6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
A) SUMMARY 1) Prehospital gastrointestinal decontamination is generally not recommended because vomiting may develop after exposure. Activated charcoal may be indicated if the ingestion is recent and the patient is not vomiting and the airway is protected.
B) ACTIVATED CHARCOAL 1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002). 1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
2) CHARCOAL DOSE 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). 1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
b) ADVERSE EFFECTS/CONTRAINDICATIONS 1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
6.5.2) PREVENTION OF ABSORPTION
A) ACTIVATED CHARCOAL 1) CHARCOAL ADMINISTRATION 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.
2) CHARCOAL DOSE 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). 1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
b) ADVERSE EFFECTS/CONTRAINDICATIONS 1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
6.5.3) TREATMENT
A) SUPPORT 1) MANAGEMENT OF MILD TO MODERATE TOXICITY: Limited data following overdose. Treatment is symptomatic and supportive. There is no antidote. Monitor vital signs frequently. Hypertension has developed with therapy; for mild to moderate elevations no therapy may be needed. Monitor liver enzymes and renal function; repeat as indicated. For persistent vomiting, treat with antiemetics and fluid and electrolyte replacement for ongoing symptoms. Obtain baseline serum electrolytes and urinalysis. Monitor cardiac function for evidence of left ventricular dysfunction (ie, CHF symptoms) or cardiac dysrhythmias (prolonged QT interval or torsades de pointes) following a significant overdose. Obtain a baseline ECG and institute continuous cardiac monitoring. Hemorrhagic events including fatal cases of GI, respiratory, tumor, urinary tract and brain have occurred with sunitinib therapy; epistaxis is most common. Carefully monitor for evidence of bleeding and obtain serial CBC with differential. Myelosuppression may develop.
2) MANAGEMENT OF SEVERE TOXICITY: Treatment is symptomatic and supportive. For severe hypertension, sodium nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives. BLEEDING: For prolonged or significant bleeding, platelet and red cell transfusions may be necessary. MYELOSUPPRESSION may develop. Colony stimulating factor (filgrastim or sargramostim) should be administered if severe neutropenia develops. Patients with severe neutropenia should be in protective isolation. Severe infections with and without neutropenia have developed with therapy. OTHER: Thyroid dysfunction, adrenal insufficiency, and severe dermatologic toxicities (ie, erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported with therapy; monitor and treat as indicated.
B) MONITORING OF PATIENT 1) Monitor vital signs frequently.
2) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
3) Monitor liver enzymes and renal function after a significant overdose. Obtain a baseline urinalysis and repeat as indicated following an overdose.
4) Hematologic events including bleeding, thrombocytopenia and neutropenia can occur. Monitor serial CBC with differential following an overdose and assess for physical evidence of bleeding (ie, GI, respiratory, tumor, urinary tract and brain).
5) In patients with neutropenia, monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
6) Obtain a baseline ECG in patients with a significant exposure; repeat as indicated. Initiate continuous cardiac monitoring in symptomatic patients.
C) HYPERTENSIVE EPISODE 1) Monitor patients for hypertension and treat as needed with standard therapy following overdose. During clinical trials, severe hypertension (greater than 200 mmHg or 110 mmHg diastolic) was infrequently reported (Prod Info SUTENT(R) oral capsules, 2014). 2) Monitor vital signs regularly. For mild/moderate hypertension without evidence of end organ damage, pharmacologic intervention is generally not necessary. 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. 3) 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), sodium nitroprusside is preferred. Nitroglycerin and phentolamine are possible alternatives. 4) SODIUM NITROPRUSSIDE/INDICATIONS 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.
5) SODIUM NITROPRUSSIDE/DOSE 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).
6) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION 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).
7) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS 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).
8) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS 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).
9) LABETALOL a) INTRAVENOUS INDICATIONS 1) Consider if severe hypertension is unresponsive to short acting titratable agents such as sodium nitroprusside. Although labetalol has mixed alpha and beta adrenergic effects (Pearce & Wallin, 1994), it should be used cautiously if sympathomimetic agents are involved in the poisoning, as worsening hypertension may develop from alpha adrenergic effects.
b) ADULT DOSE 1) INTRAVENOUS BOLUS: Initial dose of 20 mg by slow IV injection over 2 minutes. Repeat with 40 to 80 mg at 10 minute intervals. Maximum total dose: 300 mg. Maximum effects on blood pressure usually occur within 5 minutes (Prod Info Trandate(R) IV injection, 2010).
2) INTRAVENOUS INFUSION: Administer infusion after initial bolus, until desired blood pressure is reached. Administer IV at 2 mg/min of diluted labetalol solution (1 mg/mL or 2 mg/3 mL concentrations); adjust as indicated and continue until adequate response is achieved; usual effective IV dose range is 50 to 200 mg total dose; maximum dose: 300 mg. Prepare 1 mg/mL concentration by adding 200 mg labetalol (40 mL) to 160 mL of a compatible solution and administered at a rate of 2 mL/min (2 mg/min); also can be mixed as an approximate 2 mg/3 mL concentration by adding 200 mg labetalol (40 mL) to 250 mL of solution and administered at a rate of 3 mL/min (2 mg/min) (Prod Info Trandate(R) IV injection, 2010). Use of an infusion pump is recommended (Prod Info Trandate(R) IV injection, 2010).
c) PEDIATRIC DOSE 1) INTRAVENOUS: LOADING DOSE: 0.2 to 1 mg/kg, may repeat every 5 to 10 minutes (Hari & Sinha, 2011; Flynn & Tullus, 2009; Temple & Nahata, 2000; Fivush et al, 1997; Fivush et al, 1997; Bunchman et al, 1992). Maximum dose: 40 mg/dose (Hari & Sinha, 2011; Flynn & Tullus, 2009). CONTINUOUS INFUSION: 0.25 to 3 mg/kg/hour IV (Hari & Sinha, 2011; Flynn & Tullus, 2009; Temple & Nahata, 2000; Fivush et al, 1997; Miller, 1994; Deal et al, 1992; Bunchman et al, 1992).
d) ADVERSE REACTIONS 1) Common adverse events include postural hypotension, dizziness; fatigue; nausea; vomiting, sweating, and flushing (Pearce & Wallin, 1994).
e) PRECAUTIONS 1) Contraindicated in patients with bronchial asthma, congestive heart failure, greater than first degree heart block, cardiogenic shock, or severe bradycardia or other conditions associated with prolonged or severe hypotension. In patients with pheochromocytoma, labetalol should be used with caution because it has produced a paradoxical hypertensive response in some patients with this tumor (Prod Info Trandate(R) IV injection, 2010).
2) Use caution in hepatic disease or intermittent claudication; effects of halothane may be enhanced by labetalol (Prod Info Trandate(R) IV injection, 2010). Labetalol should be stopped if there is laboratory evidence of liver injury or jaundice (Prod Info Trandate(R) IV injection, 2010).
f) MONITORING PARAMETER 1) Monitor blood pressure frequently during initial dosing and infusion (Prod Info Trandate(R) IV injection, 2010).
10) NITROGLYCERIN/INDICATIONS a) May be used to control hypertension, and is particularly useful in patients with acute coronary syndromes or acute pulmonary edema (Rhoney & Peacock, 2009).
11) NITROGLYCERIN/ADULT DOSE 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).
12) NITROGLYCERIN/PEDIATRIC DOSE 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).
13) PHENTOLAMINE/INDICATIONS a) Useful for severe hypertension, particularly if caused by agents with alpha adrenergic agonist effects usually induced by catecholamine excess (Rhoney & Peacock, 2009).
14) PHENTOLAMINE/ADULT DOSE a) BOLUS DOSE: 5 to 15 mg IV bolus repeated as needed (U.S. Departement of Health and Human Services, National Institutes of Health, and National Heart, Lung, and Blood Institute, 2004). Onset of action is 1 to 2 minutes with a duration of 10 to 30 minutes (Rhoney & Peacock, 2009).
b) CONTINUOUS INFUSION: 1 mg/hr, adjusted hourly to stabilize blood pressure. Prepared by adding 60 mg of phentolamine mesylate to 100 mL of 0.9% sodium chloride injection; continuous infusion ranging from 12 to 52 mg/hr over 4 days has been used in case reports (McMillian et al, 2011).
15) PHENTOLAMINE/PEDIATRIC DOSE a) 0.05 to 0.1 mg/kg/dose (maximum of 5 mg per dose) intravenously every 5 minutes until hypertension is controlled, then every 2 to 4 hours as needed (Singh et al, 2012; Koch-Weser, 1974).
16) PHENTOLAMINE/ADVERSE EFFECTS a) Adverse events can include orthostatic or prolonged hypotension, tachycardia, dysrhythmias, angina, flushing, headache, nasal congestion, nausea, vomiting, abdominal pain and diarrhea (Rhoney & Peacock, 2009; Prod Info Phentolamine Mesylate IM, IV injection Sandoz Standard, 2005).
17) CAUTION a) Phentolamine should be used with caution in patients with coronary artery disease because it may induce angina or myocardial infarction (Rhoney & Peacock, 2009).
D) PROLONGED QT INTERVAL 1) Therapeutic doses of sunitinib have produced prolongation of the QT interval and infrequent reports of torsades de pointes. Concomitant use of sunitinib and other drugs that prolong the QT interval may increase the risk of torsades de pointes (Prod Info SUTENT(R) oral capsules, 2014).
E) TORSADES DE POINTES 1) SUMMARY a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).
2) MAGNESIUM SULFATE a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).
3) OVERDRIVE PACING a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).
4) POTASSIUM REPLETION a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).
5) ISOPROTERENOL a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010). b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010). c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013). 1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013). e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013). 6) OTHER DRUGS a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).
7) AVOID a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.
F) MYELOSUPPRESSION 1) Monitor CBC and platelet count for evidence of severe bone marrow suppression. Severe myelosuppression may occur following an overdose. a) In a phase I dose-escalation study in patients with solid malignancies, grade 3 to 4 thrombocytopenia occurred in 5 out of 28 patients. Thrombocytopenia resolved during the 2-week off-treatment and recurred during on-treatment of sunitinib (Faivre et al, 2006).
b) In a phase I dose-escalation study in patients with solid malignancies, grade 3 to 4 neutropenia occurred in 5 out of 28 patients. Neutropenia resolved during the 2-week off-treatment and recurred during on-treatment of sunitinib (Faivre et al, 2006).
2) Patients with severe neutropenia should be in protective isolation. Monitor CBC with differential daily. If fever or infection develops during leukopenic phase, cultures should be obtained and appropriate antibiotics started. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage. 3) Recombinant human erythropoietin may be used to prevent or correct antineoplastic-induced anemia. G) NEUTROPENIA 1) COLONY STIMULATING FACTORS a) DOSING 1) FILGRASTIM: The recommended starting dose for adults is 5 mcg/kg/day administered as a single daily subQ injection, by short IV infusion (15 to 30 minutes), or by continuous subQ or IV infusion (Prod Info NEUPOGEN(R) IV, subcutaneous injection, 2010). According to the American Society of Clinical Oncology (ASCO), treatment should be continued until the ANC is at least 2 to 3 x 10(9)/L (Smith et al, 2006).
2) SARGRAMOSTIM: The recommended dose is 250 mcg/m(2) day administered intravenously over a 4-hour period. Treatment should be continued until the ANC is at least 2 to 3 x 10(9)/L (Smith et al, 2006).
2) HIGH-DOSE THERAPY a) Higher doses of filgrastim, such as those used for bone marrow transplant, may be indicated after overdose. b) FILGRASTIM: In patients receiving bone marrow transplant (BMT), the recommended dose of filgrastim is 10 mcg/kg/day given as an IV infusion of 4 or 24 hours, or as a continuous 24 hour subQ infusion. The daily dose of filgrastim should be titrated based on neutrophil response (ie, absolute neutrophil count (ANC)) as follows (Prod Info NEUPOGEN(R) IV, subcutaneous injection, 2010): 1) When ANC is greater than 1000/mm(3) for 3 consecutive days; reduce filgrastim to 5 mcg/kg/day.
2) If ANC remains greater than 1000/mm(3) for 3 more consecutive days; discontinue filgrastim.
3) If ANC decreases again to less than 1000/mm(3); resume filgrastim at 5 mcg/kg/day.
c) In BMT studies, patients received up to 138 mcg/kg/day without toxic effects. However, a flattening of the dose response curve occurred at daily doses of greater than 10 mcg/kg/day (Prod Info NEUPOGEN(R) IV, subcutaneous injection, 2010). d) SARGRAMOSTIM: This agent has been indicated for the acceleration of myeloid recovery in patients after autologous or allogenic BMT. Usual dosing is 250 mcg/m(2)/day as a 2-hour IV infusion. Duration is based on neutrophil recovery (Prod Info LEUKINE(R) subcutaneous, IV injection, 2008). 3) SPECIAL CONSIDERATIONS a) In pediatric patients, the use of colony stimulating factors (CSFs) can reduce the risk of febrile neutropenia. However, this therapy should be limited to patients at high risk due to the potential of developing a secondary myeloid leukemia or myelodysplastic syndrome associated with the use of CSFs. Careful consideration is suggested in using CSFs in children with acute lymphocytic leukemia (ALL) (Smith et al, 2006).
4) ANTIBIOTIC PROPHYLAXIS a) Treat high risk patients with fluoroquinolone prophylaxis, if the patient is expected to have prolonged (more than 7 days), profound neutropenia (ANC 100 cells/mm(3) or less). This has been shown to decrease the relative risk of all cause mortality by 48% and or infection-related mortality by 62% in these patients (most patients in these studies had hematologic malignancies or received hematopoietic stem cell transplant). Low risk patients usually do not routinely require antibacterial prophylaxis (Freifeld et al, 2011).
H) FEBRILE NEUTROPENIA 1) SUMMARY a) Although febrile neutropenia has not been reported with sunitinib therapy, severe infections without and without neutropenia have developed. Patients should be monitored for the development of febrile neutropenia following a significant exposure or as indicated.
2) CLINICAL GUIDELINES FOR ANTIMICROBIAL THERAPY IN NEUTROPENIC PATIENTS WITH CANCER a) SUMMARY: The following are guidelines presented by the Infectious Disease Society of America (IDSA) to manage patients with cancer that may develop chemotherapy-induced fever and neutropenia (Freifeld et al, 2011). b) DEFINITION: Patients who present with fever and neutropenia should be treated immediately with empiric antibiotic therapy; antibiotic therapy should broadly treat both gram-positive and gram-negative pathogens (Freifeld et al, 2011). c) CRITERIA: Fever (greater than or equal to 38.3 degrees C) AND neutropenia (an absolute neutrophil count (ANC) of less than or equal to 500 cells/mm(3)). Profound neutropenia has been described as an ANC of less than or equal to 100 cells/mm(3) (Freifeld et al, 2011). d) ASSESSMENT: HIGH RISK PATIENT: Anticipated neutropenia of greater than 7 days, clinically unstable and significant comorbidities (ie, new onset of hypotension, pneumonia, abdominal pain, neurologic changes). LOW RISK PATIENT: Neutropenia anticipated to last less than 7 days, clinically stable with no comorbidities (Freifeld et al, 2011). e) LABORATORY ANALYSIS: CBC with differential leukocyte count and platelet count, hepatic and renal function, electrolytes, 2 sets of blood cultures with a least a set from a central and/or peripheral indwelling catheter site, if present. Urinalysis and urine culture (if urinalysis positive, urinary symptoms or indwelling urinary catheter). Chest x-ray, if patient has respiratory symptoms (Freifeld et al, 2011). f) EMPIRIC ANTIBIOTIC THERAPY: HIGH RISK patients should be admitted to the hospital for IV therapy. Any of the following can be used for empiric antibiotic monotherapy: piperacillin-tazobactam; a carbapenem (meropenem or imipenem-cilastatin); an antipseudomonal beta-lactam agent (eg, ceftazidime or cefepime). LOW RISK patients should be placed on an oral empiric antibiotic therapy (ie, ciprofloxacin plus amoxicillin-clavulanate), if able to tolerate oral therapy and observed for 4 to 24 hours. IV therapy may be indicated, if patient poorly tolerating an oral regimen (Freifeld et al, 2011). 1) ADJUST THERAPY: Adjust therapy based on culture results, clinical assessment (ie, hemodynamic instability or sepsis), catheter-related infections (ie, cellulitis, chills, rigors) and radiographic findings. Suggested therapies may include: vancomycin or linezolid for cellulitis or pneumonia; the addition of an aminoglycoside and switch to carbapenem for pneumonia or gram negative bacteremia; or metronidazole for abdominal symptoms or suspected C. difficile infection (Freifeld et al, 2011).
2) DURATION OF THERAPY: Dependent on the particular organism(s), resolution of neutropenia (until ANC is equal or greater than 500 cells/mm(3)), and clinical evaluation. Ongoing symptoms may require further cultures and diagnostic evaluation, and review of antibiotic therapies. Consider the use of empiric antifungal therapy, broader antimicrobial coverage, if patient hemodynamically unstable. If the patient is stable and responding to therapy, it may be appropriate to switch to outpatient therapy (Freifeld et al, 2011).
g) COMMON PATHOGENS frequently observed in neutropenic patients (Freifeld et al, 2011): 1) GRAM-POSITIVE PATHOGENS: Coagulase-negative staphylococci, S. aureus (including MRSA strains), Enterococcus species (including vancomycin-resistant strains), Viridans group streptococci, Streptococcus pneumoniae and Streptococcus pyrogenes.
2) GRAM NEGATIVE PATHOGENS: Escherichia coli, Klebsiella species, Enterobacter species, Pseudomonas aeruginosa, Citrobacter species, Acinetobacter species, and Stenotrophomonas maltophilia.
h) HEMATOPOIETIC GROWTH FACTORS (G-CSF or GM-CSF): Prophylactic use of these agents should be considered in patients with an anticipated risk of fever and neutropenia of 20% or greater. In general, colony stimulating factors are not recommended for the treatment of established fever and neutropenia (Freifeld et al, 2011). I) VOMITING 1) SUMMARY a) TREATMENT OF BREAKTHROUGH NAUSEA AND VOMITING 1) Treat patients with high-dose dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol); diphenhydramine may be required to prevent dystonic reactions from dopamine antagonists, phenothiazines, and antipsychotics. It may be necessary to treat with multiple concomitant agents, from different drug classes, using alternating schedules or alternating routes. In general, rectal medications should be avoided in patients with neutropenia.
2) DOPAMINE RECEPTOR ANTAGONISTS: Metoclopramide: Adults: 10 to 40 mg orally or IV and then every 4 or 6 hours, as needed. Dose of 2 mg/kg IV every 2 to 4 hours for 2 to 5 doses may also be given. Monitor for dystonic reactions; add diphenhydramine 25 to 50 mg orally or IV every 4 to 6 hours as needed for dystonic reactions (None Listed, 1999). Children: 0.1 to 0.2 mg/kg IV every 6 hours; MAXIMUM: 10 mg/dose (Dupuis & Nathan, 2003).
3) PHENOTHIAZINES: Prochlorperazine: Adults: 25 mg suppository as needed every 12 hours or 10 mg orally or IV every 4 or 6 hours as needed; Children (2 yrs or older): 20 to 29 pounds: 2.5 mg orally 1 to 2 times daily (MAX 7.5 mg/day); 30 to 39 pounds: 2.5 mg orally 2 to 3 times daily (MAX 10 mg/day); 40 to 85 pounds: 2.5 mg orally 3 times daily or 5 mg orally twice daily (MAX 15 mg/day) OR 2 yrs or older and greater than 20 pounds: 0.06 mg/pound IM as a single dose (Prod Info COMPAZINE(R) tablets, injection, suppositories, syrup, 2004; Prod Info Compazine(R), 2002). Promethazine: Adults: 12.5 to 25 mg orally or IV every 4 hours; Children (2 yr and older) 12.5 to 25 mg OR 0.5 mg/pound orally every 4 to 6 hours as needed (Prod Info promethazine hcl rectal suppositories, 2007). Chlorpromazine: Children: greater than 6 months of age, 0.55 mg/kg orally every 4 to 6 hours, or IV every 6 to 8 hours; max of 40 mg per dose if age is less than 5 years or weight is less than 22 kg (None Listed, 1999).
4) SEROTONIN 5-HT3 ANTAGONISTS: Dolasetron: Adults: 100 mg orally daily or 1.8 mg/kg IV or 100 mg IV. Granisetron: Adults: 1 to 2 mg orally daily or 1 mg orally twice daily or 0.01 mg/kg (maximum 1 mg) IV or transdermal patch containing 34.3 mg granisetron. Ondansetron: Adults: 16 mg orally or 8 mg IV daily (Kris et al, 2006; None Listed, 1999); Children (older than 3 years of age): 0.15 mg/kg IV 4 and 8 hours after chemotherapy (None Listed, 1999).
5) BENZODIAZEPINES: Lorazepam: Adults: 1 to 2 mg orally or IM/IV every 6 hours; Children: 0.05 mg/kg, up to a maximum of 3 mg, orally or IV every 8 to 12 hours as needed (None Listed, 1999).
6) STEROIDS: Dexamethasone: Adults: 10 to 20 mg orally or IV every 4 to 6 hours; Children: 5 to 10 mg/m(2) orally or IV every 12 hours as needed; methylprednisolone: children: 0.5 to 1 mg/kg orally or IV every 12 hours as needed (None Listed, 1999).
7) ANTIPSYCHOTICS: Haloperidol: Adults: 1 to 4 mg orally or IM/IV every 6 hours as needed (None Listed, 1999).
J) STOMATITIS 1) Treat mild mucositis with bland oral rinses with 0.9% saline, sodium bicarbonate, and water. For moderate cases with pain, consider adding a topical anesthetic (eg, lidocaine, benzocaine, dyclonine, diphenhydramine, or doxepin). Treat moderate to severe mucositis with topical anesthetics and systemic analgesics (eg, morphine, hydrocodone, oxycodone, fentanyl). Patients with mucositis and moderate xerostomia may receive sialagogues (eg, sugarless candy/mints, pilocarpine/cevimeline, or bethanechol) and topical fluorides to stimulate salivary gland function. Patients who are receiving myelosuppressive therapy may receive prophylactic antiviral and antifungal agents to prevent infections. Topical oral antimicrobial mouthwashes, rinses, pastilles, or lozenges may be used to decrease the risk of infection (Bensinger et al, 2008).
2) Palifermin is indicated to reduce the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support. In these patients, palifermin is administered before and after chemotherapy. DOSES: 60 mcg/kg/day IV bolus injection for 3 consecutive days before and 3 consecutive days after myelotoxic therapy for a total of 6 doses. Palifermin should not be given within 24 hours before, during infusion, or within 24 hours after administration of myelotoxic chemotherapy, as this has been shown to increase the severity and duration of mucositis (Hensley et al, 2009; Prod Info KEPIVANCE(TM) IV injection, 2005). In patients with a sunitinib overdose, administer palifermin 60 mcg/kg/day IV bolus injection starting 24 hours after the overdose for 3 consecutive days.
3) Total parenteral nutrition may provide nutritional requirements during the healing phase of drug-induced oral ulceration, mucositis, and esophagitis.
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