VENLAFAXINE

E. HYPERTENSION

1. Monitor vital signs regularly. For mild/moderate asymptomatic hypertension, pharmacologic intervention is generally not necessary.

a. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients, especially if a sympathomimetic agent is involved in the poisoning.
b. For hypertensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20% to 25% within one hour), nitroprusside is preferred. Nitroglycerine and phentolamine are possible alternatives.

2. NITROPRUSSIDE/INDICATIONS

a. Nitroprusside is preferred for hypertensive emergencies (emergent need to lower mean arterial pressure by 20 to 25 percent within one hour, or evidence of end organ (CNS, cardiac, renal) damage).

3. NITROPRUSSIDE/DOSE

a. Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required. Frequent hemodynamic monitoring and administration by an infusion system that ensures a precise flow rate is mandatory.

4. NITROPRUSSIDE/SOLUTION PREPARATION

a. Dilute a 50-milligram vial in 500 milliliters of dextrose 5 percent in water (100 micrograms/milliliter). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution.

5. NITROPRUSSIDE/MAJOR ADVERSE REACTIONS

a. Severe hypotension; thiocyanate or cyanide toxicity; methemoglobinemia; lactic acidosis; chest pain or dysrhythymias (high doses). 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.

6. NITROPRUSSIDE/MONITORING PARAMETERS

a. Monitor blood pressure every 30 to 60 seconds at onset of drip; once stabilized, monitor every 5 minutes.

7. NITROGLYCERIN/INDICATIONS

a. May be used as an alternative or in addition to nitroprusside to control hypertension (particularly useful in patients with coronary artery disease or congestive heart faliure).

8. NITROGLYCERIN/ADULT DOSE

a. A bolus dose of 12.5 to 25 micrograms may be administered intravenously prior to the initiation of a continuous infusion. Begin infusion at 10 to 20 micrograms/minute and increase by 5 or 10 micrograms/minute every 5 to 10 minutes until the desired hemodynamic response is achieved.

9. NITROGLYCERIN/PEDIATRIC DOSE

a. 1 microgram/kilogram/minute by continuous infusion; increase by 1 microgram/kilogram/minute every 20 to 60 minutes as needed until the desired hemodynamic response is achieved.

F. SEROTONIN SYNDROME

1. HYPERTHERMIA

a. Control agitation and muscle activity. Undress patient and enhance evaporative heat loss by keeping skin damp and using cooling fans.
b. MUSCLE ACTIVITY - Benzodiazepines may be useful. Diazepam: Adult: 5 to 10 milligrams IV every 5 to 10 minutes as needed, monitor for respiratory depression and need for intubation. Child: 0.25 milligram/kilogram IV every 5 to 10 minutes; monitor for respiratory depression and need for intubation.
c. Non-depolarizing paralytics may be used in severe cases.

2. HYPERTENSION

a. Monitor vital signs regularly. For mild/moderate asymptomatic hypertension, pharmacologic intervention may not be necessary. For hypertensive emergencies (emergent need to lower mean BP 30 percent within 30 minutes and achieve diastolic BP of 100 mmHg or less within one hour), nitroprusside is preferred.
b. NITROPRUSSIDE

(1) NITROPRUSSIDE/INDICATIONS

(a) Nitroprusside is preferred for hypertensive emergencies (emergent need to lower mean BP 30 percent within 30 minutes and achieve a diastolic BP of 100 mmHg or less within one hour).

(2) NITROPRUSSIDE/DOSE

(a) 0.1 to 5 microgram/kilogram/minute intravenous infusion; up to 10 micrograms/kilogram/minute may be required (AHA, 1992).

(3) NITROPRUSSIDE/SOLUTION PREPARATION

(a) Dilute a 50-milligram vial in 500 milliliters of dextrose 5 percent in water (100 micrograms/milliliter). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution.

(4) NITROPRUSSIDE/MAJOR ADVERSE REACTIONS

(a) Severe hypotension; cyanide toxicity; methemoglobinemia; lactic acidosis; chest pain or arrhthymias (high doses).

(5) NITROPRUSSIDE/MONITORING PARAMETERS

(a) Monitor blood pressure every 30 to 60 seconds at onset of drip; once stabilized, monitor every 30 minutes.

c. NITROGLYCERIN

(1) In theory, nitroglycerin may help alleviate the serotonin syndrome through nitric oxide mediated downregulation of serotonin.
(2) ADULT - Begin continuous infusion at 5 micrograms/minute and titrate to desired effect.
(3) CHILD - Begin infusion at 0.25 to 0.5 micrograms/kilogram/minute and titrate to desired effect.

3. HYPOTENSION

a. Administer 10 to 20 milliliters/kilogram 0.9% saline bolus and place patient in Trendelenburg position. Further fluid therapy should be guided by central venous pressure or right heart catheterization to avoid volume overload.
b. Control hyperthermia.
c. Pressor agents with dopaminergic effects may theoretically worsen serotonin syndrome and should be used with caution.
d. DOPAMINE

(1) PREPARATION: Add 200 or 400 milligrams to 250 milliliters of normal saline or dextrose 5% in water to produce 800 or 1600 micrograms per milliliter or add 400 milligrams to 500 milliliters of normal saline or dextrose 5% in water to produce 800 micrograms per milliliter.
(2) DOSE: Begin at 2 to 5 micrograms per kilogram per minute progressing in 5 to 10 micrograms per kilogram per minute increments as needed.
(3) CAUTION: If VENTRICULAR ARRHYTHMIAS occur, decrease rate of administration.

e. NOREPINEPHRINE

(1) PREPARATION: Add 4 milliliters of 0.1 percent solution to 1000 milliliters of dextrose 5% in water to produce 4 micrograms/milliliter.
(2) INITIAL DOSE

(a) ADULTS: 2 to 3 milliliters (8 to 12 micrograms)/minute
(b) ADULT AND CHILD: 0.1 to 0.2 microgram/kilogram/minute. Titrate to maintain adequate blood pressure.

(3) MAINTENANCE DOSE

(a) 0.5 to 1 milliliter (2 to 4 micrograms)/minute

4. SEIZURES

a. DIAZEPAM

(1) MAXIMUM RATE: Administer diazepam intravenously over 2 to 3 minutes (maximum rate = 5 milligrams/minute).
(2) ADULT DIAZEPAM DOSE: 5 to 10 milligrams initially, repeat every 5 to 10 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 30 milligrams.
(3) PEDIATRIC DIAZEPAM DOSE: 0.2 to 0.5 milligram per kilogram, repeat every 5 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 10 milligrams in children over 5 years or 5 milligrams in children under 5 years of age.
(4) RECTAL USE: If an intravenous line cannot be established, diazepam may be given per rectum (not FDA approved), or lorazepam may be given intramuscularly.

b. LORAZEPAM

(1) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 milligrams/minute (Prod Info Ativan(R), 1991).
(2) ADULT LORAZEPAM DOSE: 4 to 8 milligrams intravenously. Initial doses may be repeated in 10 to 15 minutes if seizures persist (AMA, 1991).
(3) PEDIATRIC LORAZEPAM DOSE: 0.05 to 0.1 milligram/kilogram intravenously, repeated twice at intervals of 15 to 20 minutes (Benitz & Tatro, 1988; Giang & McBride, 1988).

c. RECURRING SEIZURES: If seizures cannot be controlled with diazepam or recur, give phenobarbital.
d. PHENOBARBITAL

(1) SERUM LEVEL MONITORING: Monitor serum levels over next 12 to 24 hours for maintenance of therapeutic levels (15 to 25 micrograms per milliliter).
(2) ADULT PHENOBARBITAL LOADING DOSE: 600 to 1200 milligrams of phenobarbital intravenously initially (10 to 20 milligrams per kilogram) diluted in 60 milliliters of 0.9 percent saline given at 25 to 50 milligrams per minute.
(3) ADULT PHENOBARBITAL MAINTENANCE DOSE: Additional doses of 120 to 240 milligrams may be given every 20 minutes.
(4) MAXIMUM SAFE ADULT PHENOBARBITAL DOSE: No maximum safe dose has been established. Patients in status epilepticus have received as much as 100 milligrams/minute until seizure control was achieved or a total dose of 10 milligrams/kilogram.
(5) PEDIATRIC PHENOBARBITAL LOADING DOSE: 15 to 20 milligrams per kilogram of phenobarbital intravenously at a rate of 25 to 50 milligrams per minute.
(6) PEDIATRIC PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 5 to 10 milligrams per kilogram may be given every 20 minutes.
(7) MAXIMUM SAFE PEDIATRIC PHENOBARBITAL DOSE: No maximum safe dose has been established. Children in status epilepticus have received doses of 30 to 120 milligrams/kilogram within 24 hours. Vasopressors and mechanical ventilation were needed in some patients receiving these doses.
(8) INDICATIONS FOR INTUBATION: Intubation should be considered after total doses of greater than 20 milligrams/kilogram.
(9) NEONATAL PHENOBARBITAL LOADING DOSE: 20 to 30 milligrams/kilogram intravenously at a rate of no more than 1 milligram/kilogram per minute in patients with no preexisting phenobarbital serum levels.
(10) NEONATAL PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 2.5 milligrams/kilogram every 12 hours may be given; adjust dosage to maintain serum levels of 20 to 40 micrograms/milliliter.
(11) MAXIMUM SAFE NEONATAL PHENOBARBITAL DOSE: Doses of up to 20 milligrams/kilogram/minute up to a total of 30 milligrams/kilogram have been tolerated in neonates.
(12) CAUTIONS: Adequacy of ventilation must be continuously monitored in children and adults. Intubation may be necessary with increased doses.

5. CYPROHEPTADINE

a. Cyproheptadine is a non-specific 5-HT antagonist that has been shown to block development of serotonin syndrome in animals (Sternbach, 1991). Cyproheptadine has been used in the treatment of serotonin syndrome (Mills, 1997; Goldberg & Huk, 1992). There are no controlled human trials substantiating its efficacy.
b. ADULT - 4 to 8 milligrams orally repeated every 1 to 4 hours until therapeutic response is observed or maximum of 32 milligrams administered (Mills, 1997).
c. CHILD - 0.25 milligram/kilogram/day divided every 6 hours, maximum dose 12 milligrams/day (Mills, 1997).

6. NITROGLYCERIN

a. In theory nitroglycerin may help alleviate the serotonin syndrome through nitric oxide mediated downregulation of serotonin. It has been used in human cases with apparent benefit (Brown et al, 1996). There are no human trials substantiating its efficacy
b. ADULT - Begin continuous infusion at 5 micrograms/minute and titrate to desired effect.
c. CHILD - Begin infusion at 0.25 to 0.5 microgram/kilogram/minute and titrate to desired effect.

7. PROPRANOLOL

a. Propranolol is a 5-HT1A receptor antagonist (Sternbach, 1991). Propranolol has been used in human cases of serotonin syndrome with apparent benefit (Guze & Baxter, 1986; Dursun et al, 1997). There are no controlled human trials substantiating its efficacy.
b. PROPRANOLOL/ADULT DOSE

(1) 1 milligram/dose intravenously, administered no faster than 1 milligram/minute repeated every 2 to 5 minutes until desired response is seen or a maximum of 5 milligrams has been given.

c. PROPRANOLOL/PEDIATRIC DOSE

(1) 0.01 to 0.1 milligram/kilogram/dose over 10 minutes. Maximum 1 milligram/dose (Benitz & Tatro, 1988).

8. CHLORPROMAZINE -

a. Chlorpromazine is a 5-HT2 receptor antagonist that has been used to treat cases of serotonin syndrome (Graham, 1997; Gillman, 1996). Controlled human trial documenting its efficacy are lacking.
b. ADULT - 25 to 100 milligrams intramuscularly repeated in one hour if necessary.
c. CHILD - 0.5 to 1 milligram/kilogram repeated as needed every 6 to 12 hours not to exceed 2 milligrams/kilogram/day.

9. OTHER

a. Other agents which have been used to treat serotonin syndrome include methysergide and mirtazapine (Mills, 1997; Hoes, 1996).

10. NOT RECOMMENDED

a. BROMOCRIPTINE - Is 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).

6.11 ENHANCED ELIMINATION

A. SUMMARY

1. No studies have addressed the utilization of extracorporeal elimination techniques in poisoning with this agent.

7.0 RANGE OF TOXICITY

7.1 SUMMARY

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.

7.2 THERAPEUTIC DOSE

7.2.1 ADULT

A. GENERAL

1. In adults, effective oral doses of venlafaxine used for depression are 75 to 375 milligrams/day, given in two to three divided doses and taken with food (Riley, 2000).
2. In patients with moderate hepatic impairment it is recommended that the total daily dose be reduced by at least 50% (Riley, 2000).
3. In patients with mild to moderate renal impairment, it is recommended that the total daily dose be reduced by 25% to 50%; in patients undergoing hemodialysis the total daily dose should be reduced by 50% and the dose should be withheld until the dialysis treatment is completed (4 hours) (Riley, 2000).

7.3 MINIMUM LETHAL EXPOSURE

A. GENERAL/SUMMARY

1. The minimum lethal human dose to this agent has not been delineated.

7.4 MAXIMUM TOLERATED EXPOSURE

A. ADULT

1. CASE REPORT - An adult patient who ingested an estimated 6.75 grams recovered with no sequelae (Prod Info Effexor(R), 2000).
2. CASE REPORT - A 41-year-old female suffered severe CNS depression following ingestion of 4.5 grams venlafaxine. Recovery was complete (Fantaskey & Burkhart, 1995).
3. CASE REPORT - A 34-year-old female experienced a generalized seizure approximately 1 hour after ingesting 1400 to 1500 milligrams of venlafaxine (Leaf, 1998).
4. CASE REPORT - A 29-year-old male ingested 2.8 grams of venlafaxine and experienced seizures 2 and 4 hours after ingestion (Coorey & Wenck, 1998).
5. CASE REPORT - A 45-year-old female ingested 10.9 grams of venlafaxine and 35 milligrams of clonazepam and subsequently developed somnolence, severe hypotension, myoclonic jerking, and intraventricular block (Rosen et al, 1997).
6. 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). 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).

B. PEDIATRIC

1. In a retrospective series of 63 pediatric cases of venlafaxine ingestion with doses ranging from 18.75 to 75 milligrams (2.1 to 5.5 milligrams/ kilogram), only one patient developed minor effects (lethargy) (Herrington & Gorman, 1996). Children ingesting 5.5 milligrams/kilogram or less can be managed at home.

7.5 SERUM/PLASMA/BLOOD CONCENTRATIONS

7.5.1 THERAPEUTIC CONCENTRATIONS

A. CONCENTRATION LEVEL

1. Therapeutic serum levels of venlafaxine have not been defined. After single oral doses of 25, 75, and 150 milligrams, mean peak serum concentrations were 37, 102, and 163 nanograms/milliliter, respectively, in one study. Corresponding levels of O-desmethylvenlafaxine, its major active metabolite, were 61, 168, and 325 nanograms/milliliter following these doses (Klamerus et al, 1992).
2. After doses of 25, 75, and 150 milligrams every 8 hours for 3 days, mean peak serum levels were 53, 167, and 393 nanograms/milliliter; corresponding levels of O-desmethylvenlafaxine were 148, 397, and 686 nanograms/milliliter (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 milligrams per day (Prod Info Effexor(R), 2000).

7.5.2 TOXIC CONCENTRATIONS

A. CONCENTRATION LEVEL

1. Peak plasma levels following acute ingestions of 2.75 and 2.5 grams were 6.24 and 2.35 micrograms/milliliter respectively, and the peak plasma levels of O-desmethylvenlafaxine were 3.37 and 1.30 micrograms/milliliter respectively (Prod Info Effexor(R), 2000).
2. Peak plasma levels were 12,000 and 1,200 nanograms/milliliter, respectively, for venlafaxine and O-desmethylvenlafaxine after overdose of 5.6 grams (Kokan & Dart, 1996).
3. Post-mortem venlafaxine level was 89,000 nanograms/milliliter in one case (Dahl et al, 1996).

8.0 KINETICS

8.1 ABSORPTION

A. SUMMARY

1. Venlafaxine is rapidly absorbed with peak plasma levels occurring at 1.8 hours following oral administration. At least 92% of a single dose is absorbed. Mean half-life is approximately 4 hours and mean half-life of O-desmethylvenlafaxine, its active metabolite, is approximately 10 hours (Schweizer et al, 1988; Prod Info Effexor(R), 2000).
2. Two randomized crossover studies were performed to determine the bioavailability of extended-release formulations of venlafaxine as compared to the immediate-release venlafaxine formulations. The results of the studies showed that the extended-release formulations were bioequivalent to the immediate-release formulations with respect to the rate and extent of absorption of venlafaxine and the formation of its active metabolite, O-desmethylvenlafaxine (Troy et al, 1997).
3. Peak plasma levels were achieved 6.3 hours after ingestion of therapeutic amounts of an extended release product (Troy et al, 1997).

8.2 DISTRIBUTION

8.2.1 DISTRIBUTION SITES

A. PROTEIN BINDING

1. Plasma binding of venlafaxine at concentrations ranging from 2.5 to 2215 ng/ mL is approximately 27% +/- 2%. Plasma binding of the active metabolite, O-desmethylvenlafaxine, is approximately 30% +/- 12% at concentrations ranging from 100 to 500 ng/mL. The large volume of distribution (6 to 7 L/kg) and the low plasma protein binding is typical of extensive tissue binding (Prod Info Effexor(R), 2000; Klamerus et al, 1992).

B. TISSUE/FLUID SITES

1. POSTMORTEM LEVELS

§ Blood 89 milligrams/liter

§ Liver fluid 132 milligrams/liter

§ Liver 20.5 milligrams/liter

§ Total gastric content 800 milligrams

§ Reference: Dahl et al, 1996

8.2.2 DISTRIBUTION KINETICS

A. VOLUME OF DISTRIBUTION

1. The apparent volume of distribution at steady state of venlafaxine is approximately 6 to 7 L/kg. The volume of distribution at steady state of the active metabolite, O-desmethylvenlafaxine, is approximately 4 to 6 L/kg. Plasma steady state concentrations of both venlafaxine and its major metabolite are attained within 3 days of multiple dose therapy (Klamerus et al, 1992; Prod Info Effexor(R), 2000).

B. STEADY STATE LEVELS The steady state blood concentration of 393 nanograms/milliliter was obtained after 3 days of 150 milligrams of venlafaxine every 8 hours (Dahl et al, 1996).

8.3 METABOLISM

8.3.1 METABOLISM SITES AND KINETICS

A. GENERAL

1. After oral administration, venlafaxine undergoes substantial first-pass metabolism in the liver, via probable saturable biotransformation, to its major active metabolite, O-desmethylvenlafaxine (Klamerus et al, 1992; Prod Info Effexor(R), 2000).

8.3.2 METABOLITES

A. GENERAL

1. O-desmethylvenlafaxine is the major active metabolite of venlafaxine, which is of similar activity as venlafaxine. Two other less active metabolites are also formed: N-desmethylvenlafaxine and N,O-didesmethyl- venlafaxine, which appear to possess minimal to no pharmacologic activity. This appears to be a saturable metabolic pathway (Klamerus et al, 1992).
2. CYP2D6 poor metabolizers have four-fold less oral clearance of venlafaxine and less O-desmethylvenlafaxine metabolite (Lessard et al, 1999).

8.4 EXCRETION

8.4.1 KIDNEY

A. The primary route of elimination of venlafaxine and its metabolites appears to be renal. After single oral doses of venlafaxine 80 to 100 mg, approximately 1 to 10% is excreted in the urine as unchanged drug. Approximately 30% of a dose is excreted in the urine as O-desmethylvenlafaxine. Approximately 6 to 19% and 1%, respectively, are excreted in the urine as N,O-didesmethylvenlafaxine and N-desmethylvenlafaxine (Klamerus et al, 1992; Wang et al, 1992).

8.5 ELIMINATION HALF-LIFE

8.5.1 PARENT COMPOUND

A. THERAPEUTIC DOSE

1. The elimination half-life of venlafaxine was reported to be approximately 3 to 4 hours, and is independent of doses ranging from 25 to 150 mg (Klamerus et al, 1992).

B. OVERDOSE

1. Half-life was prolonged to 15 hours in one overdose (Kokan & Dart, 1996).

8.5.2 METABOLITE

A. THERAPEUTIC DOSE

1. The elimination half-life of O-desmethylvenlafaxine, the major active metabolite of venlafaxine, was reported to be approximately 10 hours after single oral doses of 25 to 150 mg or after administration of 25 to 100 mg every 8 hours for 3 days (Klamerus et al, 1992).

9.0 PHARMACOLOGY/TOXICOLOGY

9.1 PHARMACOLOGIC MECHANISM

A. Venlafaxine, a bicyclic antidepressant, is a potentiator of neurotransmitter activity in the CNS. Both venlafaxine and its active metabolite, O- desmethylvenlafaxine, inhibit the neuronal uptake of serotonin, noradrenaline, and dopamine in order of decreasing potency, without inhibiting monoamine oxidase. It does not show the degree of anticholinergic, sedative, or cardiovascular effects other antidepressants have been shown to exhibit.
B. Animal studies have demonstrated no affinity for central muscarinic- cholinergic, dopaminergic, histaminic, opioid (mu), benzodiazepine, or alpha1-adrenergic receptors for venlafaxine or O-desmethylvenlafaxine. Venlafaxine has been shown to inhibit neuronal activity in the locus coeruleus of the brain. Other antidepressant properties include its ability to reverse reserpine hypothermia and to cause pineal beta-adrenergic subsensitivity (Haskins et al, 1985; Klamerus et al, 1992; Muth et al, 1986; Saletu et al, 1992; Yardley et al, 1990).
C. Venlafaxine is a racemic mixture; while the pharmacologic profile of the levo (-) isomer is similar to that of the racemate, the dextro (+) isomer is primarily a serotonin uptake inhibitor (Klamerus et al, 1992).

10.0 PHYSICOCHEMICAL

10.3 MOLECULAR WEIGHT

A. 313.87

12.0 REFERENCES

12.2 GENERAL BIBLIOGRAPHY
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