VENLAFAXINE AND RELATED AGENTS
- USES: Venlafaxine and desvenlafaxine are primarily used to treat anxiety and depressive disorders. Off-label uses for venlafaxine include treatment of ADHD, eating disorders, chronic pain, headache and agoraphobia. Extended release formulations of both drugs are available. PHARMACOLOGY: Venlafaxine and desvenlafaxine inhibit neuronal reuptake of both serotonin and norepinephrine in the CNS. TOXICOLOGY: Increases in serotonin, norepinephrine, and dopamine can lead to cardiovascular toxicity (due to sodium and potassium channel blockade), and seizures. Venlafaxine and desvenlafaxine are highly serotonergic and have been implicated in causing serotonin syndrome in therapeutic doses or (rarely) in overdose, as single agents or in combination with other serotonergic agents. EPIDEMIOLOGY: Poisoning is common and several deaths occur each year. MILD TO MODERATE TOXICITY: Mild serotonergic effects include tremor, hyperreflexia, anxiety, and agitation. Palpitations, tachycardia and exacerbation of congestive heart failure have been reported with both therapeutic use and overdose. Somnolence is common in mild toxicity though delirium is more likely as toxicity increases. SEVERE TOXICITY: Serotonin syndrome (altered mental status, neuromuscular abnormalities/rigidity, autonomic instability) is a severe manifestation of overdose. Cardiovascular toxicity includes, PR, QRS, and QT prolongation occasionally culminating in ventricular tachycardia, fibrillation, and cardiac arrest. Interval prolongation is common though ventricular dysrhythmias are rare and are associated with large overdose (greater than 8 g). Seizures are common in patients taking over 1 g. Seizures have been reported in neonates exposed in utero from mothers taking therapeutic doses. Rhabdomyolysis is common in severe toxicity. Development of eosinophilic pneumonia was reported in a young adult following overdose. Coma is a rare effect of severe toxicity. ADVERSE EVENTS: Mild effects include nausea/vomiting, dry mouth, constipation, loss of appetite, asthenia, dizziness, headache, insomnia, somnolence, blurred vision, nervousness and tremor following therapeutic venlafaxine therapy. The most commonly reported adverse events reported with desvenlafaxine were similar to venlafaxine. The following adverse effects have also rarely occurred with therapeutic doses of these agents: hyponatremia, hypochloremia, hepatitis, seizures, serotonin syndrome (generally if used with another serotonergic agent), thrombocytopenia, exacerbation of congestive heart failure, and elevated blood pressure.
Range of Toxicity:
VENLAFAXINE AND RELATED AGENTS
- TOXICITY: VENLAFAXINE: ADULTS: Doses larger than 1500 mg have been associated with seizures. Life-threatening cardiovascular toxicity manifested by ventricular dysrhythmias are associated with doses larger than 8000 mg. PEDIATRIC: Doses less than 5.5 mg/kg in children are unlikely to result in toxicity. DESVENLAFAXINE: Limited data. In a premarketing study, 4 adults ingested desvenlafaxine succinate (4000 mg [desvenlafaxine alone], 900, 1800 and 5200 mg [in combination with other drugs]) and each patient recovered. Adverse events reported and likely associated with a 5-day overdose of greater than 600 mg daily, included: headache, nausea/vomiting, diarrhea, agitation, dizziness, paresthesia and tachycardia. An 11-month-old ingested 600 mg of desvenlafaxine succinate and recovered completely with treatment. THERAPEUTIC DOSE: VENLAFAXINE: ADULT: 37.5 to 75 mg/day orally; MAX dose of 375 mg/day of immediate-release and 225 mg of extended-release. DESVENLAFAXINE: ADULT: 50 mg daily; PEDIATRIC: Not approved for use.
VENLAFAXINE AND RELATED AGENTS
- Support: MANAGEMENT OF MILD TO MODERATE TOXICITY: Supportive care is the mainstay of mild/moderate toxicity. Benzodiazepines are the treatment of choice for agitation, mild serotonergic effects, and hyperadrenergic vital signs. Treat mild hypotension with intravenous fluids. MANAGEMENT OF SEVERE TOXICITY: Benzodiazepines should be used for seizures and agitation; often large doses are necessary. Patients with agitation, tachycardia, fever, or seizures that are unresponsive to benzodiazepines should be intubated and sedated with propofol or barbiturates. Neuromuscular paralysis with continuous EEG monitoring should be considered if hyperthermia persists despite adequate sedative administration. Isotonic fluids should be given to replace large insensible losses, facilitate myoglobin clearance, and promote renal clearance of the agent. Severe hypotension may require vasopressors, if hypotension persists consider insulin and dextrose infusion, or intravenous fat emulsion therapy. Consider extracorporeal support (cardiopulmonary bypass, extracorporeal membrane oxygenation, aortic balloon pump) in patients who remain unstable despite maximal medical therapy.
- Decontamination: PREHOSPITAL: In general, there is no role for prehospital decontamination because of the risk of seizures and subsequent aspiration. HOSPITAL: Activated charcoal should be considered in asymptomatic or minimally symptomatic patients who present within a few hours of ingestion, or in symptomatic patients who have a secure airway. Gastric lavage may be considered for large overdoses who present within approximately 1 hour of ingestion, though airway protection should be considered prior to the procedure. Gastroscopy has been used rarely to remove extended release formulations from the stomach. COMBINED THERAPY: The combination of single-dose activated charcoal and whole bowel irrigation has been shown to decrease peak blood concentrations and may be beneficial in decreasing the risk of seizures and cardiovascular toxicity, following airway management, in a large overdose predominated by CNS depression.
- Airway management: Though respiratory depression is not a manifestation of toxicity, airway protection may be necessary in patients with profound agitation, seizures, or cardiac dysrhythmias.
- Antidote: There is no known antidote.
- Seizure: Seizures and agitated delirium should be treated with benzodiazepines; large doses may be necessary. Diazepam: ADULT: 5 to 10 mg repeat every 10 to 15 minutes as needed. CHILD: 0.2 to 0.5 mg/kg, repeat every 5 minutes as needed; or Lorazepam: ADULT: 2 to 4 mg; CHILD: 0.05 to 0.1 mg/kg. If unresponsive to benzodiazepines, propofol or barbiturates can be used.
- Hypotensive episode: Treat with isotonic fluids. If unresponsive to 2 liters (or 40 mL/kg in children) direct acting vasopressor agents should be used (norepinephrine or phenylephrine). If hypotension persists consider insulin and dextrose infusion, or intravenous fat emulsion therapy.
- Insulin: Administer a bolus of 1 unit/kg of insulin followed by an infusion of 0.1 to 1 unit/kg/hr, titrated to a systolic blood pressure of greater than 90 to 100 mmHg (bradycardia may or may not respond). Reassess every 30 minutes to titrate insulin infusion. Administer dextrose bolus to patients with an initial blood glucose of less than 250 mg/dL (adults 25 to 50 mL dextrose 50%, children 0.25 g/kg dextrose 25%). Begin a dextrose infusion of 0.5 g/kg/hr in all patients. Monitor blood glucose every 15 to 30 minutes until consistently 100 to 200 mg/dL for 4 hours, then monitor every hour. Titrate dextrose infusion to maintain blood glucose in the range of 100 to 200 mg/dL. As the patient improves, insulin resistance abates and dextrose requirements will increase. Supplemental dextrose will be needed for at least several hours after the insulin infusion is discontinued. Administer supplemental potassium initially if patient is hypokalemic (serum potassium less than 2.5 mEq/L). Monitor serum potassium every 4 hours and supplement as needed to maintain potassium of 2.5 to 2.8 mEq/L.
- Fat Emulsion: Lipid emulsion has been successful in animal studies and case reports of patients with refractory hypotension and dysrhythmias after overdose from other lipid soluble xenobiotics. It should be considered in patients with severe cardiac toxicity from venlafaxine overdose. Administer 1.5 mL/kg of 20% lipid emulsion over 2 to 3 minutes as an IV bolus, followed by an infusion of 0.25 mL/kg/min. If possible, discontinue after 30 to 60 minutes. Longer periods of lipid therapy should be considered if the patient’s hemodynamic stability is dependent on continued lipid infusion.
- Tachycardia: Treat with fluids and sedative agents, benzodiazepines should be a first-line therapy.
- Conduction disorder of the heart: QRS widening (progressive widening on serial ECGs or a single ECG with a duration longer than 120 msec) should be treated with bicarbonate boluses of 50 mEq until the QRS narrows. The serum pH should be maintained between 7.45 and 7.55 (CHILD: 1 to 2 mEq/kg of sodium bicarbonate).
- Ventricular arrhythmia: Unstable ventricular dysrhythmias should be treated according to ACLS protocols. Lidocaine has been suggested as the antiarrhythmic of choice for ventricular tachycardia or ventricular fibrillation.
- Nausea and vomiting: Severe vomiting can be treated with antiemetics. Metoclopramide: ADULT: 10 to 20 mg every hour as needed; CHILD: 0.1 to 0.2 mg/kg repeated every 6 hours as needed.
- Hyperthermia treatment: Benzodiazepines should be used liberally to control agitation. Enhance heat loss using evaporation (keep skin damp and use fans to encourage air circulation), ice water immersion or packing the patient in ice for severe hyperthermia. In severe cases, the patient should be intubated and higher doses of sedatives, such as propofol, should be used. Occasionally, paralysis is necessary to eliminate the neuromuscular tone that is the etiology of rhabdomyolysis and fever.
- Serotonin syndrome: Benzodiazepines should be administered to control neuromuscular hyperactivity. Cyproheptadine has been used as a serotonin receptor antagonist minimizing the serotonergic effects in overdose. Adult dosing of cyproheptadine is 8 mg every 6 hours. It is only available in an oral formulation; it can be crushed and administered via nasogastric tube if the patient is unable to take orally. CHILD: 0.25 mg/kg, maximum 8 mg/dose.
- Monitoring of patient: Monitor vital signs, institute continuous cardiac monitoring and obtain an ECG. In moderate to severe toxicity serum electrolytes, CBC, and creatinine kinase should be obtained. EEG monitoring may be necessary for patients that require paralysis. Monitor glucose following a significant exposure. Infrequent reports of prolonged/recurrent hypoglycemia have occurred following overdose. Venlafaxine may cause false positive results for phencyclidine or tramadol on drug screening assays.
- Enhanced elimination procedure: Venlafaxine and desvenlafaxine have large volumes of distribution, so hemodialysis is unlikely to be effective in overdose.
- Patient disposition: HOME CRITERIA: An inadvertent ingestion of a single agent of less than 5.5 mg/kg venlafaxine in an asymptomatic child may be managed at home. OBSERVATION CRITERIA: Patients who are symptomatic, those who have taken deliberate ingestions, and children with inadvertent ingestions of more than 5.5 mg/kg venlafaxine should be sent to a healthcare facility for observation. IMMEDIATE RELEASE: Observe patients for at least 6 hours (Tmax of venlafaxine is 2 hours for venlafaxine and 3 hours for the active metabolite, O-desmthylvenlafaxine (ODV)) as symptoms will likely develop within this time period. EXTENDED RELEASE: Patients that have ingested an extended release product (Tmax of venlafaxine 150 mg extended release capsule is 5.5 hours for venlafaxine and 9 hours for the active metabolite, ODV) have the potential to manifest delayed symptoms and should be observed for 11 to 18 hours. Patients should be observed until vital signs are normal and symptoms have resolved. ADMISSION CRITERIA: Overdose patients with delirium, seizures, rhabdomyolysis, or ventricular dysrhythmias should be admitted until toxicity resolves. All patients with cardiac dysrhythmias or serotonin syndrome should be admitted to an ICU. CONSULT CRITERIA: A medical toxicologist or poison control center should be consulted for any patient with moderate or severe toxicity.