SIBUTRAMINE

c. FOSPHENYTOIN

(1) ADULT DOSAGE AND ADMINISTRATION: The dose, concentration in dosing solutions, and infusion rate of fosphenytoin are expressed as phenytoin sodium equivalents.
(2) ADULT LOADING DOSE FOSPHENYTOIN: 15 to 20 milligrams/kilogram of phenytoin sodium equivalents at a rate of 100 to 150 milligrams phenytoin equivalent/minute.
(3) Fosphenytoin should not be infused at rates greater than 150 milligrams phenytoin equivalent/minute because of the risk of hypotension.
(4) CAUTIONS: Perform continuous monitoring of respiratory function, cardiac rhythm, and blood pressure throughout infusion and for at least 30 minutes thereafter.
(5) ADULT MAINTENANCE DOSING: 4 to 6 milligrams phenytoin equivalents/kilogram/day. Rate of administration should not exceed 150 milligrams phenytoin equivalent/minute.
(6) SERUM LEVEL MONITORING: Monitor serum phenytoin levels over the next 12 to 24 hours; therapeutic levels 10 to 20 microgram/milliliter. Do not obtain serum phenytoin concentrations until at least 2 hours after infusion is complete to allow for conversion of fosphenytoin to phenytoin.

C. TACHYDYSRHYTHMIAS

1. TACHYCARDIA SUMMARY

a. Sinus tachycardia does not generally require treatment unless hemodynamic compromise develops. If therapy is required, a short acting, cardioselective agent such as esmolol is generally preferred.
b. ESMOLOL/PREPARATION

(1) Add 2.5 grams of esmolol to 250 milliliters of dextrose 5% in water or 0.9% sodium chloride (final concentration 10 milligrams per milliliter).

c. ESMOLOL/ADULT LOADING DOSE

(1) Infuse 500 micrograms/kilogram for one minute

d. ESMOLOL/ADULT MAINTANANCE DOSE
e. Follow loading dose with infusion of 50 micrograms/kilogram per minute for 4 minutes
f. EVALUATION OF RESPONSE - If inadequate response to initial loading dose and 4 minute maintenance dose, repeat loading dose (infuse 500 micrograms/kilogram for one minute) followed by a maintenance infusion of 100 micrograms/kilogram/minute for 4 minutes. Reevaluate therapeutic effect.
g. If response is inadequate, repeat loading dose and increase the maintenance dose by increments of 50 micrograms/kilogram/minute, administered as above.
h. END POINT OF THERAPY - As the desired heart rate or blood pressure is approached, omit loading dose and adjust maintenance infusion as required.
i. USUAL ADULT DOSE - 25 to 200 micrograms/kilogram/minute
j. MAXIMUM ADULT DOSE - 300 micrograms/kilogram/minute

2. CAUTIONS

a. Esmolol is a short acting beta-adrenergic blocking agent with negative inotropic effects. Esmolol may be hazardous in patients with bronchospastic disease (asthmatics, COPD) or myocardial depression.

D. PVCS/VENTRICULAR DYSRHYTHMIAS

1. Treatment of ventricular dysrhythmias may include lidocaine, phenytoin, or overdrive transvenous pacing.
2. LIDOCAINE

a. LIDOCAINE/INDICATIONS

(1) Ventricular tachycardia or ventricular fibrillation. Consider in patients with frequent PVCs (greater than 5 per minute), coupled, multifocal, or R on T phenomenon associated with ingestion.

b. LIDOCAINE/DOSE

(1) ADULT: 1 to 1.5 milligram/kilogram intravenously push; begin maintenance infusion of 1 to 4 milligrams per minute; repeat 0.5 milligram/kilogram bolus 10 minutes after initial load.
(2) CHILD: 1 milligram/kilogram initial bolus intravenously; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute.

c. LIDOCAINE/PREPARATION

(1) Add 1 gram of lidocaine to 250 milliliters of dextrose 5 percent in water, to make a 4 milligram/milliliter solution. An increase in the infusion rate of 1 milliliter/minute increases the dose by 4 milligrams/minute.

d. LIDOCAINE/DOSING IN SPECIAL SITUATIONS

(1) Although the loading dose of lidocaine does not need to be reduced, the maintenance dose should be decreased by 50% in the presence of impaired hepatic blood flow (acute myocardial infarction, congestive heart failure, or circulatory shock) and in patients over 70 years of age.

e. LIDOCAINE/MAJOR ADVERSE REACTIONS

(1) Paresthesias; muscle twitching; confusion; seizures; respiratory depression or arrest; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block.

f. LIDOCAINE/MONITORING PARAMETERS

(1) ECG; plasma concentrations.

3. BRETYLIUM

a. BRETYLIUM/INDICATIONS

(1) Ventricular tachycardia or ventricular fibrillation refractory to defibrillation, epinephrine, and lidocaine.

b. BRETYLIUM/ADULT DOSE

(1) VENTRICULAR TACHYCARDIA LOADING DOSE: 5 to 10 milligrams/kilogram of a 10-milligrams/milliliter solution intravenously over 8 to 10 minutes.
(2) VENTRICULAR TACHYCARDIA MAINTENANCE DOSE: A continuous infusion of 2 milligrams/minute can be used following the loading dose.
(3) REFRACTORY VENTRICULAR FIBRILLATION DOSE: 5 milligrams/kilogram intravenous bolus, followed by defibrillation; if VF persists, administer 10 milligrams/kilogram 5 minutes later. Doses of 10 milligrams/kilogram may be repeated twice at 5 to 30 minute intervals.
(4) MAXIMUM DOSE: 30 to 35 milligrams/kilogram; reduce dose in impaired renal function.

c. BRETYLIUM/PRECAUTIONS

(1) Caution in renal insufficiency; severe pulmonary hypertension; aortic stenosis. Maximal antiarrhythmic effect may not be apparent for 20 minutes to 12 hours postinjection; may aggravate digitalis toxicity.

d. BRETYLIUM/MAJOR ADVERSE REACTIONS

(1) Hypotension (usually 1 hour postinjection) preceded by hypertension; respiratory depression; hyperthermia; bradycardia; anginal attacks.

e. BRETYLIUM/MONITORING PARAMETERS

(1) ECG, blood pressure

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.

10. PHENTOLAMINE/INDICATIONS

a. Useful for severe hypertension caused by agents with alpha adrenergic agonist effects. Generally reserved for cases not responsive to shorter acting, titratable agents, such as nitroprusside.

11. PHENTOLAMINE/ADULT DOSE

a. 2.5 to 5 milligrams intravenously every 5 minutes until hypertension is controlled, then every 2 to 4 hours as needed.

12. PHENTOLAMINE/PEDIATRIC DOSE

a. 0.05 to 0.1 milligram/kilogram (2.5 milligrams maximum) intravenously every 5 minutes until hypertension is controlled, then every 2 to 4 hours as needed.

13. PHENTOLAMINE/ADVERSE EFFECTS

a. Hypotension, dysrhythmias, angina, tachycardia, nausea, vomiting, abdominal pain, diarrhea.

14. LABETALOL/INTRAVENOUS INDICATIONS

a. Consider if severe hypertension is unresponsive to short acting titratable agents such as nitroprusside. Use cautiously if sympathomimetic agents are involved in the poisoning, as worsening hypertension may develop from alpha adrenergic effects despite the mixed alpha and beta adrenergic effects of labetalol.

15. LABETALOL/ADULT DOSE

a. INTRAVENOUS: Initial dose of 20 milligrams by slow injection over 2 minutes. Repeat with 40 to 80 milligrams every 10 to 15 minutes. Alternatively, 1 to 2 milligrams/kilogram may be given as a bolus followed by an infusion of 0.5 to 4 milligrams/minute, until desired blood pressure is reached. Maximum total dose 300 milligrams.

16. LABETALOL/DOSING IN SPECIAL SITUATIONS

a. Reduce dose in hepatic insufficiency; dose reduction not required in renal failure; dose in children - not established.

17. LABETALOL/ADVERSE REACTIONS

a. Postural hypotension causing dizziness; fatigue; tremors; abdominal cramps.
b. MAJOR ADVERSE REACTIONS: Withdrawal reactions observed mainly in patients who have received large doses (more than 1.2 milligrams daily, or those who are also receiving a beta- blocker).
c. Decrease dose gradually over a period of one week or more; if withdrawn prior to emergency, control blood pressure with sodium nitroprusside, either alone or in combination with phentolamine.

18. LABETALOL/PRECAUTIONS

a. Contraindicated in patients with pheochromocytoma, bronchial asthma, congestive heart failure, greater than first degree heart block, cardiogenic shock, or severe bradycardia (Med Lett, 1989; Wright et al, 1986).
b. Use caution in hepatic disease or intermittent claudication; effects of halothane may be enhanced by labetalol; safe for use in pregnancy.

19. LABETALOL/MONITORING PARAMETERS: Monitor blood pressure frequently during initial dosing and infusion.

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. The benefits of forced diuresis and hemodialysis are not known. However, due to the extensive protein binding of sibutramine and its active metabolites, it is anticipated that hemodialysis would be of minimal benefit.

7.0 RANGE OF TOXICITY

7.1 SUMMARY

A. Overdose experience is limited. An overdose of 400 milligrams in an adult resulted in tachycardia with no apparent sequelae. A 2-year-old child ingested up to 800 milligrams without complications.

7.2 THERAPEUTIC DOSE

7.2.1 ADULT

A. DISEASE STATE

1. OBESITY - Starting dose is 10 milligrams once daily. The dose may be titrated after 4 weeks to a total dose of 15 milligrams once daily. If 10 milligrams daily is not tolerated, 5 milligrams daily may be taken. Maximum recommended daily dose is 15 milligrams (Prod Info Meridia(R), 1997).

7.2.2 PEDIATRIC

A. DISEASE STATE

1. OBESITY - Sibutramine is not approved for use in pediatric patients (Prod Info Meridia(R), 1997).

7.4 MAXIMUM TOLERATED EXPOSURE

A. ADULT

1. Acute overdose of 100 milligrams in a 30-year-old male resulted in no adverse effects or ECG abnormalities (Prod Info Meridia(R), 1997).
2. Acute overdose of 400 milligrams in a 45-year-old male resulted in a heart rate of 120 bpm. No other adverse effects were reported, and the patient was discharged the following day with no apparent sequelae (Prod Info Meridia(R), 1997).

B. PEDIATRIC

1. Acute intoxication with up to 800 milligrams in a 2-year-old child was reported. The child was observed during overnight hospitalization with no complications reported (Prod Info Meridia(R), 1997).

8.0 KINETICS

8.1 ABSORPTION

A. THERAPEUTIC DOSE

1. Absorption from the gastrointestinal tract is rapid, with T(max) of 1.2 hr. Peak plasma concentrations of the two active metabolites are reached within 3 to 4 hours (Prod Info Meridia(R), 1997).

8.2 DISTRIBUTION

8.2.1 DISTRIBUTION SITES

A. TISSUE/FLUID SITES

1. Animal studies show rapid and extensive distribution into tissues, with the highest concentrations occurring in the eliminating organs, liver and kidney. Pregnancy did not affect tissue distribution, with only low transfer to the fetus (Prod Info Meridia(R), 1997).