a) A withdrawal syndrome was reported following the rapid reduction of venlafaxine therapy.

a) 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.

a) 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. Evaluate the patient's response after 3 minutes at this infusion rate. The infusion rate may be decreased to 0.025 mL/kg/min (ie, 1/10 the initial rate) in patients with a significant response. This recommendation has been proposed because of possible adverse effects from very high cumulative rates of lipid infusion. Monitor blood pressure, heart rate, and other hemodynamic parameters every 15 minutes during the infusion. If there is an initial response to the bolus followed by the re-emergence of hemodynamic instability during the lowest-dose infusion, the infusion rate may be increased back to 0.25 mL/kg/min or, in severe cases, the bolus could be repeated. A maximum dose of 10 mL/kg has been recommended by some sources. Where possible, lipid resuscitation therapy should be terminated after 1 hour or less, if the patient's clinical status permits. In cases where the patient's stability is dependent on continued lipid infusion, longer treatment may be appropriate.

a) CASE SERIES: In a prospective review of consecutive patients presenting with a venlafaxine alone overdose between January 1997 and December 2007, 369 occasions of venlafaxine overdoses (median dose: 1500 mg; Interquartile Range (IQR): 600 to 3000 mg; range: 75 to 13500 mg) in 273 patients were observed with no reports of dysrhythmias and only minor ECG changes. Tachycardia was observed in 54% of patients and mild hypertension was reported in 40% of patients; severe hypertension (systolic BP greater than 180 mm Hg) developed in 3% of patients, and mild hypotension systolic BP less than 90 mm Hg) developed in 5%. Conduction disturbances were found in 7 patients with 5 patients having a preexisting history of conduction disturbances. Alterations in QRS and QT interval were considered mild (the median maximum QRS width was 85 ms (IQR: 80 to 90 ms; range: 70 to 145 ms); 24 patients (7%) had a QRS of greater than or equal to 120 ms. QTc was prolonged in 22 patients (6%) and patients ingesting larger doses were more likely to develop QTc prolongation. The findings suggest that a mild exposure does not result in cardiotoxicity; however, doses greater than 8 g may produce significant cardiotoxicity (Isbister, 2009).

a) A low incidence of cardiovascular effects has been reported for venlafaxine as compared to tricyclic antidepressants. Out of 14 reported cases of venlafaxine acute overdoses two patients were reported to have developed a mild sinus tachycardia and a third patient was reported to have a prolongation of QTc to 500 msec, compared with 405 msec at baseline(Prod Info Effexor(R) oral tablets, 2010).
b) CASE SERIES: In a prospective review of consecutive patients presenting with a venlafaxine alone overdose between January 1997 and December 2007, 369 occasions of venlafaxine overdoses (median dose: 1500 mg; Interquartile Range (IQR): 600 to 3000 mg; range: 75 to 13500 mg) in 273 patients, tachycardia was observed in 54% of patients (Isbister, 2009).
c) CASE SERIES: In a retrospective review of 235 consecutive cases of venlafaxine (median dose 1500 mg; range: 919 to 2800 mg) overdose, tachycardia (heart rate greater than 100 beats per minute) occurred in 94 patients (40%) and was found to be dose-dependent (Howell et al, 2007).
d) CASE REPORT: A 41-year-old woman who ingested 4.5 g venlafaxine, 500 mg diphenhydramine and 50 mg thiothixene presented to the ED with sinus tachycardia and diffuse nonspecific T wave changes on ECG. Treatment was symptomatic with resultant full recovery (Fantaskey & Burkhart, 1995).
e) Tachycardia has also been reported in other patients with venlafaxine overdose (Paparrigopoulos et al, 2011; Pascale et al, 2005; Shaw & Sheard, 2005; Hanekamp et al, 2005; Mazur et al, 2003; Woo et al, 1995; Dahl et al, 1996; Peano et al, 1996; Kokan & Dart, 1996; Adesanya & Varma, 1997; Leaf, 1998; Coorey & Wenck, 1998; Rosen et al, 1997; Blythe & Hackett, 1999; Thorsson et al, 2000).

a) CASE REPORT: A 38-year-old man developed ventricular tachycardia after ingesting venlafaxine and lamotrigine (Peano et al, 1996).
b) CASE REPORT/FATALITY: A 45-year-old woman ingested 8.4 g of venlafaxine and was found pulseless. She was in ventricular fibrillation on paramedics arrival; spontaneous rhythm was restored with intubation/oxygenation, epinephrine, atropine, and direct current shock but she remained severely hypotensive and was determined to be brain dead (Banham, 1998).
c) CASE REPORT: Ventricular tachycardia, ventricular fibrillation, and supraventricular tachycardia have been reported in a patient who took 7.5 g of venlafaxine and an unknown amount of oxazepam (Thorsson et al, 2000).
d) CASE REPORT: A 24-year-old woman developed sinus tachycardia (130 to 155 beats per minute) and seizures followed by intraventricular conduction abnormalities and an episode of torsades de pointes after an intentional ingestion of 8.85 g venlafaxine. ECG abnormalities resolved over 24 hours following administration of intravenous magnesium. The patient was discharged home without further complications (Oliver et al, 2002).

a) CASE SERIES: In a prospective review of consecutive patients presenting with a venlafaxine alone overdose between January 1997 and December 2007, 369 occasions of venlafaxine overdoses (median dose: 1500 mg; Interquartile Range (IQR): 600 to 3000 mg; range: 75 to 13500 mg) in 273 patients were observed with no reports of dysrhythmias and only minor ECG changes. QTc was prolonged in 22 patients (6%) and patients ingesting larger doses were more likely to develop QTc prolongation(Isbister, 2009).
b) CASE SERIES: In a retrospective review of 235 consecutive cases of venlafaxine (median dose 1500 mg; range: 919 to 2800 mg) overdose, QTc prolongation (greater than 450 ms) occurred in 24 patients (10.7%) and was found to be dose-dependent. No related dysrhythmias or fatalities were reported (Howell et al, 2007).
c) CASE REPORT: A 41-year-old man developed hypotension, QRS widening and QTc prolongation after ingesting 5.6 g of venlafaxine (Kokan & Dart, 1996).
d) Out of 14 reported cases of venlafaxine acute overdoses, 2 patients were reported to have developed a mild sinus tachycardia and a third patient was reported to have a prolongation of QTc to 500 msec, compared with 405 msec at baseline (Prod Info Effexor(R) oral tablets, 2010).
e) CASE REPORT: A 29-year-old man ingested 2.8 g of venlafaxine and developed prolonged QRS complexes (limb leads, 0.12 sec) and rSR' pattern in the anterior chest leads on ECG (Coorey & Wenck, 1998).
f) CASE REPORT: A 45-year-old woman ingested 10.9 g of venlafaxine and 35 mg of clonazepam, presented to the Emergency Department with a normal ECG, but subsequently developed, over the next hour, flattening of ST segments and intraventricular conduction delay (Rosen et al, 1997).
g) CASE REPORT: A 33-year-old woman ingested 8.4 g of venlafaxine and developed right axis deviation, a prolonged QT interval (469 msec) and a prolonged QRS complex (129 msec). It is suggested that cardiotoxicity is more likely in patients with the poor CYP2D6 metabolizer phenotype (Blythe & Hackett, 1999).
h) CASE REPORT: A 44-year-old woman overdosed with venlafaxine (3 g), clonazepam (20 mg), lormetazepam (24 mg) and thioridazine (10 mg). She presented with incomplete right bundle branch block, and subsequently developed hypotension followed by atrial fibrillation with wide QRS complexes. Sinus rhythm with normal QRS complexes resumed within 15 minutes of infusion of 100 mL 1M sodium bicarbonate (Combes et al, 2001).
i) CASE REPORT: After ingesting 4.5 g of venlafaxine, a 25-year-old woman developed a generalized seizure, sinus tachycardia (150 bpm), incomplete right bundle branch block, QRS duration of 100 msec, prolonged QTc duration (0.46 seconds), and rhabdomyolysis (CK 52,600 Units/L). ECG abnormalities resolved by the day after admission (Pascale et al, 2005).

a) CASE REPORT/FATALITY: A 40-year-old man intentionally ingested 19 g of extended release venlafaxine (90 150-mg venlafaxine and 75 75-mg venlafaxine extended-release tablets) and was admitted within 45 minutes of exposure, and was alert with mild tachycardia. An initial ECG showed tachycardia with no evidence of ischemia. Decontamination included activated charcoal and whole bowel irrigation. Toxicology screening was negative. Over the course of several hours the patient developed 2 seizures and was admitted to the intensive care. Approximately 9 hours after exposure, the patient was increasingly lethargic and developed refractory ventricular fibrillation (VF). The authors suggest that sodium channel toxicity was responsible for the fatal dysrhythmia. Although the patient developed no evidence of ventricular ectopy, the ECG showed a new onset of QRS widening (158 msec) and QTc prolongation (564 msec) shortly before the patient's death (Bosse et al, 2008).

a) CASE SERIES: In a prospective review of consecutive patients presenting with a venlafaxine alone overdose between January 1997 and December 2007, 369 occasions of venlafaxine overdoses (median dose: 1500 mg; Interquartile Range (IQR): 600 to 3000 mg; range: 75 to 13500 mg) in 273 patients were observed with no reports of dysrhythmias and only minor ECG changes. Alterations in QRS interval was considered mild (the median maximum QRS width was 85 ms (IQR: 80 to 90 ms; range: 70 to 145 ms; 24 patients (7%) had a QRS of greater than or equal to 120 ms (Isbister, 2009).
b) CASE REPORT/FATALITY: A 30-year-old woman developed tachycardia followed by asystole after a mixed ingestion including venlafaxine and carbamazepine (Dahl et al, 1996). Postmortem blood venlafaxine level was 89,000 ng/mL (225 times therapeutic).
c) CASE REPORT: A 44-year-old woman overdosed with venlafaxine (3 g), clonazepam (20 mg), lormetazepam (24 mg) and thioridazine (10 mg). She presented with incomplete right bundle branch block, and subsequently developed hypotension followed by atrial fibrillation with wide QRS complexes. Sinus rhythm with normal QRS complexes resumed within 15 minutes of infusion of 100 mL 1M sodium bicarbonate (Combes et al, 2001).
d) CASE REPORT: A 35 year-old woman taking 225 mg daily of venlafaxine and 300 mg daily of bupropion received an ICD for severe, nonischemic cardiomyopathy. Initial testing of the ICD failed to convert induced ventricular fibrillation at 15 Joules and 20 Joules. Venlafaxine and bupropion were discontinued and the ICD performed normally on testing 4 days later. Venlafaxine was thought to be responsible for the elevated defibrillation threshold due to its inhibition of cardiac sodium channels (Carnes et al, 2004).

a) Hypotension has been reported following venlafaxine overdose (Durback & Scharman, 1996; Kokan & Dart, 1996; Rosen et al, 1997).
b) CASE REPORT/FATALITY: A 39-year-old woman presented to the ED after ingesting 30 g of extended-release venlafaxine capsules approximately 12 to 24 hours prior to arrival. Initial blood pressure was 85/45 mmHg, but gradually worsened requiring intensive care and ventilatory support. A dopamine infusion was titrated up to 20 mcg/kg/min for worsening hypotension; norepinephrine and phenylephrine infusions were subsequently added. A lidocaine infusion was started following two episodes of ventricular tachycardia. Dobutamine was also started, but discontinued due to tachycardia. Weaning from all vasopressors and inotropic support occurred by hospital day 4; however, the patient remained unresponsive, developed complications of bowel perforation and died on hospital day 43 (Mazur et al, 2003).
c) CASE REPORT: A 41-year-old man developed hypotension after ingesting 5.6 grams of venlafaxine (Kokan & Dart, 1996).
d) CASE REPORT: A 45-year-old woman developed somnolence and hypotension after an overdose ingestion of venlafaxine (10.9 grams) and clonazepam (35 mg). The patient's blood pressure increased following supportive care (Rosen et al, 1997).
e) CASE REPORT: A 44-year-old woman overdosed with venlafaxine (3 g), clonazepam (20 mg), lormetazepam (24 mg) and thioridazine (10 mg). She presented with incomplete right bundle branch block, and subsequently developed hypotension followed by atrial fibrillation with wide QRS complexes. Sinus rhythm with normal QRS complexes resumed within 15 minutes of infusion of 100 mL 1M sodium bicarbonate (Combes et al, 2001).
f) CASE REPORT/FATALITY: A 45-year-old woman ingested 8.4 g of venlafaxine and was found pulseless. She was in ventricular fibrillation on paramedics arrival; spontaneous rhythm was restored with intubation/oxygenation, epinephrine, atropine, and direct current shock but she remained severely hypotensive and was determined to be brain dead (Banham, 1998).

a) Sustained increases in blood pressure have been reported in patients receiving therapeutic doses of venlafaxine. Premarketing studies have shown an incidence of sustained increased supine diastolic blood pressure of 3% for venlafaxine doses less than 100 mg/day, 5% for doses between 101 and 200 mg/day, 7% for doses between 201 and 300 mg/day, and 13% for doses greater than 300 mg/day. Most of the blood pressure increases were between 10 and 15 mmHg (Prod Info Effexor(R) oral tablets, 2010).

a) CASE SERIES: In a retrospective review of 235 consecutive cases of venlafaxine (median dose 1500 mg; range: 919 to 2800 mg) overdose, hypertension (systolic greater than 140 mmHg (28.4%; n=64)) occurred in 64 patients (28.4%) (Howell et al, 2007).
b) CASE REPORT: Hypertension (BP 168/101 mmHg) was evident in a 41-year-old woman following ingestion of 4.5 g venlafaxine, 500 mg diphenhydramine and 50 mg thiothixene (Fantaskey & Burkhart, 1995).

a) Palpitations were reported in 3 of 66 patients receiving venlafaxine 75 to 375 mg/day in one study; however, a causal relationship was not established (Khan et al, 1991).

a) CASE REPORT: A 21-year-old woman experienced progressive dyspnea, cough, vomiting, and weight loss over two months. She had been taking venlafaxine since two months prior to symptom onset. Echocardiography demonstrated an ejection fraction of 38% with normal coronary angiography. CT of the chest showed multiple, small interstitial nodules. Lung biopsy noted a lymphocytic interstitial infiltrate with occasional granulomas. Clinical condition improved over two weeks following corticosteroid therapy and discontinuation of venlafaxine. She remained asymptomatic at 3 years follow-up (Drent et al, 2003).

a) CASE REPORT: A 30-year-old woman took an overdose of 5.5 g venlafaxine, as well as 250 mg hydroxyzine and 500 mg alprazolam. She presented with symptoms of seizures and severe serotonin syndrome. Within 10 hours she developed cardiogenic pulmonary edema. Echocardiography demonstrated global left ventricular hypokinesia (sparing the apex) and an ejection fraction of 35%. She improved with supportive care. Follow-up echocardiography obtained 10 days later was normal (Fangio et al, 2007).
b) CASE REPORTS: Four healthy women with no history of cardiovascular disease were admitted with left ventricular (LV) failure following overdose of venlafaxine. Three patients died and one completely recovered. The amount of venlafaxine ranged from 3150 to 13500 mg (extended-release preparations in 2 cases). LV ejection fraction on echocardiography was between 15% and 18% in 3 patients. A 38-year-old woman ingested 4200 mg and developed serotonin syndrome and LV failure and was improving, but died on day 11 of refractory hypoxemia. The second patient, a 35-year-old woman ingested 90 (150 mg extended release) tablets and developed generalized seizures and LV failure (15% ejection fraction). At 17 hours, despite aggressive care the patient died of a sudden cardiac arrest. The final patient, a 65-year-old woman ingested 7000 mg of immediate-release venlafaxine and was comatose within 7 hours and died 7 hours later. The patient developed low cardiac output (1 L/min) and died of refractory cardiogenic shock; an echocardiogram was not performed (Batista et al, 2013).

a) CASE REPORTS/FATALITY: Two adult women were admitted with CNS depression, tachycardia and hypotension following large ingestions of venlafaxine (approximately 14.7 g of extended-release capsules in one patient). Shortly after admission, episodes of ventricular tachycardia and ventricular fibrillation (in one patient) occurred and were initially responsive to therapy. However, both patients developed cardiac arrest which failed to respond to resuscitation efforts. One patient died within 3.5 hours of admission, and the second patient died within the first 24 hours of admission. Both had high venlafaxine concentrations at autopsy performed 48 hours after death (Hojer et al, 2008).
b) CASE REPORT: Prolonged cardiac arrest has been reported in a patient who took 7.5 g of venlafaxine and an unknown amount of oxazepam (Thorsson et al, 2000).
c) CASE REPORT/FATALITY: After ingesting an unknown amount of venlafaxine, a 34-year-old man developed signs and symptoms of serotonin syndrome, and developed rhabdomyolysis, renal and cardiac failure and died a day later (Shaw & Sheard, 2005).

a) CASE REPORT: A 51-year-old woman with no prior history of heart disease developed a non-ST elevation myocardial infarction and severe CNS depression following a mixed ingestion of an unknown amount of venlafaxine, metoprolol and acetaminophen. One day after ingestion, serum concentrations of venlafaxine and O-desmethylvenlafaxine were 21.82 mg/L (therapeutic range: 0.1 to 0.5 mg/L) and 3.33 mg/L (0.2 to 0.4 mg/L), respectively. Elevated levels of alcohol and acetaminophen were also reported. The patient was found to have normal coronary arteries following cardiac catheterization and gradually improved with supportive care. It was suggested that venlafaxine may have been associated with an acute ischemic event, although the role of coingestants in this patient cannot be determined (Godkar et al, 2009).

a) CASE REPORT: A 27-year-old man developed serotonin syndrome (diaphoresis, tremor, tachycardia and hypertension) and chest pain after overdose with venlafaxine and paroxetine. ECG showed LVH with strain, initial CK was 233 IU/L with an MB fraction of 34 IU/L (14.6%) with a peak CK of 1748 IU/L. Echocardiogram showed an area of hypokinesia of the anterior septum and reduced LV function (fractional shortening 20%). Chest pain resolved, and blood pressure and ECG normalized after several days but a repeat echocardiogram showed a persistent area of hypokinesia and improved LV function (fractional shortening 29%) (Patridge et al, 2000).

a) CASE REPORT: A 55-year-old woman developed worsening fatigue and exertional dyspnea over 6 months. Her medication regimen included: venlafaxine (for 18 months), furosemide, valdecoxcib, atorvastatin, levothyroxine, ezetimibe, and an estradiol patch. CT of the chest noted bilateral ground-glass opacities and prominent hilar lymph nodes. Cardiac catheterization noted an ejection fraction of 60% to 65%. Lung biopsy showed chronic interstitial pneumonia and chronic bronchiolitis consistent with extrinsic allergic alveolitis. Evaluations for fungal infections or hypersensitivity pneumonitis were negative. The patient was treated with methylprednisolone and venlafaxine was discontinued. She recovered 10 days later with improved appearance of her chest radiograph. The patient remained well 4 months later (Turner et al, 2005).
b) CASE REPORT: A 41-year-old man developed fever, cough, dyspnea and myalgias approximately two weeks after initiation of venlafaxine therapy. CT of the chest noted patchy ground-glass opacities, thickened interlobular septae and bilateral pleural effusions. Transbronchial biopsy showed intravascular and intra-alveolar accumulation of eosinophils, neutrophils and macrophages. Evaluations for infectious or autoimmune etiologies were negative. Venlafaxine was discontinued and the patient was treated with methylprednisolone and clarithromycin. He recovered 10 days later and remained well 2 months later (Fleisch et al, 2000).

a) CASE REPORT: A 27-year-old man with schizoaffective disorder developed dyspnea and tachycardia of 125 beats/minute on day 2 of admission after intentionally ingesting 6.3 g of extended-release venlafaxine. Diffuse crackles were noted on exam with bilateral interstitial infiltrates and pulmonary consolidations confirmed on x-ray. Arterial blood gases showed PaCO2 30 mmHg, PaO2 49 mmHg, SaO2 84%, and pH 7.44. He was started on empiric antibiotics with a WBC of 18.5 x 10(3)mcL. On day 3 he developed respiratory failure and shock; bronchoalveolar lavage showed 80% eosinophils, supporting a potential diagnosis of eosinophilic pneumonia. He was intubated, treated with vasopressors and corticosteroids, and discharged uneventfully from the ICU 7 days later. Ten days from admission a chest x-ray was clear. Eosinophilia resolved within 2 months (Paparrigopoulos et al, 2011).

a) Seizures were reported to occur in 0.26% of patients receiving therapeutic doses of venlafaxine (Prod Info Effexor(R) oral tablets, 2010).

a) INCIDENCE: In a prospective series of 146 cases of venlafaxine overdose, 7 (5%) had seizures (Setz et al, 1995).
b) COMBINATION OVERDOSE: A 44-year-old woman ingested diazepam 200 mg, lamotrigine 20 g, and venlafaxine 4.5 g, and was found unconscious at home. After admission, a tonic-clonic seizure, rigidity, hyperreflexia, and reflex myocloni were observed. Laboratory results revealed sodium level of 129 mmol/L, creatinine kinase of 1915 Units/L, and creatine kinase-MB of 31 Units/L. Despite supportive therapy, including 8 hours of hemodialysis, her rigidity and hyperreflexia did not improve. Following treatment with an intravenous bolus (150 mL, 2.5 mL/kg) of 20% lipid emulsion, all symptoms resolved completely. On day 6, she was transferred to a psychiatric ward. Before hemodialysis, plasma concentrations of lamotrigine, diazepam, and venlafaxine were 42.4 mg/L (therapeutic range, 1 to 4 mg/L), 560 mcg/L (therapeutic range, 200 to 500 mcg/L), and 1254 mcg/L (therapeutic range, 30 to 150 mcg/L), respectively (Dagtekin et al, 2011).
c) In preclinical trials there were 14 reports of venlafaxine overdoses. One patient, who ingested 2.75 grams, along with 0.5 milligrams thyroxine, was reported to have two generalized seizures and recovered without sequelae (Anon, 1993a).
d) Seizures have been reported in several other overdose cases (Paparrigopoulos et al, 2011; Pascale et al, 2005; Kokan & Dart, 1996; Durback & Scharman, 1996; Dahl et al, 1996; Peano et al, 1996; Woo et al, 1995; White et al, 1997; Coorey & Wenck, 1998).
e) CASE REPORT: A case of venlafaxine overdose (1.3 g total), superimposed on a venlafaxine-phenelzine (MAO inhibitor) drug interaction, resulted in a generalized seizure which did not require treatment and no further sequelae occurred (White et al, 1997).
f) CASE REPORT: A 34-year-old woman ingested 1400 to 1500 mg of venlafaxine, and approximately 1 hour later, experienced a generalized seizure (Leaf, 1998).
g) CASE REPORT: A 45-year-old woman ingested 10.9 g of venlafaxine and 35 mg of clonazepam and subsequently developed myoclonic jerking of the face and extremities (Rosen et al, 1997).
h) CASE REPORT: A 22-year-old man ingested approximately 3 g of venlafaxine and subsequently developed tonic-clonic activity with facial grimacing and teeth clenching (Zhalkovsky et al, 1997).
i) CASE REPORT: A 33-year-old woman ingested 8.4 g of venlafaxine and experienced a grand mal seizure (Blythe & Hackett, 1999).

a) CASE REPORT: A 39-year-old woman presented to the ED after ingesting 30 g of extended-release venlafaxine capsules approximately 12 to 24 hours prior to arrival. She gradually became obtunded and required intensive care and ventilatory support. She was noted to have several episodes of myoclonic jerking; however, seizure activity was ruled out following EEG. The patient remained minimally responsive, developed complications of hypotension and bowel perforation and died on hospital day 43 (Mazur et al, 2003).

a) Somnolence was reported in 24% of patients receiving therapeutic doses of venlafaxine in one clinical trial (Anon, 1993).

a) Out of 14 cases of acute venlafaxine overdoses, the most commonly reported symptom was somnolence (Prod Info Effexor(R) oral tablets, 2010).
b) CASE REPORT: A man presented to the ED drowsy, but arousable following an ingestion of 2.25 g venlafaxine. The patient recovered after receiving supportive treatment (Adesanya & Varma, 1997).

a) CASE REPORT: Profound CNS depression requiring intubation was reported in a 41-year-old woman following ingestion of 4.5 g venlafaxine, 500 mg diphenhydramine, and 50 mg thiothixene (Fantaskey & Burkhart, 1995).
b) CASE SERIES: In a prospective series of 146 cases of venlafaxine overdose, 57 (39%) were drowsy, 6 (4%) were responsive to pain only, and 4 (3%) were unresponsive (Setz et al, 1995).
c) CASE REPORT: A 45-year-old woman became somnolent with nonreactive dilated pupils and roving eye movements following an ingestion of 10.9 g venlafaxine and 35 mg clonazepam (Rosen et al, 1997).

a) Serotonin syndrome, which may include cognitive changes, rigidity, hyperreflexia, tachycardia, diaphoresis, tremulousness, and fever, has been reported after venlafaxine ingestion in conjunction with tranylcypromine or phenelzine (Buckley & Faunce, 2003; Hodgman et al, 1995; Brubacher et al, 1995; Weiner et al, 1998).
b) CASE REPORT: A 60-year-old woman presented to the ED obtunded, tachycardic, hyperthermic, hyperreflexic, diaphoretic, weak, and confused following unintentional ingestion of a single dose of venlafaxine while on maintenance tranylcypromine therapy. The patient recovered following supportive treatment (Hodgman et al, 1997).
c) CASE REPORT: A 44-year-old woman ingested phenelzine and venlafaxine concurrently and experienced nausea, anxiety, shortness of breath, inability to swallow, and fever 30 minutes later. The patient presented to the ED 45 minutes after ingestion with lower extremity shaking and increasingly rapid respirations. A diagnosis of serotonin syndrome was subsequently made. The patient recovered following supportive care (Weiner et al, 1998).

a) Serotonin syndrome, which may include cognitive changes, rigidity, hyperreflexia, tachycardia, diaphoresis, tremulousness, and fever, has been reported after venlafaxine overdose, alone or in conjunction with other serotonergic agents (Kolecki & Miller, 1996; Daniels, 1998; Patridge et al, 2000).
b) INCIDENCE: A retrospective review of 96 cases of venlafaxine overdose found features suggestive of serotonin syndrome in 8 (8.3%) patients (Kelly et al, 2004).
c) CASE REPORT: After ingesting an unknown amount of venlafaxine, a 34-year-old man developed signs and symptoms of serotonin syndrome, and developed rhabdomyolysis, renal and cardiac failure and died a day later (Shaw & Sheard, 2005).
d) CASE REPORT: Serotonin syndrome and rhabdomyolysis occurred in a 21-year-old woman after ingesting 7.8 g of the extended-release venlafaxine. Her plasma CK levels, 5 hours and 41 hours after ingestion, were 43 Units/L and 42,340 Units/L, respectively. She developed somnolence and disorientation with a Glasgow Coma Scale of 4-6-3, nausea, vomiting, diaphoresis, and sinus tachycardia 160 to 170 bpm, and tonic-clonic seizures. Following supportive care, she recovered (Hanekamp et al, 2005).
e) CASE REPORT: A 29-year-old woman developed anxiety, tremor, shivering, diarrhea, nausea, vomiting, myoclonus, ataxia, and tachycardia three days after starting venlafaxine at 18.75 to 37.5 mg daily. She was taking imipramine 50 mg daily immediately prior to starting venlafaxine (Pan & Shen, 2003).
f) CASE REPORT: Features consistent with serotonin syndrome developed in a 44-year-old woman who ingested diazepam 200 mg, lamotrigine 20 g, and venlafaxine 4.5 g, and was found unconscious at home. After admission, a tonic-clonic seizure, rigidity, hyperreflexia, and reflex myocloni were observed. Laboratory results revealed sodium level of 129 mmol/L, creatinine kinase of 1915 Units/L, and creatine kinase-MB of 31 Units/L. Despite supportive therapy, including 8 hours of hemodialysis, her rigidity and hyperreflexia did not improve. Following treatment with an intravenous bolus (150 mL, 2.5 mL/kg) of 20% lipid emulsion, all symptoms resolved completely. On day 6, she was transferred to a psychiatric ward. Before hemodialysis, plasma concentrations of lamotrigine, diazepam, and venlafaxine were 42.4 mg/L (therapeutic range, 1 to 4 mg/L), 560 mcg/L (therapeutic range, 200 to 500 mcg/L), and 1254 mcg/L (therapeutic range, 30 to 150 mcg/L), respectively (Dagtekin et al, 2011).
g) CASE REPORT: A 30-year-old woman was thought to have intentionally ingested a one month supply of 150 mg venlafaxine, 300 mg bupropion, and 3 mg lorazepam that were prescribed 3 days earlier. Soon after admission the patient developed tachycardia, fever (40.6 degrees C), a prolonged QRS complex with a deep slurred S wave on lead I and a R wave on lead aVR. Within an hour she required endotracheal intubation due to respiratory distress and decreased mental alertness; sodium bicarbonate was given for ECG changes. In addition, the patient had an elevated creatine kinase (520 Units/L) and creatinine (1.5 mg/dL) levels. The combination of findings suggested serotonin syndrome, and cyproheptadine and lorazepam were given. Clinically, she improved over the next 2 days. Her creatine kinase and alanine transaminase levels peaked at 107,895 Units/L and 2453 Units/L, respectively, approximately 43 and 102 hours after exposure. She was extubated on day 7 and the patient was found to have persistent choreoathetosis with frontal release signs, impaired recent memory, language and executive function. A MRI performed 7 weeks after exposure showed bilateral pallidal necrosis (Lin et al, 2012).

a) CASE REPORT: A 10-year-old boy was inadvertently given venlafaxine (extended-release formulation) over a 2-day period (total ingested 600 mg; 6.86 mg/kg/day) instead of trimethoprim/sulfamethoxazole and developed anticholinergic-type symptoms. The child was on no other medications. Mydriasis, urinary retention, constipation and a brief episode of auditory and visual hallucinations were reported. By day 4, most symptoms had completely resolved, and the patient was discharged to home (Miller et al, 2008).

a) Dizziness is a relatively common side effect with venlafaxine and usually occurs at higher doses and disappears spontaneously without treatment (Klamerus et al, 1992).

a) CASE SERIES: In a prospective series of 146 cases of venlafaxine overdose, 4 (3%) were dizzy (Setz et al, 1995).

a) Headache and fatigue are frequently reported side effects and have occurred with higher single doses of venlafaxine; these effects may be due to its serotonergic activity (Saletu et al, 1992). Migraine headache is reported as a frequent adverse effect in premarketing trials of venlafaxine (Prod Info Effexor(R) oral tablets, 2010).

a) CASE SERIES: In a prospective series of 146 cases of venlafaxine overdose, 2 complained of headache (Setz et al, 1995).

a) Nervousness was reported in 25% of patients taking therapeutic doses of venlafaxine in one study compared to placebo (Schweizer et al, 1991).

a) CASE SERIES: In a prospective series of 146 cases of venlafaxine overdose, 2 were nervous (Setz et al, 1995).

a) CASE REPORT: A healthy 4-year-old girl inadvertently ingested an unknown amount of venlafaxine (urine mass spectrometry was positive) and developed an acute dystonic reaction (including: mutism, akinesis, and hypomimia). She had significant limb rigidity and was unable to walk due to rigid ankle equinus and marked truncal flexion when held upright. A head CT and serum creatinine kinase level was normal. She was transferred to the ICU and given IV benztropine and showed some improvement 4 hours later. Sixteen hours after admission, hypomimia, bradykinesia and rigidity were still present. Symptoms completely resolved within 2 days with no permanent sequelae (Ware et al, 2012).

a) Extrapyramidal effects have been reported after therapeutic use of venlafaxine (Tzallas & Rynn, 1995).

a) CASE SERIES: In a prospective series of 146 cases of venlafaxine overdose, 7 (5%) were tremulous (Setz et al, 1995).

a) CASE REPORT: A 44-year-old man developed neuroleptic malignant syndrome 12 hours after adding venlafaxine 75 milligrams daily to trifluoperazine 1 milligram three times daily. The patient presented with profound anxiety, malaise, rigidity, tremor, and severe diaphoresis. On examination, the blood pressure was between 130/80 mm Hg and 165/100 mm Hg. His pulse was 163 bpm, temperature 38.3 degrees C, and respiratory rate 25 breaths per minute (Nimmagadda et al, 2000). This case may actually represent serotonin syndrome (Cassidy & O'Kearne, 2000).

a) Schweizer et al reported a 55% incidence of nausea in 60 patients receiving therapeutic doses of venlafaxine as compared to 25% incidence in patients receiving placebo. Nausea and vomiting appear to be relatively common adverse reactions observed with venlafaxine; however, these effects usually occur with higher doses and subside with continued treatment (Schweizer et al, 1991; Klamerus et al, 1992; Saletu et al, 1992; Schweizer et al, 1988).

a) Nausea and vomiting have been reported following venlafaxine overdose (Hanekamp et al, 2005).

a) Constipation was reported in a small number of patients receiving therapeutic venlafaxine doses but in no patients receiving placebo in one clinical trial (Khan et al, 1991). Dry mouth was reported in 22% of patients receiving venlafaxine in another clinical trial (Anon, 1993).

a) CASE REPORT: A 39-year-old woman developed refractory hypotension after ingesting 30 g of extended-release venlafaxine. Abdominal distention with pain was noted 14 days after presentation and abdominal radiographs showed pneumatosis coli. Laparoscopy revealed perforations of the cecum and distal small bowel with numerous tiny, white drug pellets in the colon and peritoneum. Following antibiotic treatment, surgical reexploration found numerous abscesses and computed tomography (CT) scan revealed a new bowel perforation. The patient died on hospital day 43. Bowel perforation was thought to be a consequence of refractory hypotension resulting in bowel ischemia (Mazur et al, 2003).

a) CASE REPORT: A 47-year-old woman ingested an estimated 15 g of sustained-release venlafaxine and developed, seizures, severe respiratory distress, hemodynamic instability, and acute renal failure. A gastroscopy was performed 5 days after exposure and a gelatinous mass of partially dissolved tablets was found coating the entire greater curvature of the stomach. Gastric lavage was performed with no improvement noted; therefore, multiple gastroscopies using basket extraction were required to remove the bezoar. Despite intensive medical care, the patient had complications from cerebrovascular infarcts which resulted in a persistent vegetative state. Care was eventually withdrawn by the family (Djogovic et al, 2007).

a) CASE REPORT: A 22-year-old man ingested approximately 3 g of venlafaxine and subsequently developed repeated seizure activity and elevated serum creatine phosphokinase, lactate dehydrogenase, alanine aminotransferase and aspartate aminotransferase levels. Enzyme levels peaked on the second day following the overdose and gradually decreased to normal levels by day 20. The authors postulated that the elevated enzymes most likely represented muscle injury from seizures rather than hepatotoxicity (Zhalkovsky et al, 1997).
b) CASE REPORT: After ingesting 4.5 g of venlafaxine, a 25-year-old woman developed a generalized seizure, sinus tachycardia, incomplete right bundle branch block, QRS duration of 100 msec, prolonged QTc duration (0.46 seconds), and rhabdomyolysis (CK 52,600 Units/L). Laboratory data revealed elevated liver enzymes, SGOT/AST 588 Units/Liter (reference less than 60 Units/L); SGPT/ALT 130 Units/L (less than 55 Units/L). Following supportive care, she was discharged to the psychiatry department on day 5 (Pascale et al, 2005).

a) CASE REPORT: A 78-year-old man with a past history of Parkinson's disease and a major depression episode developed icteric acute hepatitis after taking venlafaxine for almost 2 months. Liver function returned to normal after venlafaxine therapy was progressively discontinued (Cardona et al, 2000).
b) CASE REPORT: A 60-year-old woman experienced right upper quadrant abdominal pain, fever, headache and myalgias one month after starting venlafaxine XR 75 mg daily for postmenopausal symptoms. Her other medications included acetaminophen, vitamin D, cetirizine, estradiol vaginal tablets, lansoprazole and assorted herbal supplements. Lab values included ALT 372 U/L, AST 99 U/L, alkaline phosphatase 483 U/L and GGT 962 U/L. Symptoms and lab abnormalities improved with discontinuation of acetaminophen and venlafaxine. Two months later, the patient noted recurrence of symptoms one week after restarting venlafaxine; hepatic enzymes were again abnormal. Symptoms and lab abnormalities again resolved within two weeks of discontinuing venlafaxine (Phillips et al, 2006).

a) CASE REPORT: After ingesting an unknown amount of venlafaxine, a 34-year-old man developed signs and symptom of serotonin syndrome, and developed rhabdomyolysis, renal and cardiac failure and died a day later. The postmortem histology examination of the liver showed confluent coagulative necrosis, occurring mainly as an acinar zone 3 pattern (notably perivenular and centrilobular) with midzone involvement to a lesser extent. Macrovesicular steatosis with a scattered inflammatory infiltrate, indicating acute hepatitis, was also observed (Shaw & Sheard, 2005).

a) Sexual dysfunction has been reported in a small number of patients receiving venlafaxine 30 to 375 mg/day in divided doses. Erectile failure, delayed orgasm, anorgasmia, impotence, and abnormal ejaculation have occurred (Anon, 1993; Schweizer et al, 1988).

a) CASE REPORT: After ingesting an unknown amount of venlafaxine, a 34-year-old man developed signs and symptom of serotonin syndrome, and developed rhabdomyolysis, renal and cardiac failure and died a day later (Shaw & Sheard, 2005).

a) CASE REPORT: A 27-year-old woman noted abnormal bruising and hematomas in response to minimal trauma 6 weeks after starting venlafaxine and lorazepam for anxiety. Platelet count, PT and aPTT were all normal. Venlafaxine was discontinued and symptoms resolved. Symptoms recurred within 2 weeks of restarting venlafaxine therapy. Platelet count, PT and aPTT levels remained normal. Tests of platelet aggregation were performed on the patient’s blood samples. In vitro addition of venlafaxine inhibited the normal platelet responses to collagen, ADP, and epinephrine (Sarma & Horne, 2006).

a) Schweizer et al reported a 25% incidence of increased sweating in patients receiving venlafaxine 75 to 375 mg/day, compared to no increased sweating in patients receiving placebo. In a premarketing dose comparison trial of venlafaxine, 12.4% of patients receiving 225 mg/day incurred sweating as compared to 19.3% of patients receiving 375 mg/day (Schweizer et al, 1991; Prod Info Effexor(R) oral tablets, 2010).
b) CASE REPORTS: Profuse sweating has been reported in two patients following oral venlafaxine therapy for the treatment of depression. Symptoms resolved following discontinuation of the venlafaxine (Adesanya & Varma, 1997; Garber & Gregory, 1997).

a) CASE REPORT: A 38-year-old woman experienced fever, truncal rash, and oral and vaginal ulcerations 12 days after starting venlafaxine at 37.5 mg daily. The rash was purpuric with central vesiculation. Skin biopsy findings were consistent with Stevens-Johnson syndrome or erythema multiforme. Venlafaxine was discontinued after 2 days. Rash improved over three days with intravenous steroid treatment. The patient's other medications included topiramate, alprazolam, temazepam, and estradiol/levonorgestrel. These medications were also withheld. However, they were restarted following clinical improvement without recurrence of rash (Weiss et al, 2004).

a) CASE REPORT: A 57-year-old man developed hyperkeratosis of the palms and soles, as well as subungual hyperkeratosis over 6 months. He had been treated with venlafaxine for the prior 10 months. No other etiology could be determined. Lesions did not respond to therapy with oral retinoid or topical urea, salicylate or caryolysin. Symptoms resolved spontaneously over 4 to 5 weeks after discontinuation of venlafaxine (Dalle et al, 2006).

a) CASE REPORT: A 30-year-old man experienced pain in the left thigh 2 months after starting venlafaxine therapy for anxiety. Creatinine kinase level was 7700 Units/L while tests for autoimmune disease were normal. MRI of the thigh revealed increased T2-weighted signal intensity within the semimembranosus and semitendinosus muscles. Symptoms improved within three weeks of discontinuing venlafaxine. Biopsy noted intact muscles fibers with a modest mononuclear infiltrate (Jewell et al, 2004).

a) CASE SERIES: A review of 235 cases of venlafaxine overdose found creatinine kinase levels greater than 1000 Units/L in 9 patients (3.8%). Analysis of the patients who did not have seizures (n=214), found creatinine kinase levels greater than 1000 Units/L in 6 patients (3.6%) (Wilson et al, 2007).
b) CASE REPORT: A 38-year-old man developed ventricular tachycardia, seizures, and rhabdomyolysis after ingesting venlafaxine and lamotrigine (Peano et al, 1996).
c) CASE SERIES: Two cases of a delayed rise in plasma creatine kinase (CK) occurred following intentional ingestions of venlafaxine. Case 1 was a 24-year-old woman who ingested 8.85 g with wine and developed dysrhythmias and grand-mal seizures. On hospital day 3, CK peaked at 4346 IU/L with a normal CK-MB fraction; she was discharged home on hospital day 5 without complications. Case 2 was a 21-year-old woman who ingested 1.05 g venlafaxine with 1.6 g citalopram and an unknown amount of co-codamol (acetaminophen and codeine phosphate) and became unconscious with seizures requiring intubation and mechanical ventilation. CK peaked at 10,475 IU/L on hospital day 5; she was discharged home after 6 days (Oliver et al, 2002).
d) CASE REPORT: After ingesting an unknown amount of venlafaxine, a 34-year-old man developed signs and symptom of serotonin syndrome, and developed rhabdomyolysis (CK 111,000 Units/L), renal and cardiac failure and died a day later (Shaw & Sheard, 2005).
e) CASE REPORT: Serotonin syndrome and rhabdomyolysis occurred in a 21-year-old woman after ingesting 7.8 g of the extended-release venlafaxine. Her plasma CK levels, 5 hours and 41 hours after ingestion, were 43 Units/L and 42,340 Units/L, respectively. She developed somnolence and disorientation with a Glasgow Coma Scale of 4-6-3, nausea, vomiting, diaphoresis, and sinus tachycardia 160 to 170 bpm, and tonic-clonic seizures. Following supportive care, her CK level decreased to 1276 Units/L (Hanekamp et al, 2005).
f) CASE REPORT: After ingesting 4.5 g of venlafaxine, a 25-year-old woman developed a generalized seizure, sinus tachycardia (150 bpm), incomplete right bundle branch block, QRS duration of 100 msec, prolonged QTc duration (0.46 seconds), and rhabdomyolysis (CK 52,600 Units/L). This patient had a single brief seizure and was never comatose, suggesting that venlafaxine might cause rhabdomyolysis directly (Pascale et al, 2005).
g) COMBINATION OVERDOSE: A 44-year-old woman ingested diazepam 200 mg, lamotrigine 20 g, and venlafaxine 4.5 g, and was found unconscious at home. After admission, a tonic-clonic seizure, rigidity, hyperreflexia, and reflex myocloni were observed. Laboratory results revealed sodium level of 129 mmol/L, creatinine kinase of 1915 Units/L, and creatine kinase-MB of 31 Units/L. Despite supportive therapy, including 8 hours of hemodialysis, her rigidity and hyperreflexia did not improve. Following treatment with an intravenous bolus (150 mL, 2.5 mL/kg) of 20% lipid emulsion, all symptoms resolved completely. On day 6, she was transferred to a psychiatric ward. Before hemodialysis, plasma concentrations of lamotrigine, diazepam, and venlafaxine were 42.4 mg/L (therapeutic range, 1 to 4 mg/L), 560 mcg/L (therapeutic range: 200 to 500 mcg/L), and 1254 mcg/L (therapeutic range, 30 to 150 mcg/L), respectively (Dagtekin et al, 2011).
h) COMBINATION OVERDOSE: A 30-year-old woman was thought to have intentionally ingested a one month supply of 150 mg venlafaxine, 300 mg bupropion, and 3 mg lorazepam that were prescribed 3 days earlier. Soon after admission the patient developed tachycardia, fever (40.6 degrees C), a prolonged QRS complex, respiratory distress, serotonin syndrome and rhabdomyolysis. Her creatine kinase and alanine transaminase levels peaked at 107,895 Units/L and 2453 Units/L, respectively, approximately 43 and 102 hours after exposure. Cyproheptadine and lorazepam were given. Clinically, she improved over the next 2 days. She was extubated on day 7 and the patient was found to have persistent choreoathetosis with frontal release signs, impaired recent memory, language and executive function. A MRI performed 7 weeks after exposure showed bilateral pallidal necrosis (Lin et al, 2012).

a) CASE REPORT: A 42-year-old woman with a history of depression intentionally ingested 9 g of venlafaxine. She arrived at the ED 4 hours later and was somnolent with tachycardia, mydriasis and tremor. Her initial blood glucose was 2.6 mmol/L (46.8 mg/dL); all other labs were within normal limits. She received a 50 mL bolus of 50% glucose and was decontaminated with gastric lavage and activated charcoal. Immediately following decontamination, she developed a grand mal seizure. A continuous glucose infusion (10% glucose) was started for ongoing intermittent hypoglycemia (0.9 to 3.2 mmol/L) which persisted for 40 hours after exposure. Plasma insulin and C-peptide levels were found to be within normal range during periods of hypoglycemia. Fourteen hours after ingestion, her venlafaxine concentration was 14.7 mg/L (therapeutic, 0.07 to 0.27 mg/L); a toxicology screen was negative for ethanol and other drugs. It is suggested that a venlafaxine overdose can produce prolonged normoinsulinemic hypoglycemia that is resistant to glucose therapy and it is due to increased glucose uptake in peripheral tissues and/or inhibition of hepatic gluconeogenesis (Brvar et al, 2015).
b) CASE REPORT: A 29-year-old man with a history of depression and posttraumatic stress disorder took 22.5 g venlafaxine and 5 g oxazepam. Initial vital signs were normal, but his bedside glucose was 2.7 mmol/L (reference range: 4.4 to 5.5 mmol/L). The patient required intubation secondary to decreased consciousness. He required supplemental dextrose infusion for 30 hours after ingestion because of recurrent hypoglycemia. The patient gradually improved and regained consciousness on day 3 and was extubated on day 5. Serum insulin and C peptide concentrations were high. Coingestion of an oral hypoglycemic was not completely excluded in this patient. Although the pathogenetic mechanism remained unknown, the authors suggested a serotonergic effect on insulin secretion by venlafaxine and recommended close glucose monitoring following intoxication (Meertens et al, 2007).

a) Monitor blood pressure for possible hypotension or hypertension.
b) Monitor temperature for possible hyperthermia.
c) Monitor fluid status and electrolytes as indicated in patients with profuse sweating.
d) ECG should be monitored for possible tachycardia.

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.

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).
b) ADVERSE EFFECTS/CONTRAINDICATIONS

a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.

a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.

a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.

a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).

a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.

a) NEOSTIGMINE: Neostigmine (2.5 mg IV) was found to be effective in treating a drug-induced ileus in 2 adult patients who intentionally ingested extended-release venlafaxine along with other agents (ie, valproate and dothiepin). Each patient was decontaminated with whole-bowel irrigation, but the treatment was found to be ineffective (ie, new onset of abdominal distension, lack of bowel sounds, lack of rectal effluent). Following neostigmine an almost immediate response was observed in one patient, the other patient required a second dose; whole bowel irrigation was continued for up to 48 hours in one patient until pill fragments were no longer visible. Both patients clinically improved with no permanent sequelae (Chan et al, 2005).

a) WHOLE BOWEL IRRIGATION/INDICATIONS: Whole bowel irrigation with a polyethylene glycol balanced electrolyte solution appears to be a safe means of gastrointestinal decontamination. It is particularly useful when sustained release or enteric coated formulations, substances not adsorbed by activated charcoal, or substances known to form concretions or bezoars are involved in the overdose.
b) CONTRAINDICATIONS: This procedure should not be used in patients who are currently or are at risk for rapidly becoming obtunded, comatose, or seizing until the airway is secured by endotracheal intubation. Whole bowel irrigation should not be used in patients with bowel obstruction, bowel perforation, megacolon, ileus, uncontrolled vomiting, significant gastrointestinal bleeding, hemodynamic instability or inability to protect the airway (Tenenbein et al, 1987).
c) ADMINISTRATION: Polyethylene glycol balanced electrolyte solution (e.g. Colyte(R), Golytely(R)) is taken orally or by nasogastric tube. The patient should be seated and/or the head of the bed elevated to at least a 45 degree angle (Tenenbein et al, 1987). Optimum dose not established. ADULT: 2 liters initially followed by 1.5 to 2 liters per hour. CHILDREN 6 to 12 years: 1000 milliliters/hour. CHILDREN 9 months to 6 years: 500 milliliters/hour. Continue until rectal effluent is clear and there is no radiographic evidence of toxin in the gastrointestinal tract.
d) ADVERSE EFFECTS: Include nausea, vomiting, abdominal cramping, and bloating. Fluid and electrolyte status should be monitored, although severe fluid and electrolyte abnormalities have not been reported, minor electrolyte abnormalities may develop. Prolonged periods of irrigation may produce a mild metabolic acidosis. Patients with compromised airway protection are at risk for aspiration.

a) CASE REPORT: A 47-year-old woman ingested 15 g of venlafaxine and developed multiple seizures and mechanical ventilation was required secondary to aspiration that progressed to acute respiratory distress syndrome. The patient remained hypotensive with a depressed level of consciousness. On day 5, a gastroscopy detected venlafaxine pellets coating the entire stomach and gastric lavage was performed for 24 hours to clear the pellets. A repeat gastroscopy showed no significant change and the pellets were removed endoscopically; the retained pellets likely altered normal pharmacokinetics (Hudson & Djogovic, 2007).

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).

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 .

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).

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).

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).

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):

a) VENTRICULAR DYSRHYTHMIAS SUMMARY

a) Sodium bicarbonate may be useful to treat QRS prolongation or dysrhythmias after venlafaxine overdose. A reasonable starting dose is 1 to 2 mEq/kg intravenous bolus, repeated as necessary. Monitor arterial blood gases to maintain a pH of 7.45 to 7.55.
b) CASE REPORT: A 44-year-old woman overdosed with venlafaxine (3 g), clonazepam (20 mg), lormetazepam (24 mg) and thioridazine (10 mg). She presented with incomplete right bundle branch block, and subsequently developed hypotension followed by atrial fibrillation with wide QRS complexes. Sinus rhythm with normal QRS complexes resumed within 15 minutes of infusion of 100 mL 1M sodium bicarbonate (Combes et al, 2001).

a) LIDOCAINE/INDICATIONS
b) LIDOCAINE/DOSE
c) LIDOCAINE/MAJOR ADVERSE REACTIONS
d) LIDOCAINE/MONITORING PARAMETERS

a) AMIODARONE/INDICATIONS
b) AMIODARONE/ADULT DOSE
c) AMIODARONE/PEDIATRIC DOSE
d) ADVERSE EFFECTS

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.

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

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

a) Initial intravenous bolus of 1.5 mL/kg 20% lipid emulsion (eg, Intralipid) over 2 to 3 minutes. Asystolic patients or patients with pulseless electrical activity may have a repeat dose, if there is no response to the initial bolus.
b) Follow with an intravenous infusion of 0.25 mL/kg/min of 20% lipid emulsion (eg, Intralipid). Evaluate the patient's response after 3 minutes at this infusion rate. The infusion rate may be decreased to 0.025 mL/kg/min (ie, 1/10 the initial rate) in patients with a significant response. This recommendation has been proposed because of possible adverse effects from very high cumulative rates of lipid infusion. Monitor blood pressure, heart rate, and other hemodynamic parameters every 15 minutes during the infusion.
c) If there is an initial response to the bolus followed by the re-emergence of hemodynamic instability during the lowest-dose infusion, the infusion rate may be increased back to 0.25 mL/kg/min or, in severe cases, the bolus could be repeated. A maximum dose of 10 mL/kg has been recommended by some sources.
d) Where possible, LRT should be terminated after 1 hour or less, if the patient's clinical status permits. In cases where the patient's stability is dependent on continued lipid infusion, longer treatment may be appropriate.

a) COMBINATION OVERDOSE: A 44-year-old woman ingested diazepam 200 mg, lamotrigine 20 g, and venlafaxine 4.5 g, and was found unconscious at home. After admission, a tonic-clonic seizure, rigidity, hyperreflexia, and reflex myocloni were observed. Laboratory results revealed sodium level of 129 mmol/L, creatinine kinase of 1915 Units/L, and creatine kinase-MB of 31 Units/L. Despite supportive therapy, including 8 hours of hemodialysis, her rigidity and hyperreflexia did not improve. Following treatment with an intravenous bolus (150 mL, 2.5 mL/kg) of 20% lipid emulsion, all symptoms resolved completely. On day 6, she was transferred to a psychiatric ward. Before hemodialysis, plasma concentrations of lamotrigine, diazepam, and venlafaxine were 42.4 mg/L (therapeutic range: 1 to 4 mg/L), 560 mcg/L (therapeutic range: 200 to 500 mcg/L), and 1254 mcg/L (therapeutic range: 30 to 150 mcg/L), respectively (Dagtekin et al, 2011).

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).

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.

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).

a) Monitor vital signs regularly. For mild/moderate asymptomatic hypertension, pharmacologic intervention is usually not necessary.

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

a) DIAZEPAM
b) LORAZEPAM
c) RECURRING SEIZURES
d) PHENOBARBITAL

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.

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).

a) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.

a) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).

a) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

a) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

a) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

a) May be used to control hypertension, and is particularly useful in patients with acute coronary syndromes or acute pulmonary edema (Rhoney & Peacock, 2009).

a) Begin infusion at 10 to 20 mcg/min and increase by 5 or 10 mcg/min every 5 to 10 minutes until the desired hemodynamic response is achieved (American Heart Association, 2005). Maximum rate 200 mcg/min (Rhoney & Peacock, 2009).

a) Usual Dose: 29 days or Older: 1 to 5 mcg/kg/min continuous IV infusion. Maximum 60 mcg/kg/min (Laitinen et al, 1997; Nam et al, 1989; Rasch & Lancaster, 1987; Ilbawi et al, 1985; Friedman & George, 1985).

1) In a prospective review of consecutive patients presenting with a venlafaxine alone overdose between January 1997 and December 2007, 369 occasions of venlafaxine overdoses (median dose: 1500 mg; Interquartile Range (IQR): 600 to 3000 mg; range: 75 to 13500 mg) in 273 patients were observed with no reports of dysrhythmias and only minor ECG changes. Tachycardia was observed in 54% of patients and mild hypertension was reported in 40% of patients; severe hypotension and hypertension were uncommon. Conduction disturbances were found in 7 patients with 5 patients having a preexisting history of conduction disturbances. Alterations in QRS and QT interval were considered mild (the median maximum QRS width was 85 ms (IQR: 80 to 90 ms; range: 70 to 145 ms; 24 patients had a QRS of greater than or equal to 120 ms). The findings suggest that a mild exposure does not result in cardiotoxicity; however, doses greater than 8 g may produce significant cardiotoxicity (Isbister, 2009).

1) CASE REPORT: A 24-year-old woman who ingested 8.85 g venlafaxine developed seizures, cardiac dysrhythmias and late onset rhabdomyolysis, but recovered fully. The maximum plasma venlafaxine level recorded was 10.5 mg/L (Oliver et al, 2002).
2) CASE REPORT: A 45-year-old woman ingested 10.9 g of venlafaxine and 35 mg of clonazepam and subsequently developed somnolence, severe hypotension, myoclonic jerking, and intraventricular block (Rosen et al, 1997).
3) CASE REPORT: A 33-year-old woman ingested 8.4 g of venlafaxine and developed right axis deviation, a prolonged QT interval (469 msec) and a prolonged QRS complex (129 msec). In addition, she experienced a grand mal seizure. It is suggested that cardiotoxicity is more likely in patients with the poor CYP2D6 metabolizer phenotype (Blythe & Hackett, 1999).

1) CASE REPORT: COMBINATION OVERDOSE: A 30-year-old woman was thought to have intentionally ingested a one month supply of 150 mg venlafaxine (estimate 4.5 g), 300 mg bupropion, and 3 mg lorazepam that were prescribed 3 days earlier. The patient developed tachycardia, fever (40.6 degrees C), a prolonged QRS complex with a deep slurred S wave, respiratory distress, serotonin syndrome and rhabdomyolysis. Her creatine kinase and alanine transaminase levels peaked at 107,895 Units/L and 2453 Units/L, respectively, approximately 43 and 102 hours after exposure. She was extubated on day 7 and the patient was found to have persistent choreoathetosis with frontal releasing signs, impaired recent memory, language and executive function. A MRI performed 7 weeks after exposure showed bilateral pallidal necrosis (Lin et al, 2012).
2) CHRONIC ABUSE/CASE REPORT: A 35-year-old man, with a history of schizophrenia and generalized anxiety disorder, presented to the ED seeking to refill a prescription for venlafaxine to suppress his severe anxiety. He reportedly said that his prior prescription was "stolen", but venlafaxine had been discontinued 1 month previously by his primary psychiatrist due to abuse. Upon chart review, the patient was being treated with risperidone for his schizophrenia, but his compliance was inconsistent. He denied issues with psychotic, depressive, or manic symptoms and claimed he was misdiagnosed as a schizophrenic. He also reported a prior history of substance abuse (ie, alcohol, benzodiazepines, cocaine, and marijuana), but refused a toxicology screen. The patient was admitted involuntarily to the psychiatric unit and was continued on risperidone and started on sertraline for generalized anxiety. As the patient improved and rapport was built, he reported taking 10 to 15 tablets of 225 mg (2250 to 3375 mg/day) extended-release venlafaxine daily and stated it made him feel "full of energy" and "alive" and helped him to feel focused. He would often chew the tablets to make the drug work faster. During his hospitalization, symptoms of withdrawal were absent and his vital signs remained normal (Namdari, 2013).
3) CASE REPORT: A 46-year-old woman intentionally ingested 3150 mg of immediate-release and 2100 mg of extended-release venlafaxine and developed tonic-clonic seizures and hypotension. An echocardiogram showed acute left ventricular failure with an ejection fraction of 18%. With inotropic support, LV function improved by day 3 (ejection fraction 65%) and the patient recovered completely (Batista et al, 2013).
4) CASE REPORT: A 27-year-old man intentionally ingested 6.3 g of extended-release venlafaxine resulting in respiratory failure and eosinophilic pneumonia. He was intubated and treated with empiric antibiotics, vasopressors, and corticosteroids. Seven days later he was discharged from the ICU without further event (Paparrigopoulos et al, 2011).
5) CASE REPORT: An adult patient who ingested an estimated 6.75 g recovered with no sequelae (Prod Info Effexor(R) oral tablets, 2010).
6) CASE REPORT: Serotonin syndrome and rhabdomyolysis occurred in a 21-year-old woman after ingesting 7.8 g of the extended-release venlafaxine. Her plasma CK levels, 5 hours and 41 hours after ingestion, were 43 Units/L and 42,340 Units/L, respectively. She developed somnolence and disorientation with a Glasgow Coma Scale of 4-6-3, nausea, vomiting, diaphoresis, and sinus tachycardia 160 to 170 beats per minute, and tonic-clonic seizures. Following supportive care, her CK level decreased to 1276 Units/L (Hanekamp et al, 2005).
7) CASE REPORT: A 38-year-old man developed chest pain without ECG or cardiac enzyme changes following an ingestion of 4050 mg of crushed extended-release venlafaxine capsules (Sattar et al, 2003).
8) CASE REPORT: A 34-year-old woman experienced a generalized seizure approximately 1 hour after ingesting 1400 to 1500 mg of venlafaxine (Leaf, 1998).
9) CASE REPORT: A 29-year-old man ingested 2.8 g of venlafaxine and experienced seizures 2 and 4 hours after ingestion (Coorey & Wenck, 1998).
10) CASE REPORT: A 41-year-old woman suffered severe CNS depression following ingestion of 4.5 g venlafaxine. Recovery was complete (Fantaskey & Burkhart, 1995).

1) CASE SERIES: In a retrospective series of 14 pediatric cases of venlafaxine ingestion with doses ranging from 18.75 to 75 mg (2.1 to 5.5 mg/ kg), only one patient developed minor effects (lethargy) (Herrington & Gorman, 1996). Children ingesting 5.5 mg/kg or less can be managed at home.

a) Therapeutic serum levels of venlafaxine have not been defined. After single oral doses of 25, 75, and 150 mg, mean peak serum concentrations were 37, 102, and 163 nanograms/mL, respectively, in one study. Corresponding levels of o-desmethylvenlafaxine, its major active metabolite, were 61, 168, and 325 nanograms/mL following these doses (Klamerus et al, 1992).
b) After doses of 25, 75, and 150 mg every 8 hours for 3 days, mean peak serum levels were 53, 167, and 393 nanograms/mL; corresponding levels of O-desmethylvenlafaxine were 148, 397, and 686 nanograms/mL (Klamerus et al, 1992). With multiple doses, steady state concentrations of venlafaxine and O-desmethylvenlafaxine are achieved within three days and both drugs demonstrate linear kinetics for doses between 75 and 450 mg per day (Prod Info Effexor(R) oral tablets, 2010).
c) After a single 150 mg dose, peak plasma levels of venlafaxine normally occur 2.4 hours after oral dosing, reaching 33 to 172 mcg/L (Pascale et al, 2005).
d) In patients experiencing improved depression symptoms during venlafaxine therapy, median serum level was 54 mcg/L. Serum levels varied between 10.1 and 200 mcg/L. The median serum level of venlafaxine plus its active metabolite, O-desmethylvenlafaxine, was 193 mcg/L (Charlier et al, 2002).

a) COMBINATION OVERDOSE: In one case, a woman who ingested diazepam 200 mg, lamotrigine 20 g, and venlafaxine 4.5 g developed coma, seizures, rigidity, and hyperreflexia. Plasma concentrations of lamotrigine, diazepam, and venlafaxine were 42.4 mg/L (therapeutic range, 1 to 4 mg/L), 560 mcg/L (therapeutic range, 200 to 500 mcg/L), and 1254 mcg/L (therapeutic range, 30 to 150 mcg/L), respectively. Following treatment with intravenous lipid emulsion, all symptoms resolved completely (Dagtekin et al, 2011).
b) Peak plasma levels following acute ingestions of 2.75 and 2.5 grams were 6.24 and 2.35 mcg/mL respectively, and the peak plasma levels of O-desmethylvenlafaxine were 3.37 and 1.30 mcg/mLrespectively (Prod Info Effexor(R) oral tablets, 2010).
c) Peak plasma levels were 12,000 and 1,200 nanograms/mL, respectively, for venlafaxine and O-desmethylvenlafaxine after overdose of 5.6 grams (Kokan & Dart, 1996).
d) A 24-year-old woman ingested 8.85 g venlafaxine was found to have a plasma venlafaxine level of 10.5 mg/L. She recovered fully (Oliver et al, 2002).
e) CASE REPORT: After ingesting 4.5 g of venlafaxine, a 25-year-old woman developed a generalized seizure, sinus tachycardia (150 bpm), incomplete right bundle branch block, QRS duration of 100 msec, prolonged QTc duration (0.46 seconds), and rhabdomyolysis (CK 52,600 Units/L). Following supportive care, she was discharged to the psychiatry department on day 5. The serum concentration of venlafaxine and desmethylvenlafaxine were 251 mcg/L and 319 mcg/L, respectively, 37 hours after ingestion (Pascale et al, 2005).
f) CASE REPORT: A woman ingested 5 g venlafaxine and was found unconscious with seizures and developed hypotension. Electrocardiogram showed a right bundle branch block with a QRS duration of 144 ms and 428 ms corrected QT intervals. Plasma venlafaxine concentration was 25.8 micromol/L (gas chromatography; therapeutic range 0.25 to 0.85, quantification limit 0.2). By day 3, the patient had improved following an epinephrine infusion and supportive care and was extubated successfully (Megarbane et al, 2007).

a) CASE REPORT: An adult male intentionally ingested 19 g of venlafaxine extended-release tablets (90 150-mg venlafaxine extended-release and 75 75-mg venlafaxine extended-release) and died approximately 9 hours after exposure of refractory ventricular fibrillation. His venlafaxine blood concentration obtained about 5 hours after exposure was 9000 ng/mL and the O-desmethylvenlafaxine blood concentration (metabolite) was 3000 ng/mL. A postmortem concentration obtained from a peripheral site was 5500 ng/mL. No other substances were found on postmortem exam (Bosse et al, 2008).
b) CASE REPORTS: Two women were admitted with CNS depression, tachycardia and hypotension following large ingestions of venlafaxine. Both died of cardiac arrest within 24 hours of admission. Autopsy was performed at 48 hours after death in both patients; the first patient had an estimated ingestion of 14.7 g, with a venlafaxine concentration of 95 mcg/mL (metabolite O-desmethyl-venlafaxine 8 mcg/mL). The second patient also had a large ingestion (exact amount unknown) with a venlafaxine concentration of 79 mcg/mL (metabolite O-desmethyl-venlafaxine 17.7 mcg/mL) (Hojer et al, 2008).
c) Postmortem venlafaxine level was 89,000 nanograms/mL in one case (Dahl et al, 1996).
d) A 45-year-old woman died after ingestion of 8.4 g venlafaxine. Venlafaxine level was 14 mg/L on presentation to the hospital and 16 mg/L postmortem (Banham, 1998).
e) Postmortem venlafaxine concentrations of 53 mg/L and 78 mg/L have been reported in two other cases. Venlafaxine undergoes postmortem distribution from tissues into blood (Jaffe et al, 1999).
f) EXTENDED RELEASE: Following an intentional ingestion of 30 g of extended release venlafaxine, a 39-year-old woman died on hospital day 43. Venlafaxine and o-desmethylvenlafaxine levels peaked 24 hours after ingestion at 21.82 mg/L and 3.33 mg/L, respectively (Mazur et al, 2003).
g) CASE REPORT: After ingesting an unknown amount of venlafaxine, a 34-year-old man developed signs and symptom of serotonin syndrome, and developed rhabdomyolysis, renal and cardiac failure and died a day later. The postmortem histology examination of the liver showed confluent coagulative necrosis, occurring mainly as an acinar zone 3 pattern (notably perivenular and centrilobular) with midzone involvement to a lesser extent. Macrovesicular steatosis with a scattered inflammatory infiltrate indicating acute hepatitis was observed. The venlafaxine concentration just before death was 18.6 mg/L (therapeutic range 0.07 and 0.27 mg/L); liver concentration was 46 mg/kg (Shaw & Sheard, 2005).