Paroksetin (Paxera)

Clinical Effects:

PAROXETINE
  • 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. 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. 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. EPIDEMIOLOGY: Paroxetine overdoses are common; however, severe toxicity from isolated ingestion is relatively rare. A majority of patients will have only mild symptoms. OVERDOSE: 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. 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. ADVERSE EFFECTS: 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). LESS FREQUENT: Less frequent adverse effects include spontaneous ecchymosis, syncope, premature ventricular contractions (PVCs), tremor, headache, extrapyramidal reactions, akathisia, orolingual movements, and bruxism. 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.

Range of Toxicity:

PAROXETINE
  • 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. 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. PEDIATRIC: There is no specific data available on pediatric dosing; safety and efficacy have not been established in pediatric patients.

Treatment:

PAROXETINE
  • Support: MANAGEMENT OF MILD TO MODERATE TOXICITY: Treatment is symptomatic and supportive. 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.
  • Decontamination: 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. 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.
  • Airway management: Rarely, patients with marked CNS depression may need intubation for respiratory support.
  • Antidote: There is no specific antidote for treatment of paroxetine overdose.
  • Hypotensive episode: IV 0.9% NaCl 10 to 20 ml/kg, add norepinephrine if hypotension persists
  • Seizure: Administer IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
  • Serotonin syndrome: 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.
  • Monitoring of patient: Monitor vital signs and mental status. Paroxetine levels are not widely available or clinically useful. Serum electrolytes, renal function, and creatine kinase (CK) should be evaluated in patients with evidence of toxicity. Patients with toxicity should receive an EKG and cardiac monitoring.
  • Enhanced elimination procedure: 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.
  • Patient disposition: 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. 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). 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. 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.
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