6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
A) SUMMARY 1) Gastrointestinal decontamination may be considered if the ingestion is recent and the patient is not vomiting.
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).
6.5.3) TREATMENT
A) SUPPORT 1) MANAGEMENT OF MILD TO MODERATE TOXICITY a) Treatment is symptomatic and supportive. Monitor patients closely for evidence of tumor lysis syndrome which has been reported with venetoclax therapy. Treat persistent diarrhea with antidiarrheals as necessary and treat persistent vomiting with several antiemetics of different classes as necessary. Consider the administration of colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe (grade 3 or 4) neutropenia.
2) MANAGEMENT OF SEVERE TOXICITY a) Treatment is symptomatic and supportive. Initiate aggressive IV therapy and correct electrolytes in patients with evidence of tumor lysis syndrome. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe (grade 3 or 4) neutropenia. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia, or hemorrhage.
B) MONITORING OF PATIENT 1) Neutropenia is a very common with venetoclax therapy; thrombocytopenia and anemia have also been reported. Monitor serial CBCs (with differential) and platelet count until there is evidence of bone marrow recovery.
2) Monitor vital signs.
3) Obtain baseline electrolytes (including potassium, uric acid, phosphorus, calcium and creatinine) and assess renal function in patients with evidence of tumor lysis syndrome or after a significant overdose. Monitor fluid balance.
4) 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.
C) TUMOR LYSIS SYNDROME 1) Tumor lysis syndrome, including fatalities and renal failure requiring dialysis, occurred in some previously treated CLL patients that had high tumor burden when treated with venetoclax. Clinical manifestations may include acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia. In some patients changes can occur within the first 6 to 8 hours after the first dose of venetoclax and as each dose increases (Prod Info VENCLEXTA(TM) oral tablets, 2016).
2) Monitor blood chemistry (potassium uric acid, phosphorus, calcium and creatinine), renal function, fluid status and radiographic studies (ie, CT scan) as indicated (Prod Info VENCLEXTA(TM) oral tablets, 2016).
3) Patients at risk of developing tumor lysis should be treated with aggressive IV fluid hydration and anti-hyperuricemic therapy (Prod Info VENCLEXTA(TM) oral tablets, 2016).
D) MYELOSUPPRESSION 1) Myelosuppression should be expected after an overdose of venetoclax.
2) 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) Colony stimulating factors have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Stull et al, 2005; Hartman et al, 1997). These agents should be considered in any patient that has a venetoclax overdose.
4) 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.
E) NEUTROPENIA 1) SUMMARY a) Neutropenia was one of the most common adverse events reported with venetoclax therapy. During clinical trials, 41% of patients (n=240) developed grade 3 or 4 neutropenia (Prod Info VENCLEXTA(TM) oral tablets, 2016).
b) Patients should be closely monitored and treated with appropriate colony stimulating therapy.
2) 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 continuous IV infusion (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2015). 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 OR 250 mcg/m(2)/day SubQ once daily (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2013). Treatment should be continued until the ANC is at least 2 to 3 x 10(9)/L (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2013; Smith et al, 2006).
3) 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 no longer than 24 hours. The daily dose of filgrastim should be titrated based on neutrophil response (ie, absolute neutrophil count (ANC)) as follows (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2015): 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) subcutaneous injection, intravenous injection, 2015). 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 over a 2-hour period. Duration is based on neutrophil recovery (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2013). 4) 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).
5) 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).
F) FEBRILE NEUTROPENIA 1) SUMMARY a) Due to the risk of potentially severe neutropenia following overdose with venetoclax, all patients should be monitored for the development of febrile neutropenia.
b) During clinical trials, 5% of patients (n=240) developed grade 3 or 4 febrile neutropenia (Prod Info VENCLEXTA(TM) oral tablets, 2016).
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). G) VOMITING 1) SUMMARY a) Vomiting has been reported with venetoclax therapy, but the symptoms have been mild in most cases (Prod Info VENCLEXTA(TM) oral tablets, 2016). The following agents may be considered, if the patient develops significant vomiting. b) 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, olanzapine); 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: Adult: 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; MAX 10 mg/dose (Dupuis & Nathan, 2003).
3) PHENOTHIAZINES: Prochlorperazine: Adult: 25 mg suppository as needed every 12 hours or 10 mg orally every 4 or 6 hours as needed. IV dose: 2.5 to 10 mg by slow IV injection or infusion not to exceed 5 mg per minute (MAX 40 mg/day); 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) oral tablets, 2013; Prod Info prochlorperazine edisylate intramuscular intravenous injection, 2011; Prod Info COMPAZINE(R) rectal suppositories, 2013). Promethazine: Adult: 12.5 to 25 mg orally or IV every 4 to 6 hours; Children (2 yr and older) 12.5 to 25 mg OR 0.5 mg/pound orally every 4 to 6 hours as needed. Monitor children closely for respiratory depression or apnea (Prod Info promethazine HCl oral tablets, 2013). 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: The following antiemetic dosing is based on high emetic risk. Dolasetron: Adult: 100 mg orally ONLY. Granisetron: Adult: 2 mg orally daily or 1 mg or 0.01 mg/kg (maximum 1 mg) IV. Ondansetron: Adult: 8 mg orally twice daily; 8 mg or 0.15 mg/kg IV. Palonosetron: Adult: 0.5 mg oral; 0.25 mg IV. Tropisetron: Adult: 5 mg oral; 5 mg IV. Ramosetron: 0.3 mg IV (Basch et al, 2011); Ondansetron: Children (older than 3 years of age): 0.15 mg/kg IV 4 and 8 hours after chemotherapy (None Listed, 1999).
5) BENZODIAZEPINES: Lorazepam: Adult: 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: Adult: 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: Adult: 1 to 4 mg orally or IM/IV every 6 hours as needed (None Listed, 1999).
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