatment of a nursing woman is necessary (Orsolini & Bellantuono, 2015).
    B) ANIMAL STUDIES
    1) In animals, more deaths were seen during the last 4 days of lactation when offspring were exposed to paroxetine during the final trimester and throughout lactation. Doses were equivalent to the maximum recommended human dose for menopause-related vasomotor symptoms. The no-effect dose for rat pup mortality and the cause of the rat pup deaths was unknown (Prod Info BRISDELLE(TM) oral capsules, 2013).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) RATS: A reduced pregnancy rate was observed during reproductive studies in rats administered paroxetine in doses approximately 19 times the maximum recommended human dose (MRHD) for menopause-related vasomotor symptoms and 2.4 to 2.9 times the MRHD for other indications. In toxicity studies, irreversible lesions, consisting of vacuolation of epididymal tubular epithelium, developed on the reproductive tract of male rats administered paroxetine in doses approximately 65 times the MRHD for menopause-related vasomotor symptoms and 8.2 to 9.8 times the MRHD for other indications. Male rats administered paroxetine in doses approximately 32 times the MRHD for menopause-related vasomotor symptoms and 4.1 to 4.9 times the MRHD for other indications) developed atrophic changes in the seminiferous tubules of the testes and arrested spermatogenesis (Prod Info BRISDELLE(TM) oral capsules, 2013; Prod Info PEXEVA(R) oral film coated tablets, 2012).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) Paroxetine levels are not widely available or clinically useful.
    C) Serum electrolytes, renal function, and creatine kinase (CK) should be evaluated in patients with evidence of toxicity.
    D) Patients with toxicity should receive an EKG and cardiac monitoring.
    4.1.2) SERUM/BLOOD
    A) Paroxetine levels are not widely available or clinically useful.
    B) Serum electrolytes, renal function, and creatine kinase (CK) should be evaluated in patients with evidence of toxicity.
    4.1.4) OTHER
    A) OTHER
    1) EKG
    a) Patients with toxicity should receive an EKG and cardiac monitoring.
    2) MONITORING
    a) Monitor vital signs and mental status.

Methods

    A) CHROMATOGRAPHY
    1) A method for determining the concentrations of paroxetine and metabolites in biologic fluids using column switching HPLC with UV detection has been described (Hartter et al, 1994).
    2) An analytical method is available to isolate SSRIs by liquid/liquid extraction at alkaline pH in n-butyl chloride, and analyze by gas chromatography/mass spectrometry (GC/MS). This method is suitable for quantitation of paroxetine and is linear over the range 0.01 to 10.00 mg/L (Goeringer et al, 2000).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who develop clinical signs and symptoms of paroxetine toxicity, such as tachycardia or altered mental status, should be admitted to the hospital. Patients who develop evidence of severe toxicity with signs of serotonin syndrome may need to be admitted to an ICU setting.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Children and adults with mild symptoms (eg, vomiting, mydriasis, diaphoresis, mild somnolence) following an inadvertent ingestion of up to 100 mg paroxetine can be managed at home with instructions to call the poison center, if symptoms develop. For patients already on paroxetine, those with inadvertent ingestions of up to 5 times their own single therapeutic dose can be observed at home with instructions to call the poison center back, if symptoms develop (Nelson et al, 2007).
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or poison center for any patient with severe toxicity, suspected serotonin syndrome, or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Any patient with an intentional ingestion or who develops more than mild symptoms should be sent to a healthcare facility for evaluation and treatment. For paroxetine naive patients with ingestion of more than 100 mg paroxetine and for patients on chronic paroxetine therapy with an ingestion of more than 5 times that patient's single therapeutic dose, prompt referral to a healthcare facility is necessary for evaluation and treatment. Patients should be observed for 6 to 8 hours for regular-release and 12 to 18 hours for controlled-release formulations (Tmax at therapeutic doses is 6 to 10 hours).

Monitoring

    A) Monitor vital signs and mental status.
    B) Paroxetine levels are not widely available or clinically useful.
    C) Serum electrolytes, renal function, and creatine kinase (CK) should be evaluated in patients with evidence of toxicity.
    D) Patients with toxicity should receive an EKG and cardiac monitoring.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is not routinely required following a minor exposure.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) Activated charcoal effectively prevents gastrointestinal absorption of paroxetine (Prod Info Paxil(R), paroxetine hydrochloride, 2001; Greb et al, 1989).
    2) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    3) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY: Treatment is symptomatic and supportive.
    2) MANAGEMENT OF SEVERE TOXICITY: Patients who develop severe toxicity with serotonin syndrome should be managed primarily with benzodiazepines to control agitation and muscle activity. Patients who become hyperthermic should be externally cooled with evaporative cooling and fanning. Patients whose hyperthermia does not resolve with benzodiazepines and external cooling should be intubated and paralyzed with non-depolarizing agents. Cyproheptadine, a non-specific 5-HT antagonist, has been shown to block development of serotonin syndrome in animals and can be used in patients with severe serotonin syndrome (although there are no controlled human trials to show efficacy). Bromocriptine and dantrolene are NOT recommended for treatment of serotonin syndrome as their use may lead to worse outcomes. Hypotension should be treated initially with normal saline boluses. In patients with persistent hypotension, a direct-acting vasopressor such as norepinephrine should be used as a next agent. Dopamine carries a theoretical risk of worsened serotonin syndrome and should not be used as a first-line agent.
    B) MONITORING OF PATIENT
    1) Monitor vital signs and mental status.
    2) Paroxetine levels are not widely available or clinically useful.
    3) Serum electrolytes, renal function, and creatine kinase (CK) should be evaluated in patients with evidence of toxicity.
    4) Patients with toxicity should receive an EKG and cardiac monitoring.
    C) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    D) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    E) SEROTONIN SYNDROME
    1) SUMMARY
    a) Benzodiazepines are the mainstay of therapy. Cyproheptadine, a 5-HT antagonist, is also commonly used. Severe cases have been managed with benzodiazepine sedation and neuromuscular paralysis with non-depolarizing agents(Claassen & Gelissen, 2005).
    2) HYPERTHERMIA
    a) Control agitation and muscle activity. Undress patient and enhance evaporative heat loss by keeping skin damp and using cooling fans.
    b) MUSCLE ACTIVITY: Benzodiazepines are the drug of choice to control agitation and muscle activity. DIAZEPAM: ADULT: 5 to 10 mg IV every 5 to 10 minutes as needed, monitor for respiratory depression and need for intubation. CHILD: 0.25 mg/kg IV every 5 to 10 minutes; monitor for respiratory depression and need for intubation.
    c) Non-depolarizing paralytics may be used in severe cases.
    3) CYPROHEPTADINE
    a) Cyproheptadine is a non-specific 5-HT antagonist that has been shown to block development of serotonin syndrome in animals (Sternbach, 1991). Cyproheptadine has been used in the treatment of serotonin syndrome (Mills, 1997; Goldberg & Huk, 1992). There are no controlled human trials substantiating its efficacy.
    b) ADULT: 12 mg initially followed by 2 mg every 2 hours if symptoms persist, up to a maximum of 32 mg in 24 hours. Maintenance dose 8 mg orally repeated every 6 hours (Boyer & Shannon, 2005).
    c) CHILD: 0.25 mg/kg/day divided every 6 hours, maximum dose 12 mg/day (Mills, 1997).
    4) HYPERTENSION
    a) Monitor vital signs regularly. For mild/moderate asymptomatic hypertension, pharmacologic intervention is usually not necessary.
    5) HYPOTENSION
    a) Administer 10 to 20 mL/kg 0.9% saline bolus and place patient supine. Further fluid therapy should be guided by central venous pressure or right heart catheterization to avoid volume overload.
    b) Pressor agents with dopaminergic effects may theoretically worsen serotonin syndrome and should be used with caution. Direct acting agents (norepinephrine, epinephrine, phentolamine) are theoretically preferred.
    c) NOREPINEPHRINE
    1) PREPARATION: Add 4 mL of 0.1% solution to 1000 mL of dextrose 5% in water to produce 4 mcg/mL.
    2) INITIAL DOSE
    a) ADULT: 2 to 3 mL (8 to 12 mcg)/minute.
    b) ADULT or CHILD: 0.1 to 0.2 mcg/kg/min. Titrate to maintain adequate blood pressure.
    3) MAINTENANCE DOSE
    a) 0.5 to 1 mL (2 to 4 mcg)/minute.
    6) SEIZURES
    a) DIAZEPAM
    1) MAXIMUM RATE: Administer diazepam IV over 2 to 3 minutes (maximum rate: 5 mg/min).
    2) ADULT DIAZEPAM DOSE: 5 to 10 mg initially, repeat every 5 to 10 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 30 milligrams.
    3) PEDIATRIC DIAZEPAM DOSE: 0.2 to 0.5 mg/kg, repeat every 5 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 10 milligrams in children over 5 years or 5 milligrams in children under 5 years of age.
    4) RECTAL USE: If an intravenous line cannot be established, diazepam may be given per rectum (not FDA approved), or lorazepam may be given intramuscularly.
    b) LORAZEPAM
    1) MAXIMUM RATE: The rate of IV administration of lorazepam should not exceed 2 mg/min (Prod Info Ativan(R), 1991).
    2) ADULT LORAZEPAM DOSE: 2 to 4 mg IV. Initial doses may be repeated in 10 to 15 minutes, if seizures persist (Prod Info ATIVAN(R) injection, 2003).
    3) PEDIATRIC LORAZEPAM DOSE: 0.1 mg/kg IV push (range: 0.05 to 0.1 mg/kg; maximum dose 4 mg); may repeat dose in 5 to 10 minutes if seizures continue. It has also been given rectally at the same dose in children with no IV access (Sreenath et al, 2009; Chin et al, 2008; Wheless, 2004; Qureshi et al, 2002; De Negri & Baglietto, 2001; Mitchell, 1996; Appleton, 1995; Giang & McBride, 1988).
    c) RECURRING SEIZURES
    1) If seizures cannot be controlled with diazepam or recur, give phenobarbital or propofol.
    d) PHENOBARBITAL
    1) SERUM LEVEL MONITORING: Monitor serum levels over next 12 to 24 hours for maintenance of therapeutic levels (15 to 25 mcg/mL).
    2) ADULT PHENOBARBITAL LOADING DOSE: 600 to 1200 mg of phenobarbital IV initially (10 to 20 mg/kg) diluted in 60 mL of 0.9% saline given at 25 to 50 mg/minute.
    3) ADULT PHENOBARBITAL MAINTENANCE DOSE: Additional doses of 120 to 240 mg may be given every 20 minutes.
    4) MAXIMUM SAFE ADULT PHENOBARBITAL DOSE: No maximum safe dose has been established. Patients in status epilepticus have received as much as 100 mg/min until seizure control was achieved or a total dose of 10 mg/kg.
    5) PEDIATRIC PHENOBARBITAL LOADING DOSE: 15 to 20 mg/kg of phenobarbital intravenously at a rate of 25 to 50 mg/min.
    6) PEDIATRIC PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 5 to 10 mg/kg may be given every 20 minutes.
    7) MAXIMUM SAFE PEDIATRIC PHENOBARBITAL DOSE: No maximum safe dose has been established. Children in status epilepticus have received doses of 30 to 120 mg/kg within 24 hours. Vasopressors and mechanical ventilation were needed in some patients receiving these doses.
    8) NEONATAL PHENOBARBITAL LOADING DOSE: 20 to 30 mg/kg IV at a rate of no more than 1 mg/kg/min in patients with no preexisting phenobarbital serum levels.
    9) NEONATAL PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 2.5 mg/kg every 12 hours may be given; adjust dosage to maintain serum levels of 20 to 40 mcg/mL.
    10) MAXIMUM SAFE NEONATAL PHENOBARBITAL DOSE: Doses of up to 20 mg/kg/min up to a total of 30 mg/kg have been tolerated in neonates.
    11) CAUTION: Adequacy of ventilation must be continuously monitored in children and adults. Intubation may be necessary with increased doses.
    7) CHLORPROMAZINE
    a) Chlorpromazine is a 5-HT2 receptor antagonist that has been used to treat cases of serotonin syndrome (Graham, 1997; Gillman, 1996). Controlled human trial documenting its efficacy are lacking.
    b) ADULT: 25 to 100 mg intramuscularly repeated in 1 hour if necessary.
    c) CHILD: 0.5 to 1 mg/kg repeated as needed every 6 to 12 hours not to exceed 2 mg/kg/day.
    8) NOT RECOMMENDED
    a) BROMOCRIPTINE: It has been used in the treatment of neuroleptic malignant syndrome but is NOT RECOMMENDED in the treatment of serotonin syndrome as it has serotonergic effects (Gillman, 1997). In one case the use of bromocriptine was associated with a fatal outcome (Kline et al, 1989).

Enhanced Elimination

    A) LACK OF EFFECT
    1) Because of the large volume of distribution and high degree of protein binding of paroxetine, hemodialysis, forced diuresis, hemoperfusion and exchange transfusion would NOT be expected to be useful in overdose (Prod Info Paxil(R), paroxetine hydrochloride, 2001).

Abstracts

Case Reports

    A) ADULT
    1) A 25-year-old man ingested 400 mg of paroxetine without serious sequelae. He was treated with activated charcoal and sorbitol and observed for 4 hours (6 hours after ingestion). He experienced no adverse effects other than anxiety (Gorman et al, 1993).
    2) A 57-year-old man presented to the ED one day after intentionally ingesting a single paroxetine dose of 3600 mg, along with a pint of "hard liquor". Symptoms of serotonin syndrome, including hypertension, tachycardia, mydriasis, profuse diaphoresis, myoclonic jerks and tremors, hyperreflexia and hypertonicity, were noted. Serum paroxetine levels 27.5 and 40 hours post ingestion were 1800 and 1600 ng/mL, respectively. Symptoms gradually resolved over 6 days (Velez et al, 2004; Johnson et al, 2001).

Range Of Toxicity

Summary

    A) TOXICITY: In a series of 35 patients, ingestion of 10 to 1000 mg resulted in no toxicity. In 16 children under the age of 5 years, overdoses between 10 to 120 mg resulted in no symptoms. Overdoses between 100 to 800 mg in adolescents age 12 to 17 years had no symptoms in most cases. In 2 cases, an overdose of 3600 mg and of 180 mg, paroxetine alone resulted in serotonin syndrome. In one case of overdose in an elderly patient, ingestion of 360 mg resulted in profuse vomiting and hyponatremia with SIADH. The largest reported overdose ingestion survived and recovered from is 2000 mg.
    B) THERAPEUTIC DOSE: ADULTS: For paroxetine hydrochloride, the adult dose for immediate-release formulation is 10 to 60 mg/day. For controlled-release the dose is 12.5 to 75 mg/day. For paroxetine mesylate, the adult dose is 10 to 60 mg/day. There is no specific data available on pediatric dosing; safety and efficacy have not been established in pediatric patients. PEDIATRIC: There is no specific data available on pediatric dosing; safety and efficacy have not been established in pediatric patients.

Therapeutic Dose

    7.2.1) ADULT
    A) PAROXETINE HYDROCHLORIDE
    1) IMMEDIATE-RELEASE
    a) Varies by indication; dose range, 10 to 60 mg/day. MAXIMUM dosage, 60 mg/day (Prod Info PAXIL(R) oral tablets, oral suspension, 2014).
    2) CONTROLLED-RELEASE
    a) Varies by indication; dose range, 12.5 to 75 mg/day. MAXIMUM dosage, 75 mg/day (Prod Info PAXIL CR(R) oral controlled-release tablets, 2014).
    B) PAROXETINE MESYLATE
    1) TABLETS
    a) Varies by indication; dose range, 10 to 60 mg/day. MAXIMUM dosage, 60 mg/day (Prod Info PEXEVA(R) oral tablets, 2014).
    2) CAPSULES
    a) 7.5 mg orally once daily, at bedtime (Prod Info BRISDELLE(R) oral capsules, 2014).
    7.2.2) PEDIATRIC
    A) Safety and efficacy of paroxetine hydrochloride and paroxetine mesylate have NOT been established in pediatric patients (Prod Info PAXIL(R) oral tablets, oral suspension, 2014; Prod Info PAXIL CR(R) oral controlled-release tablets, 2014; Prod Info PEXEVA(R) oral tablets, 2014; Prod Info BRISDELLE(R) oral capsules, 2014).

Minimum Lethal Exposure

    A) There have been infrequent reports of fatalities following overdose with paroxetine. There have been 17 reported fatalities to paroxetine alone (a dose was not reported) (Nelson et al, 2007).
    B) A 55-year-old man being treated with paroxetine, atomoxetine, and bupropion developed serotonin syndrome that required aggressive sedation and endotracheal intubation after intentionally ingesting approximately 4.5 g of controlled-release paroxetine in addition to an unknown quantity of immediate-release paroxetine. He was found pulseless 9 days after the overdose, and could not be resuscitated; autopsy revealed massive pulmonary embolism (Muzyk et al, 2010).

Maximum Tolerated Exposure

    A) SUMMARY
    1) Acute ingestion of up to 100 mg is not expected to result in toxicity. Children and adults with mild symptoms (eg, vomiting, mydriasis, diaphoresis, mild somnolence) following an inadvertent ingestion of up to 100 mg paroxetine can be managed at home with instructions to call the poison center, if symptoms develop. For patients already on paroxetine with ingestions of up to 5 times their own single therapeutic dose can be observed at home with instructions to call the poison center back, if symptoms develop (Nelson et al, 2007).
    2) Among 342 reported cases of overdose worldwide, the largest ingestion survived and recovered from was 2000 mg (33 times the maximum recommended daily dose) (Prod Info PAXIL(R) oral tablets, oral suspension, 2012).
    B) CASE REPORTS
    1) ADULT
    a) Following an acute ingestion of 3600 mg paroxetine, along with a pint of liquor, a 57-year-old man developed symptoms of serotonin syndrome within 24 hours, with elevated paroxetine serum levels (1800 and 1600 ng/mL) reported 27.5 and 40 hours postingestion, respectively (Velez et al, 2004; Johnson et al, 2001).
    b) Anxiety was the only adverse effect reported in a 25-year-old man who ingested 400 mg (Gorman et al, 1993).
    c) In a series of 35 patients, minimal or no effects developed after ingestion of 10 to 1000 mg (Myers et al, 1994).
    d) Overdose of 360 mg in an elderly adult resulted in excessive vomiting and SIADH with decreased serum sodium levels (Johnsen & Hoejlyng, 1998).
    2) PEDIATRIC
    a) A series of 11 children 5 years old or younger with paroxetine only ingestions of 10 to 120 mg were treated with ipecac or activated charcoal only. All remained asymptomatic (Myers et al, 1995; Myers & Krenzelok, 1997).
    b) In a series of 11 children between 12 and 17 years old who ingested 100 to 800 mg of paroxetine, 9 received gastrointestinal decontamination and 2 did not (Myers et al, 1995; Myers & Krenzelok, 1997). Seven were asymptomatic and 4 developed minor symptoms.

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) PEAK PLASMA CONCENTRATION
    a) IMMEDIATE-RELEASE: Following administration of immediate-release paroxetine tablets 30 mg/day for 30 days in 15 healthy participants, the steady state mean peak plasma concentration (Cmax) was 61.7 nanograms/mL. The steady state Cmax is approximately 6 times what would be expected following a single dose (Prod Info PAXIL(R) oral tablets, oral suspension, 2012).
    b) EXTENDED-RELEASE: Paroxetine peak plasma concentrations (Cmax) following single dose administration of extended-release paroxetine in 23 healthy participants were 2 nanograms (ng)/mL with a 12.5 mg dose; 5.5 ng/mL with 25 mg; 9 ng/mL with 37.5 mg; 12.5 ng/mL with 50 mg. Following repeat-dosing of extended-release paroxetine 25 mg/day in 23 healthy participants, the mean peak plasma concentration (Cmax) was 30 ng/mL (Prod Info PAXIL CR(R) oral controlled release tablets, 2012).
    c) A normal paroxetine peak steady state concentration, from clinical trials (30 mg/day), is reported to be 0.06 mg/L (Goeringer et al, 2000).
    2) TIME TO PEAK PLASMA CONCENTRATION
    a) IMMEDIATE-RELEASE: Peak plasma concentrations following single doses of immediate-release paroxetine were reached (Tmax) in 6.4 hours but decreased to 4.9 hours when administered with food. At steady state, the mean Tmax was 5.2 hours (Prod Info PAXIL(R) oral tablets, oral suspension, 2012).
    b) EXTENDED RELEASE: Peak plasma concentrations following single doses of extended-release paroxetine were reached 6 to 10 hours after ingestion (Prod Info PAXIL CR(R) oral controlled release tablets, 2012).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) ADULT
    a) The lowest reported serum concentration, in the absence of other risk factors, resulting in death was 0.41 mg/L for paroxetine (no other drugs involved) (Goeringer et al, 2000).
    b) A high serum paroxetine concentration of 3.84 mg/L was reported in a fatality involving a mixed drug ingestion (Goeringer et al, 2000).
    c) FATALITY: A paroxetine blood concentration of 3420 nanograms (ng)/mL (therapeutic: 30 to 90 ng/mL) was reported 3 days after a 55-year-old man being treated with paroxetine, atomoxetine, and bupropion intentionally ingested 4.5 g of controlled-release paroxetine, in addition to an unknown quantity of immediate-release paroxetine. On day 7 of admission, the paroxetine level was 4420 ng/mL. He died 9 days after admission when he suffered a massive pulmonary embolism (Muzyk et al, 2010).
    d) Serum paroxetine levels of 1800 and 1600 nanograms/mL were reported 27.5 and 40 hours, respectively, following a single paroxetine dose of 3600 mg in a 57-year-old man, resulting in serotonin syndrome (Velez et al, 2004; Johnson et al, 2001). The author reported a therapeutic range of 20 to 200 nanograms/mL.

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) PAROXETINE HYDROCHLORIDE
    1) LD50- (ORAL)MOUSE:
    a) 378 mg/kg ((RTECS, 2002))
    2) LD50- (ORAL)RAT:
    a) 415 mg/kg ((RTECS, 2002))

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Paroxetine is a potent inhibitor of serotonin reuptake in pre-synaptic nerve terminals in the central nervous system. It has only weak anticholinergic effects (Mertens & Pintens, 1988).
    B) Paroxetine is effective in the treatment of adult night terrors. It is suggested that the terror-suppressing action of paroxetine is a direct effect of its ability to increase 5-hydroxytryptamine (5-HT) concentrations in the brainstem by blocking reuptake (Wilson et al, 1997).

Toxicologic Mechanism

    A) ECCHYMOSES have been reported as an adverse effect of paroxetine. It is speculated that a decrease in serotonin uptake into platelets is associated with paroxetine treatment. Since serotonin is associated with platelet aggregation, it is thought that paroxetine may inhibit serotonin uptake in platelets, and theoretically, could contribute to abnormalities of aggregation (Cooper et al, 1998).

Physicochemical

Physical Characteristics

    A) PAROXETINE HYDROCHLORIDE is an odorless, off-white powder with a melting point range of 120 to 138 degrees C and a solubility of 5.4 mg/mL in water (Prod Info PAXIL(R) oral tablets, suspension, 2010; Prod Info PAXIL CR(R) controlled-release oral tablets, 2010).
    B) PAROXETINE MESYLATE is an odorless, off-white powder with a melting point range of 147 to 150 degrees C and a solubility of greater than 1 g/mL in water (Prod Info PEXEVA(R) oral tablets, 2010).

Molecular Weight

    A) PAROXETINE: 329.4 (Prod Info PAXIL(R) oral tablets, suspension, 2010; Prod Info PAXIL CR(R) controlled-release oral tablets, 2010; Prod Info PEXEVA(R) oral tablets, 2010)
    B) PAROXETINE HYDROCHLORIDE: 374.8 (Prod Info PAXIL(R) oral tablets, suspension, 2010; Prod Info PAXIL CR(R) controlled-release oral tablets, 2010)
    C) PAROXETINE MESYLATE: 425.5 (Prod Info PEXEVA(R) oral tablets, 2010)

References

General Bibliography

    1) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
    2) Adler LA & Angrist BM: Paroxetine and akathisia. Biol Psychiatry 1995; 37:336-337.
    3) Ahmad S: Paroxetine-induced priapism. Arch Intern Med 1995; 155:645.
    4) Alwan S, Reefhuis J, Rasmussen SA, et al: Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med 2007; 356(26):2684-2692.
    5) Anon: Movement disorders with selective serotonin reuptake inhibitors. Adverse Drug Reactions Advisory Committee; Med J Aust 1996; 166:259.
    6) Anon: Paroxetine and dystonia. Pharm J 1993; 303.
    7) Appleton R: Lorazepam vs diazepam in the acute treatment of epileptic seizures and status epilepticus.. Dev Med Child Neuro 1995; 37:682-688.
    8) Bannister SJ, Houser VP, & Hulse JD: Evaluation of the potential for interactions of paroxetine with diazepam, cimetidine, warfarin, and digoxin. Acta Psychiatr Scand 1989; 80(Suppl 350):102-106.
    9) Barr LC, Goodman WK, & Price LH: Physical symptoms associated with paroxetine discontinuation (letter). Am J Psychiatry 1994; 151:289.
    10) Barrett J: Anisocuria associated with selective serotonin reuptake inhibitors. Br Med J 1994; 309:1620.
    11) Bascara L: A double-blind study to compare the effectiveness and tolerability of paroxetine and amitriptyline in depressed patients. Acta Pychiatr Scand 1989; 80(Suppl 350):141-142.
    12) Battegay R, Hager M, & Rauchfleisch U: Double-blind comparative study of paroxetine and amitriptyline in depressed patients of a university psychiatric outpatient clinic (pilot study). Neuropsychobiology 1985; 13:31-37.
    13) Bayer AJ, Roberts NA, & Allen EA: The pharmacokinetics of paroxetine in the elderly. Acta Psychiatr Scand 1989; 80(Suppl 350):85-86.
    14) Begg EJ, Duffull SB, & Saunders DA: Paroxetine in human milk. Br J Clin Pharmacol 1999; 48:142-147.
    15) Berard A, Ramos E, Rey E, et al: First trimester exposure to paroxetine and risk of cardiac malformations in infants: the importance of dosage. Birth Defects Res B Dev Reprod Toxicol 2007; 80(1):18-27.
    16) Berle JO, Steen VM, Aamo TO, et al: Breastfeeding during maternal antidepressant treatment with serotonin reuptake inhibitors: infant exposure, clinical symptoms, and cytochrome P450 genotypes. J Clin Psychiatry 2004; 65:1228-1234.
    17) Boukhris T, Sheehy O, Mottron L, et al: Antidepressant use during pregnancy and the risk of autism spectrum disorder in children. JAMA Pediatr 2016; 170(2):117-124.
    18) Boyer EW & Shannon M: The serotonin syndrome. N Eng J Med 2005; 352(11):1112-1120.
    19) Boyer WF & Blumhardt CL: The safety profile of paroxetine. J Clin Psychiatry 1992; 53:61-66.
    20) Boyer WF & Feighner JP: An overview of paroxetine. J Clin Psychiatry 1992; 53:3-6.
    21) Brophy GM, Bell R, Claassen J, et al: Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17(1):3-23.
    22) Budman CL, Sherling M, & Bruun RD: Combined pharmacotherapy risk (letter). J Am Acad Child Adolesc Psychiatry 1995; 34:263-264.
    23) Canan F, Korkmaz U, Kocer E, et al: Serotonin syndrome with paroxetine overdose: a case report. Prim Care Companion J Clin Psychiatry 2008; 10(2):165-167.
    24) Chamberlain JM, Altieri MA, & Futterman C: A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Ped Emerg Care 1997; 13:92-94.
    25) Chin RF , Neville BG , Peckham C , et al: Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study. Lancet Neurol 2008; 7(8):696-703.
    26) Choonara IA & Rane A: Therapeutic drug monitoring of anticonvulsants state of the art. Clin Pharmacokinet 1990; 18:318-328.
    27) Chua TP & Vong SK: Hyponatraemia associated with paroxetine (letter). Br Med J 1993; 306:143.
    28) Chua TP & Vong SK: Paroxetine and hyponatraemia. Br J Clin Pract 1994; 48:49.
    29) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    30) Claassen JAHR & Gelissen HPMM: The serotonin syndrome (letter). N Eng J Med 2005; 352(23):2455.
    31) Claghorn JL, Kiev A, & Rickels K: Paroxetine versus placebo: a double- blind comparison in depressed patients. J Clin Psychiatry 1992; 53:434-438.
    32) Cole JA, Ephross SA, Cosmatos IS, et al: Paroxetine in the first trimester and the prevalence of congenital malformations. Pharmacoepidemiol Drug Saf 2007; 16(10):1075-1085.
    33) Coleman FH, Christensen HD, & Gonzalez CL: Behavioral changes in developing mice after prenatal exposure to paroxetine (Paxil). Am J Obstet Gynecol 1999; 181:1166-1171.
    34) Cooper TA, Valcour VG, & Gibbons RB: Spontaneous ecchymoses due to paroxetine administration. Am J Med 1998; 104:197-198.
    35) Costei AM, Kozer E, Ho T, et al: Perinatal outcome following third trimester exposure to paroxetine. Arch Pediatr Adolesc Med 2002; 156(11):1129-1132.
    36) Dalhoff K, Almdal TP, & Bjerrum K: Pharmacokinetics of paroxetine in patients with cirrhosis. Eur J Clin Pharmacol 1991; 41:351-354.
    37) De Negri M & Baglietto MG: Treatment of status epilepticus in children. Paediatr Drugs 2001; 3(6):411-420.
    38) De Wilde J, Spiers R, & Mertens C: A double-blind, comparative, multicentre study comparing paroxetine with fluoxetine in depressed patients. Acta Psychiatr Scand 1993; 87:141-145.
    39) Diler RS, Tamam L, & Avci A: Withdrawal symptoms associated with paroxetine discontinuation in a nine-year-old boy (letter). J Clin Psychopharmacology 2000; 20:586-587.
    40) Doyle GD, Laher M, & Kelly JG: The pharmacokinetics of paroxetine in renal impairment. Acta Psychiatr Scand 1989; 80(Suppl 350):89-90.
    41) Dubnov-Raz G, Juurlink DN, Fogelman R, et al: Antenatal use of selective serotonin-reuptake inhibitors and QT interval prolongation in newborns. Pediatrics 2008; 122(3):e710-e715.
    42) Dunbar GC, Claghorn JL, & Kiev A: A comparison of paroxetine and placebo in depressed outpatients. Acta Psychiatr Scand 1993; 87:302-305.
    43) Dunbar GC: An interim overview of the safety and tolerability of paroxetine. Acta Psychiatr Scand 1989; 80(Suppl 350):135-137.
    44) Edwards JG, Goldie A, & Papayanni-Papasthatis S: Effect of paroxetine on the electrocardiogram. Psychopharmacology 1989; 97:96-98.
    45) Einarson A, Pistelli A, Desantis M, et al: Evaluation of the risk of congenital cardiovascular defects associated with use of paroxetine during pregnancy. Am J Psychiatry 2008; Epub:--.
    46) Eke T & Bates AK: Acute angle closure glaucoma associated with paroxetine (letter). Br Med J 1997; 314:1387.
    47) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    48) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    49) Feighner JP, Cohn JB, & Fabre LF: A study comparing paroxetine placebo and imipramine in depressed patients. J Affect Disord 1993; 28:71-79.
    50) FitzSimmons CR & Metha S: Serotonin syndrome caused by overdose with paroxetine and moclobemide. J Accid Emerg Med 1999; 16:293-295.
    51) Frost L & Lal S: Shock-like sensations after discontinuation of selective serotonin reuptake inhibitors. Am J Psychiatry 1995; 152:810.
    52) Gerber PE & Lynd LD: Selective serotonin-reuptake inhibitor-induced movement disorders. Ann Pharmacother 1998; 32:692-698.
    53) Ghose K: The pharmacokinetics of paroxetine in elderly depressed patients. Acta Psychiatr Scand 1989; 80(Suppl 350):87-88.
    54) Giang DW & McBride MC : Lorazepam versus diazepam for the treatment of status epilepticus. Pediatr Neurol 1988; 4(6):358-361.
    55) Gillman PK: Ecstasy, serotonin syndrome and the treatment of hyperpyrexia (letter). MJA 1997; 167:109-111.
    56) Gillman PK: Successful treatment of serotonin syndrome with chlorpromazine (letter). MJA 1996; 165:345.
    57) Goddard C & Paton C: Hyponatraemia associated with paroxetine (letter). Br Med J 1992; 305:1332.
    58) Goeringer KE, Raymon L, & Christian GD: Postmortem forensic toxicology of selective serotonin reuptake inhibitors: a review of pharmacology and report of 168 cases. J Forensic Sci 2000; 45:633-648.
    59) Goldberg RJ & Huk M: Serotonin syndrome from trazodone and buspirone (letter). Psychosomatics 1992; 33:235-236.
    60) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    61) Gorard DA, Libby GW, & Farthing MJG: 5-hydroxytryptamine and human small intestinal motility: effect of inhibiting 5-hydroxytryptamine reuptake. Gut 1994; 35:496-500.
    62) Gorman SE, Rice T, & Simmons HF: Paroxetine overdose (letter). Am J Emerg Med 1993; 11:682.
    63) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    64) Graham PM: Successful treatment of the toxic serotonin syndrome with chlorpromazine (letter). Med J Australia 1997; 166:166-167.
    65) Greb WH, Buscher G, & Dierdorf HD: Ability of charcoal to prevent absorption of paroxetine. Acta Psychiatr Scand 1989; 80(Suppl 350):156-157.
    66) Gupta AK, Verma P, Praharaj SK, et al: Paroxetine overdose. Indian J Psychiatry 2005; 47(3):167-168.
    67) Haddad PM, Pal BR, Clarke P, et al: Neonatal symptoms following maternal paroxetine treatment: serotonin toxicity or paroxetine discontinuation syndrome?. J Psychopharmacol 2005; 19(5):554-557.
    68) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    69) Hartter S, Hermes B, & Szegedi A: Automated determination of paroxetine and its main metabolite by column switching and on-line high-performance liquid chromatography. Ther Drug Monit 1994; 16:400-406.
    70) Hegenbarth MA & American Academy of Pediatrics Committee on Drugs: Preparing for pediatric emergencies: drugs to consider. Pediatrics 2008; 121(2):433-443.
    71) Hendrick V, Stowe ZN, & Altshuler LL: Paroxetine use during breast-feeding (letter). J Clin Psychopharmacol 2000; 20:587-589.
    72) Hilleret H, Voirol P, Bovier P, et al: Very long half-life of paroxetine following intoxication in an extensive cytochrome P4502D6 metabolizer. Ther Drug Monit 2002; 24(4):567-569.
    73) Horrigan JP & Barnhill LJ: Paroxetine-pimozide drug interaction (letter). J Am Acad Child Adolesc Psychiatry 1994; 33:1060.
    74) Hvidberg EF & Dam M: Clinical pharmacokinetics of anticonvulsants. Clin Pharmacokinet 1976; 1:161.
    75) Isbister GK, Dawson A, & Whyte IM: Neonatal paroxetine withdrawal syndrome or actually serotonin syndrome? (letter). Arch Dis Child 2001; 85:F147-F148.
    76) Jimenez-Jimenez FJ, Tejeiro J, & Martinez-Junpuera G: Parkinsonism exacerbated by paroxetine (letter). Neurology 1994; 44:2406.
    77) John L, Perreault MM, & Tao T: Serotonin syndrome associated with nefazodone and paroxetine. Ann Emerg Med 1997; 29:287-289.
    78) Johnsen CR & Hoejlyng N: Hyponatremia following acute overdose with paroxetine. Intl J Clin Pharmacol Ther 1998; 36:333-335.
    79) Johnson R, Velez LI, & Roth B: Paroxetine as a sole cause of serotonin syndrome: a massive overdose with documented serum paroxetine levels (abstract). Clin Toxicol 2001; 39:491-492.
    80) Kaye CM, Haddock RE, & Langley PF: A review of the metabolism and pharmacokinetics of paroxetine in man. Acta Psychiatr Scand 1989; 80(Suppl 350):60-75.
    81) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    82) Kline SS, Mauro LS, & Scala-Barnett DM: Serotonin syndrome versus neuroleptic malignant syndrome as a cause of death. Clin Pharmac 1989; 8:510-514.
    83) Klinger G, Frankenthal D, Merlob P, et al: Long-term outcome following selective serotonin reuptake inhibitor induced neonatal abstinence syndrome. J Perinatol 2011; 31(9):615-620.
    84) Knoppert DC, Nimkar R, Principi T, et al: Paroxetine toxicity in a newborn after in utero exposure: clinical symptoms correlate with serum levels. Ther Drug Monit 2006; 28(1):5-7.
    85) Lane R & Baldwin D: Selective serotonin reuptake inhibitor-induced serotonin syndrome: review. J Clin Psychopharmacol 1997; 17:208-221.
    86) Laursen AL, Mikkelsen PL, & Rasmussen S: Paroxetine in the treatment of depression - a randomized comparison with amitriptyline. Acta Psychiatr Scand 1985; 71:249-255.
    87) Lewis J, Braganza J, & Williams T: Psychomotor retardation and semistuporous state with paroxetine. Br Med J 1993; 306:1169.
    88) Loddenkemper T & Goodkin HP: Treatment of Pediatric Status Epilepticus. Curr Treat Options Neurol 2011; Epub:Epub.
    89) Lund J, Lomholt B, & Fabricius J: Paroxetine: pharmacokinetics, tolerance and depletion of blood 5-HT in man. Acta Pharmacol 1979; 44:289-295.
    90) Lund J, Thayssen P, & Mengel H: Paroxetine: pharmacokinetics and cardiovascular effects after oral and intravenous single doses in man. Acta Pharmacol 1982; 51:351-357.
    91) Lundmark J, Thomsen S, & Fjord-Larsen T: Paroxetine: pharmacokinetic and antidepressant effect in the elderly. Acta Psychiatr Scand 1989; 80(Suppl 350):76-80.
    92) Manno EM: New management strategies in the treatment of status epilepticus. Mayo Clin Proc 2003; 78(4):508-518.
    93) McClelland GR & Raptopoulos P: EEG and blood level of the potential antidepressant paroxetine after a single oral dose to normal volunteers. Psychopharmacology 1984; 83:327-329.
    94) Mertens C & Pintens H: Paroxetine in the treatment of depression: a double- blind multicenter study versus mianserin. Acta Psychiatr Scand 1988; 77:683-688.
    95) Miller SM, Naylor GJ, & Murtagh M: A double-blind comparison of paroxetine and placebo in the treatment of depressed patients in a psychiatric outpatient clinic. Acta Psychiatr Scand 1989; 80(Suppl 350):143-144.
    96) Mills KC: Serotonin syndrome: a clinical update. Med Toxicol 1997; 13:763-783.
    97) Misri S, Kim J, & Riggs KW: Paroxetine levels in postpartum depressed women, breast milk, and infant serum. J Clin Psychiatry 2000; 61:828-832.
    98) Mitchell PB: Drug interactions of clinical significance with selective serotonin reuptake inhibitors. Drug Safety 1997; 17:390-406.
    99) Mitchell WG: Status epilepticus and acute repetitive seizures in children, adolescents, and young adults: etiology, outcome, and treatment. Epilepsia 1996; 37(S1):S74-S80.
    100) Monmany J, Vazquez G, & Rodriguez J: Syndrome of inappropriate secretion of antidiuretic hormone induced by paroxetine (letter). Arch Intern Med 1999; 159:2089-2090.
    101) Muzyk AJ, Jakel RJ, & Preud'homme X: Serotonin syndrome after a massive overdose of controlled-release paroxetine. Psychosomatics 2010; 51(5):437-442.
    102) Myers LB & Krenzelok EP: Paroxetine (Paxil) overdose: a pediatric focus. Vet Human Toxicol 1997; 39:86-88.
    103) Myers LB, Dean BS, & Krenzelok EP: A pediatric focus: paroxetine (Paxil) overdose (Abstract 172). J Toxicol Clin Toxicol 1995; 313:551.
    104) Myers LB, Dean BS, & Krenzelok EP: Paroxetine (PAXIL): overdose assessment of a new selective serotonin reuptake inhibitor. Vet Human Toxicol 1994; 36:370.
    105) Nader P, Coralie L, Baleydier B, et al: Restless legs syndrome induced by citalopram: a psychiatric emergency?. Gen Hosp Psychiatry 2007; 29(1):72-74.
    106) Nakhai-Pour HR, Broy P, & Berard A: Use of antidepressants during pregnancy and the risk of spontaneous abortion. CMAJ 2010; Epub:Epub.
    107) Nelson LS, Erdman AR, Booze LL, et al: Selective serotonin reuptake inhibitor poisoning: An evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila) 2007; 45(4):315-332.
    108) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    109) Odeh M, Misselevech I, & Boss JH: Severe hepatotoxicity with jaundice associated with paroxetine. Am J Gastroenterol 2001; 96:2494-2496.
    110) Odeh M, Seligmann H, & Oliven A: Severe life-threatening hyponatremia during paroxetine therapy. J Clin Pharmacol 1999; 39:1290-1291.
    111) Ohman R, Hagg S, & Carleborg L: Excretion of paroxetine into breast milk. J Clin Psychiatry 1999; 60:519-523.
    112) Ohrberg S, Christiansen PE, & Severin B: Paroxetine and imipramine in the treatment of depressive patients in psychiatric practice. Acta Psychiatr Scand 1992; 86:437-444.
    113) Orsolini L & Bellantuono C: Serotonin reuptake inhibitors and breastfeeding: a systematic review. Hum Psychopharmacol 2015; 30(1):4-20.
    114) Oswald I & Adam K: Effects of paroxetine on human sleep. Br J Clin Pharmac 1986; 22:97-99.
    115) Ottervanger JP, Stricker BH, & Huls J: Bleeding attributed to intake of paroxetine (letter). Am J Psychiatry 1994; 151:781-782.
    116) Owley T & Flaherty J: New-onset narcolepsy and paroxetine (letter). Psychosomatics 1994; 35:585.
    117) Paul S & Sankaran SK: An unusually rapid onset of hyponatraemia following paroxetine. Aust NZ J Med 1998; 28:840.
    118) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
    119) Phillips SD: A possible paroxetin withdrawal syndrome (letter). Am J Psychiatry 1995; 152:645-646.
    120) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    121) Popli AP, Baldessarini RJ, & Cole JO: Interactions of serotonin reuptake inhibitors with tricyclic antidepressants (letter). Arch Gen Psychiatry 1994; 51:666-667.
    122) Product Information: ATIVAN(R) injection, lorazepam injection. Baxter Healthcare Corporation, Deerfield, IL, 2003.
    123) Product Information: BRISDELLE(R) oral capsules, paroxetine mesylate oral capsules. Noven Therapeutics, LLC (per FDA), Miami, FL, 2014.
    124) Product Information: BRISDELLE(TM) oral capsules, paroxetine mesylate oral capsules. Noven Therapeutics, LLC (per manufacturer), Miami, FL, 2013.
    125) Product Information: PAXIL CR(R) controlled-release oral tablets, paroxetine hydrochloride controlled-release oral tablets. GlaxoSmithKline, Research Triangle Park, NC, 2008.
    126) Product Information: PAXIL CR(R) controlled-release oral tablets, paroxetine hydrochloride controlled-release oral tablets. GlaxoSmithKline, Research Triangle Park, NC, 2010.
    127) Product Information: PAXIL CR(R) controlled-release oral tablets, paroxetine hydrochloride controlled-release oral tablets. GlaxoSmithKline, Research Triangle Park, NC, 2010a.
    128) Product Information: PAXIL CR(R) oral controlled release tablets, paroxetine HCl oral controlled release tablets. GlaxoSmithKline (per FDA), Research Triangle Park, NC, 2012.
    129) Product Information: PAXIL CR(R) oral controlled-release tablets, paroxetine HCl oral controlled-release tablets. Apotex Corp. (per FDA), Weston, FL, 2014.
    130) Product Information: PAXIL(R) oral tablets, oral suspension, paroxetine HCl oral tablets, oral suspension. Apotex Corp. (per FDA), Weston, FL, 2014.
    131) Product Information: PAXIL(R) oral tablets, oral suspension, paroxetine HCl oral tablets, oral suspension. GlaxoSmithKline (per FDA), Research Triangle Park, NC, 2012.
    132) Product Information: PAXIL(R) oral tablets, suspension, paroxetine hydrochloride oral tablets, suspension. GlaxoSmithKline, Research Triangle Park, NC, 2008.
    133) Product Information: PAXIL(R) oral tablets, suspension, paroxetine HCl oral tablets, suspension. GlaxoSmithKline, Research Triangle Park, NC, 2011.
    134) Product Information: PAXIL(R) oral tablets, suspension, paroxetine hydrochloride oral tablets, suspension. GlaxoSmithKline, Research Triangle Park, NC, 2010.
    135) Product Information: PEXEVA(R) oral film coated tablets, paroxetine mesylate oral film coated tablets. Noven Therapeutics, LLC (per DailyMed), Miami, FL, 2012.
    136) Product Information: PEXEVA(R) oral tablets, paroxetine mesylate oral tablets. Noven Therapeutics, LLC (per FDA), Miami, FL, 2014.
    137) Product Information: PEXEVA(R) oral tablets, paroxetine mesylate oral tablets. Noven Therapeutics, LLC, Miami, FL, 2010.
    138) Product Information: Paxil(R), paroxetine hydrochloride. SmithKline Beecham Pharmaceuticals, Philadelphia, PA, 2001.
    139) Product Information: diazepam IM, IV injection, diazepam IM, IV injection. Hospira, Inc (per Manufacturer), Lake Forest, IL, 2008.
    140) Product Information: lorazepam IM, IV injection, lorazepam IM, IV injection. Akorn, Inc, Lake Forest, IL, 2008.
    141) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    142) Pyke RE: Paroxetine withdrawal syndrome (letter). Am J Psychiatry 1995; 152:149-150.
    143) Qureshi A, Wassmer E, Davies P, et al: Comparative audit of intravenous lorazepam and diazepam in the emergency treatment of convulsive status epilepticus in children. Seizure 2002; 11(3):141-144.
    144) RTECS : Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires 2002; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    145) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    146) Reefhuis J, Devine O, Friedman JM, et al: Specific SSRIs and birth defects: bayesian analysis to interpret new data in the context of previous reports. BMJ 2015; 351:h3190.
    147) Reeves RR & Bullen JA: Serotonin syndrome produced by paroxetine and low-dose trazodone (letter). Psychosomatics 1995; 36:159.
    148) Rickels K, Amsterdam J, & Clary C: A placebo-controlled, double-blind, clinical trial of paroxetine in depressed outpatients. Acta Psychiatr Scand 1989; 80(Suppl 350):117-123.
    149) Romanelli F, Adler DA, & Bungay KM: Possible paroxetine-induced bruxism. Ann Pharmacother 1996; 30:1246-1248.
    150) Roth A, Akyol S, & Nelson JC: Delirium associated with the combination of a neuroleptic, an SSRI, and benztropine. J Clin Psychiatry 1994; 55:492-495.
    151) Ryan PM, Kelly JP, & Chambers PL: The toxicity profile of a single dose of paroxetine: an alternative approach to acute toxicity testing in the rat. Pharmacol Toxicol 2001; 88:59-66.
    152) Sauer WH, Berlin JA, & Kimmel SE: Selective serotonin reuptake inhibitors and myocardial infarction. Circulation 2001; 104:1894-1898.
    153) Scott R, Besag FMC, & Neville BGR: Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomized trial. Lancet 1999; 353:623-626.
    154) Skop BP, Finkelstein JA, & Mareth TR: The serotonin syndrome associated with paroxetine, an over-the-counter cold remedy, and vascular disease. Am J Emerg Med 1994; 12:642-644.
    155) Sreenath TG, Gupta P, Sharma KK, et al: Lorazepam versus diazepam-phenytoin combination in the treatment of convulsive status epilepticus in children: A randomized controlled trial. Eur J Paediatr Neurol 2009; Epub:Epub.
    156) Sternbach H: The serotonin syndrome. Am J Psychiatr 1991; 148:705-713.
    157) Stiskal JA, Kulin N, & Koren G: Neonatal paroxetine withdrawal syndrome. Arch Dis Child Fetal Neonatal Ed 2001; 84:F134-F135.
    158) Stowe ZN, Cohen LS, & Hostetter A: Paroxetine in human breast milk and nursing infants. Am J Psychiatry 2000; 157:185-189.
    159) Tonks A: Withdrawal from paroxetine can be severe, warns FDA. Br Med J 2002; 324:260.
    160) Van Campen JP & Voets AJ: SIADH caused by paroxetine (letter). Ann Pharmacother 1996; 30:1499.
    161) Van Walraven C, Mamdani MM, & Wells PS: Inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding in elderly patients: retrospective cohort study. Br Med J 2001; 323:655-658.
    162) Velez LI, Shepherd G, Roth BA, et al: Serotonin syndrome with elevated paroxetine concentrations. Ann Pharmacother 2004; 38:269-272.
    163) Vermeulen T: Distribution of paroxetine in three postmortem cases. J Anal Toxicol 1998; 22:541-544.
    164) Wheless JW : Treatment of status epilepticus in children. Pediatr Ann 2004; 33(6):376-383.
    165) Wilson SJ, Lillywhite AR, & Potokar JP: Adult night terrors and paroxetine. Lancet 1997; 350:185.
    166) Yazdy MM, Mitchell AA, Louik C, et al: Use of selective serotonin-reuptake inhibitors during pregnancy and the risk of clubfoot. Epidemiology 2014; 25(6):859-865.
    167) Zajecka J, Tracy KA, & Mitchell S: Discontinuation symptoms after treatment with serotonin reuptake inhibitors: a literature review. J Clin Psychiatry 1997; 58:291-297.