VENLAFAXINE

• 0.0 OVERVIEW
• 0.1 LIFE SUPPORT
• A. This overview assumes that basic life support measures have been instituted.
• 0.2 CLINICAL EFFECTS
• 0.2.1 SUMMARY OF EXPOSURE
• A. Somnolence is the most commonly observed overdose effect with venlafaxine. Other observed effects include seizures, tachycardia, hypotension, hypertension, diaphoresis, hyponatremia, and rarely ventricular dysrhythmias.
• 0.2.5 CARDIOVASCULAR
• A. Venlafaxine has caused hypotension, hypertension, palpitations, tachycardia, cardiac arrest, and prolongation of the QRS and QT intervals.
• 0.2.7 NEUROLOGIC
• A. Somnolence and generalized seizures have been reported following overdoses of venlafaxine.
• B. CNS depression, headache, fatigue, dizziness, nervousness, tremors, extrapyramidal effects, and serotonin syndrome have occurred as adverse effects following venlafaxine ingestion.
• 0.2.8 GASTROINTESTINAL
• A. Venlafaxine therapeutic use has been associated with nausea, vomiting, dry mouth, and constipation.
• 0.2.10 GENITOURINARY
• A. Sexual dysfunction has been reported in a small number of patients receiving therapeutic doses of venlafaxine.
• 0.2.12 FLUID-ELECTROLYTE
• A. Hyponatremia and hypochloremia were reported following venlafaxine therapy.
• 0.2.14 DERMATOLOGIC
• A. Sweating has occurred with venlafaxine use.
• 0.2.17 METABOLISM
• A. Venlafaxine has been associated with weight loss and an increase in serum cholesterol levels.
• 0.2.22 OTHER
• A. A drug interaction may occur between cimetidine and venlafaxine resulting in a reduction of venlafaxine clearance and an increase in the peak serum concentration of venlafaxine. Monoamine oxidase inhibitors may interact with venlafaxine resulting in a serotonin syndrome or seizures.
• B. A withdrawal syndrome was reported following the rapid reduction of venlafaxine therapy.
• 0.3 LABORATORY/MONITORING
• A. Monitor blood pressure and ECG in symptomatic patients.
• 0.4 TREATMENT OVERVIEW
• 0.4.2 ORAL/PARENTERAL EXPOSURE
• A. EMESIS: Ipecac-induced emesis is not recommended because of the potential for CNS depression and seizures.
• B. GASTRIC LAVAGE: Consider after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in Trendelenburg and left lateral decubitus position or by endotracheal intubation. Control any seizures first.
• 1. CONTRAINDICATIONS: Loss of airway protective reflexes or decreased level of consciousness in unintubated patients; following ingestion of corrosives; hydrocarbons (high aspiration potential); patients at risk of hemorrhage or gastrointestinal perforation; and trivial or non-toxic ingestion.
• C. ACTIVATED CHARCOAL: Administer charcoal as slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
• D. SEIZURES: Administer a benzodiazepine IV; DIAZEPAM (ADULT: 5 to 10 mg, repeat every 10 to 15 min as needed. CHILD: 0.2 to 0.5 mg/kg, repeat every 5 min as needed) or LORAZEPAM (ADULT: 4 to 8 mg; CHILD: 0.05 to 0.1 mg/kg).
• 1. Consider phenobarbital if seizures recur after diazepam 30 mg (adults) or 10 mg (children > 5 years).
• 2. Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, hypoxia.
• E. PVCS/SUMMARY - Treatment of PVCs may include lidocaine, phenytoin, or overdrive transvenous pacing. Atropine may used when severe bradycardia is present and PVCs are thought to represent an escape complex.
• F. HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid, place in Trendelenburg position. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (0.1 to 0.2 mcg/kg/min), titrate to desired response.
• G. HYPERTENSION: Monitor vital signs regularly. For mild/moderate asymptomatic hypertension, pharmacologic treatment is generally not necessary. For severe hypertension nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives. See main treatment section for doses.
• 0.5 RANGE OF TOXICITY
• A. The maximum tolerated human exposure to this agent has not been delineated.
• B. Children ingesting 5.5 milligrams/kilogram or less are unlikely to develop toxicity and can be managed at home.
• C. Seizures have developed in adults after ingestion of 1.4 grams.
• 1.0 SUBSTANCES INCLUDED/SYNONYMS
• 1.1 THERAPEUTIC/TOXIC CLASS
• A. Venlafaxine, a phenylethylamine bicyclic antidepressant, is a serotonin and noradrenaline reuptake inhibitor.
• 1.2 SPECIFIC SUBSTANCES

o              Cyclohexanol, 1-(2-(dimethylamino)-1-

o                (4-methoxyphenyl)ethyl) hydrochloride

o              -1-(a-(dimethyl-amino)methyl-p-methoxybenzyl

o                cyclohexanol hydrochloride

o              Wy-45030

o              Molecular Formula:  C17-H27-N-O2.Cl-H

o              CAS 93413-69-5 (venlafaxine)

o              CAS 99300-78-4 (venlafaxine hydrochloride)

• 1.6 AVAILABLE FORMS/SOURCES
• A. FORMS
• 1. Venlafaxine is commercially available as 25 mg, 37.5 mg, 50 mg, 75 mg, and 100 mg scored tablets, and 37.5 mg, 75 mg, 150 mg extended-release capsules (Prod Info Effexor(R), 2000; Prod Info Effexor(R) XR, 2000).
• B. USES
• 1. Venlafaxine is used to treat depression or generalized anxiety disorder (Prod Info Effexor(R), 2000).
• 3.0 CLINICAL EFFECTS
• 3.1 SUMMARY OF EXPOSURE
• A. Somnolence is the most commonly observed overdose effect with venlafaxine. Other observed effects include seizures, tachycardia, hypotension, hypertension, diaphoresis, hyponatremia, and rarely ventricular dysrhythmias.
• 3.4 HEENT
• 3.4.3 EYES
• A. Blurred vision has occurred in approximately 6% of patients receiving therapeutic doses of venlafaxine in clinical trials (Anon, 1993).
• 3.5 CARDIOVASCULAR
• 3.5.1 SUMMARY
• A. Venlafaxine has caused hypotension, hypertension, palpitations, tachycardia, cardiac arrest, and prolongation of the QRS and QT intervals.
• 3.5.2 CLINICAL EFFECTS
• A. TACHYCARDIA
• 1. 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), 2000).
• 2. CASE REPORT - A 41-year-old female who ingested 4.5 grams 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).
• 3. Tachycardia has also been reported in other patients with venlafaxine overdose (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).
• B. ECG ABNORMAL
• 1. CASE REPORT - A 41-year-old male developed hypotension, QRS widening and QTc prolongation after ingesting 5.6 grams of venlafaxine (Kokan & Dart, 1996).
• 2. 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), 2000).
• 3. CASE REPORT - A 29-year-old male 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).
• 4. CASE REPORT - A 45-year-old female ingested 10.9 g of venlafaxine and 35 mg of clonazepam, presented to the ED with a normal ECG, but subsequently developed, over the next hour, flattening of ST segments and intraventricular conduction delay (Rosen et al, 1997).
• 5. CASE REPORT - A 33-year-old female ingested 8.4 grams 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).
• C. DYSRHYTHMIAS -
• 1. CASE REPORT - A 30-year-old female developed tachycardia followed by asystole after a mixed ingestion including venlafaxine and carbamazepine (Dahl et al, 1996). Post-mortem blood venlafaxine level was 89,000 nanograms/milliliter (225 times therapeutic).
• 2. CASE REPORT - A 38-year-old male developed ventricular tachycardia after ingesting venlafaxine and lamotrigine (Peano et al, 1996).
• 3. CASE REPORT - Ventricular tachycardia, ventricular fibrillation, and supraventricular tachycardia have been reported in a patient who took 7.5 grams of venlafaxine and an unknown amount of oxazepam (Thorsson et al, 2000).
• D. HYPOTENSION
• 1. Hypotension has been reported following venlafaxine overdose (Durback & Scharman, 1996; Kokan & Dart, 1996; Rosen et al, 1997).
• 2. CASE REPORT - A 41-year-old male developed hypotension after ingesting 5.6 grams of venlafaxine (Kokan & Dart, 1996).
• 3. CASE REPORT - A 45-year-old female developed somnolence and hypotension after an overdose ingestion of venlafaxine (10.9 grams) and clonazepam (35 milligrams). The patient's blood pressure increased following supportive care (Rosen et al, 1997).
• E. HYPERTENSION
• 1. Sustained increases in blood pressure have been reported in patients receiving therapeutic doses of venlafaxine. Pre-marketing 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), 2000).
• 2. CASE REPORT - Hypertension (BP 168/101 mmHg) was evident in a 41-year-old female following ingestion of 4.5 grams venlafaxine, 500 mg diphenhydramine and 50 mg thiothixene (Fantaskey & Burkhart, 1995).
• F. PALPITATION
• 1. 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).
• G. CARDIAC ARREST
• 1. CASE REPORT - Prolonged cardiac arrest has been reported in a patient who took 7.5 grams of venlafaxine and an unknown amount of oxazepam (Thorsson et al, 2000).
• 3.7 NEUROLOGIC
• 3.7.1 SUMMARY
• A. Somnolence and generalized seizures have been reported following overdoses of venlafaxine.
• B. CNS depression, headache, fatigue, dizziness, nervousness, tremors, extrapyramidal effects, and serotonin syndrome have occurred as adverse effects following venlafaxine ingestion.
• 3.7.2 CLINICAL EFFECTS
• A. SEIZURES
• 1. In pre-clinical 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). Seizures were reported to occur in 0.26% of patients receiving therapeutic doses of venlafaxine (Prod Info Effexor(R), 2000).
• 2. Seizures have been reported in several other overdose cases (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).
• 3. 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).
• 4. CASE SERIES - In a prospective series of 146 cases of venlafaxine overdose, 7 (5%) had seizures (Setzer et al, 1995).
• 5. CASE REPORT - A 34-year-old female ingested 1400 to 1500 mg of venlafaxine, and approximately 1 hour later, experienced a generalized seizure (Leaf, 1998).
• 6. CASE REPORT - A 45-year-old female 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).
• 7. CASE REPORT - A 22-year-old male ingested approximately 3 g of venlafaxine and subsequently developed tonic-clonic activity with facial grimacing and teeth clenching (Zhalkovsky et al, 1997).
• 8. CASE REPORT - A 33-year-old female ingested 8.4 grams of venlafaxine and experienced a grand mal seizure (Blythe & Hackett, 1999).
• B. SOMNOLENCE
• 1. Somnolence was reported in 24% of patients receiving therapeutic doses of venlafaxine in one clinical trial (Anon, 1993). Out of 14 cases of acute venlafaxine overdoses, the most commonly reported symptom was somnolence (Prod Info Effexor(R), 2000).
• 2. CASE REPORT - A male presented to the ED drowsy, but arousable following an ingestion of 2.25 grams venlafaxine. The patient recovered after receiving supportive treatment (Adesanya & Varma, 1997).
• C. CNS DEPRESSION
• 1. CASE REPORT - Profound CNS depression requiring intubation was reported in a 41-year-old female following ingestion of 4.5 grams venlafaxine, 500 mg diphenhydramine, and 50 mg thiothixene (Fantaskey & Burkhart, 1995).
• 2. 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 (Setzer et al, 1995).
• 3. CASE REPORT - A 45-year-old female 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).
• D. SEROTONIN SYNDROME
• 1. Serotonin syndrome, which may include cognitive changes, rigidity, hyperreflexia, tachycardia, diaphoresis, tremulousness, and fever, has been reported after venlafaxine overdose and therapeutic use of tranylcypromine and venlafaxine (Hodgman et al, 1995; Brubacher et al, 1995; Kolecki & Miller, 1996; Daniels, 1998; Graudins et al, 1998).
• 2. CASE REPORT - A 60-year-old female 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).
• 3. CASE REPORT - A 44-year-old female 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).
• E. DIZZINESS
• 1. Dizziness is a relatively common side effect with venlafaxine and usually occurs at higher doses and disappears spontaneously without treatment (Klamerus et al, 1992).
• 2. CASE SERIES - In a prospective series of 146 cases of venlafaxine overdose, 4 (3%) were dizzy (Setzer et al, 1995).
• F. HEADACHE
• 1. 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), 2000).
• 2. CASE SERIES - In a prospective series of 146 cases of venlafaxine overdose, 2 complained of headache (Setzer et al, 1995).
• G. NERVOUSNESS
• 1. Nervousness was reported in 25% of patients taking therapeutic doses of venlafaxine in one study compared to placebo (Schweizer et al, 1991).
• 2. CASE SERIES - In a prospective series of 146 cases of venlafaxine overdose, 2 were nervous (Setzer et al, 1995).
• H. EXTRAPYRAMIDAL DISORDER
• 1. Extrapyramidal effects have been reported after therapeutic use of venlafaxine (Tzallas & Rynn, 1995).
• I. TREMOR
• 1. CASE SERIES - In a prospective series of 146 cases of venlafaxine overdose, 7 (5%) were tremulous (Setzer et al, 1995).
• J. NEUROLEPTIC MALIGNANT SYNDROME
• 1. CASE REPORT - A 44-year-old male 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).
• 3.8 GASTROINTESTINAL
• 3.8.1 SUMMARY
• A. Venlafaxine therapeutic use has been associated with nausea, vomiting, dry mouth, and constipation.
• 3.8.2 CLINICAL EFFECTS
• A. NAUSEA VOMITING
• 1. Schweizer et al (1991) 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 (Klamerus et al, 1992; Saletu et al, 1992; Schweizer et al, 1988).
• B. CONSTIPATION
• 1. 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).
• 3.9 HEPATIC
• 3.9.2 CLINICAL EFFECTS
• A. HEPATIC ENZYMES INCREASED
• 1. CASE REPORT - A 22-year-old male 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 (Zhakjivsky et al, 1997).
• B. HEPATITIS
• 1. CASE REPORT - A 78-year-old man with a past history of Parkinson 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).
• 3.10 GENITOURINARY
• 3.10.1 SUMMARY
• A. Sexual dysfunction has been reported in a small number of patients receiving therapeutic doses of venlafaxine.
• 3.10.2 CLINICAL EFFECTS
• A. SEXUAL FUNCTION ABNORMAL
• 1. 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).
• 3.12 FLUID-ELECTROLYTE
• 3.12.1 SUMMARY
• A. Hyponatremia and hypochloremia were reported following venlafaxine therapy.
• 3.12.2 CLINICAL EFFECTS
• A. HYPONATREMIA
• 1. CASE REPORT - A 76-year-old female developed hyponatremia (serum sodium level of 118 mEq/L) following oral venlafaxine therapy, 75 mg daily. The venlafaxine was discontinued and the patient's serum sodium level returned to baseline three days later following fluid restriction, infusion of normal saline, and furosemide administration (Gupta & Saravay, 1997).
• 2. Hyponatremia was reported in 15 patients following therapeutic use of venlafaxine. The average onset of the hyponatremia was 9 days after initiation of venlafaxine therapy and the serum sodium concentrations ranged from 116 to 130 mEq/L (normal 135 to 145 mEq/L) (Boyd, 1998a).
• B. HYPOCHLOREMIA
• 1. Two cases of hypochloremia were reported following therapeutic use of venlafaxine. The average minimum serum chloride concentration was 81 mEq/L (normal 95 to 109 mEq/L) (Boyd, 1998a).
• 3.14 DERMATOLOGIC
• 3.14.1 SUMMARY
• A. Sweating has occurred with venlafaxine use.
• 3.14.2 CLINICAL EFFECTS
• A. SWEATING INCREASED
• 1. Schweizer et al (1991) 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 (Prod Info Effexor(R), 2000).
• 2. 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. The patient, reported by Garber & Gregory (1997), was restarted on venlafaxine therapy, 75 mg twice daily, with the addition of benztropine, 0.5 mg twice daily. The diaphoresis did not recur, and the venlafaxine was increased to 75 mg three times daily with no subsequent side effects.
• 3.15 MUSCULOSKELETAL
• 3.15.2 CLINICAL EFFECTS
• A. RHABDOMYOLYSIS
• 1. CASE REPORT - A 38-year-old male developed ventricular tachycardia, seizures, and rhabdomyolysis after ingesting venlafaxine and lamotrigine (Peano et al, 1996).
• 3.17 METABOLISM
• 3.17.1 SUMMARY
• A. Venlafaxine has been associated with weight loss and an increase in serum cholesterol levels.
• 3.17.2 CLINICAL EFFECTS
• A. WEIGHT DECREASE
• 1. A total body weight loss of 5% or more occurred in 6% of venlafaxine patients as compared to 1% of placebo patients and 3% of patients taking a different antidepressant (Prod Info Effexor(R), 2000). In one trial, 2% of patients receiving venlafaxine experienced weight loss of approximately 3 pounds, which was statistically significant compared with placebo (Anon, 1993).
• B. HYPERCHOLESTEREMIA
• 1. Small but statistically significant increases in serum cholesterol (2 to 3 mg/dL) have been reported in patients receiving venlafaxine (Anon, 1993); the clinical significance of this is unclear. Until more is known concerning the effects of venlafaxine on serum lipids, periodic monitoring is recommended.
• 3.18 PSYCHIATRIC
• 3.18.2 CLINICAL EFFECTS
• A. MANIC REACTION
• 1. Wilson & Jenkins (1997) reported two patients (both with bipolar affective disorder) that became hypomanic after receiving venlafaxine therapy. Symptoms resolved in both patients after discontinuation of the venlafaxine.
• 3.20 REPRODUCTIVE
• 3.20.2 TERATOGENICITY
• A. LACK OF INFORMATION
• 1. At the time of this review, no data were available to assess the teratogenic potential of this agent.
• 3.20.3 EFFECTS IN PREGNANCY
• A. PREGNANCY CATEGORY
• 1. US FDA Pregnancy Category C by the manufacturer (Prod Info Effexor(R), 2000).
• 3.21 CARCINOGENICITY
• 3.21.3 HUMAN STUDIES
• A. LACK OF INFORMATION
• 1. At the time of this review, no data were available to assess the carcinogenic or mutagenic potential of this agent.
• 3.23 OTHER
• 3.23.1 SUMMARY
• A. A drug interaction may occur between cimetidine and venlafaxine resulting in a reduction of venlafaxine clearance and an increase in the peak serum concentration of venlafaxine. Monoamine oxidase inhibitors may interact with venlafaxine resulting in a serotonin syndrome or seizures.
• B. A withdrawal syndrome was reported following the rapid reduction of venlafaxine therapy.
• 3.23.2 CLINICAL EFFECTS
• A. DRUG INTERACTION
• 1. CIMETIDINE - Concurrent administration of venlafaxine and cimetidine (both at steady state) has resulted in a 43% reduction in the oral clearance of venlafaxine and a 60% increase in the AUC and peak concentration of venlafaxine (Prod Info Effexor(R), 2000). The major metabolite, O-desmethylvenlafaxine, was unaffected by cimetidine, and is present in much greater amounts than the parent drug. It is not known if a clinically significant interaction will occur with this combination. Patients should be monitored for signs of venlafaxine toxicity, and the dose of venlafaxine reduced if necessary.
• 2. DESIPRAMINE - An anticholinergic syndrome (confusion with stupor, urinary retention, and paralytic ileus) has been associated with the concomitant administration of venlafaxine and desipramine. It is postulated that venlafaxine, a cytochrome P450 inhibitor, may inhibit the metabolism of desipramine, causing an increase in the serum concentration of desipramine and resulting in the anticholinergic syndrome (Benazzi, 1998).
• 3. MAO INHIBITORS - Serotonin syndrome, which may include cognitive changes, rigidity, hyperreflexia, tachycardia, diaphoresis, tremulousness, and fever, has been reported after therapeutic use of tranylcypromine and venlafaxine and an unintentional ingestion of phenelzine and venlafaxine (Hodgman et al, 1995; Brubacher et al, 1995; Hodgman et al, 1997; Weiner et al, 1998).
• a. CASE REPORT - Generalized seizures were reported in a patient following a venlafaxine overdose superimposed on a venlafaxine-phenelzine and trazodone drug interaction (White et al, 1997).
• 4. FLUOXETINE - In several case reports, anticholinergic side effects (extreme difficulty urinating, blurred vision, dry mouth, constipation, dizziness, insomnia, tremor of the hands) were reported after concurrent use of venlafaxine and fluoxetine. All symptoms were resolved upon discontinuation of venlafaxine (Benazzi, 1999).
• B. WITHDRAWAL SYNDROME
• 1. CASE REPORT - A 51-year-old male developed severe nausea, anorexia, dizziness, unsteady gait, tinnitus, and a bitemporal headache 72 hours after rapid reduction of venlafaxine therapy, 300 mg daily. The symptoms resolved completely after reintroducing venlafaxine at 75 mg daily. The dose was then tapered off slowly without any adverse effects (Macbeth & Rajagopalan, 1998).