a) CASE REPORT: An 88-year-old man, with a history of glioblastoma multiforme, developed fever, weakness, dyspnea, and a nonproductive cough after completing 2 cycles of adjuvant chemotherapy with temozolomide, 200 mg/m(2) daily for 5 days every 4 weeks. Oxygen saturation on room air was 85%. Lung auscultation revealed inspiratory crackles of lung bases bilaterally without wheezing or rub, and a chest CT demonstrated diffuse ground-glass infiltrates in both lungs. Bronchoalveolar lavage fluid was clear and tested negative for mycobacteria, fungi and Pneumocystis pneumonia, and transbronchial lung biopsy specimens indicated organizing pneumonitis without granuloma, vasculitis, or malignant infiltration. Following discontinuation of temozolomide therapy and administration of prednisone, the patient's condition improved dramatically, with a repeat CT scan, performed 1 month later, indicating resolution of the diffuse infiltrates (Maldonado et al, 2007).

a) In postmarketing experience, opportunistic infections, including Pneumocystis carinii pneumonia (PCP), have developed (Prod Info TEMODAR(R) oral capsules, IV injection, 2011; Marosi, 2006).
b) Ongoing therapy with temozolomide can lead to depletion of CD4 lymphocytes which may lead to PCP. Prophylactic PCP therapy has been recommended when lymphocytes reach 500/mm(3) (Villano et al, 2009). Patients may also be at risk for immunosuppression because of the frequent use of corticosteroids in patients with brain tumors and concomitant radiation therapy (Villano et al, 2009; Marosi, 2006).

a) Headache has frequently occurred following therapeutic administration of temozolomide (Bleehan et al, 1995; Estlin et al, 1998a).
b) INCIDENCE: In a clinical efficacy trial, headache was reported in 41% of patients with anaplastic astrocytoma, with 6% of those patients experiencing grade 3/4 toxicity, following temozolomide administration (Prod Info TEMODAR(R) oral capsules, IV injection, 2011).

a) Fatigue is a common adverse event with temozolomide therapy (Prod Info TEMODAR(R) oral capsules, IV injection, 2011; Estlin et al, 1998a; Bleehan et al, 1995; Brock et al, 1998; Dhodapkar et al, 1994).
b) In a study of 213 patients with recurrent malignant glioma treated with standard doses (150 to 200 mg/m(2) daily for 5 days every 28 days) of temozolomide, grade 3 fatigue occurred in 10 (4%) patients, while there were no episodes of grade 4 toxicity (Chang et al, 2004).

a) Seizures were reported in 23% (n=153) of patients with anaplastic astrocytoma after receiving temozolomide therapy. Grade 3/4 toxicity occurred in 5% of patients (Prod Info TEMODAR(R) oral capsules, IV injection, 2011). It is unclear whether the seizures were drug-related or as a consequence of the patients' underlying disease.

a) During a phase I clinical trial of temozolomide in pediatric patients with advanced cancer, 14% (n=16) of patients reported mild to moderate ataxia (Estlin et al, 1998a).

a) Other common (greater or equal to 10% incidence) adverse neurologic events have included: hemiparesis, asthenia, dizziness, coordination abnormal, amnesia, and insomnia (Prod Info TEMODAR(R) oral capsules, IV injection, 2011).

a) INTRACEREBRAL HEMORRHAGE: A 26-year-old man with a history of glioma (previously treated with surgical resection and chemotherapy) was treated 4 years after the initial diagnosis with temozolomide (7 cycles of dose-dense temozolomide at 100 mg/m(2), 3 weeks on/one week off) for recurrence of tumor growth. The patient was admitted with a persistent headache and a platelet count of less than 8000/mcL. A head CT revealed hemorrhage in the right cerebellum near the fourth ventricle; surgical evacuation was done. Bleeding continued postoperatively, despite platelet transfusions. A hematoma formed after surgery along with a significant decline in the patient's neurologic function. Despite a second attempt to evacuate the hematoma, it immediately recurred and care was withdrawn. Prior exposure to chemotherapeutic agents may have placed this patient at risk for developing a fatal intracerebral bleed secondary to severe thrombocytopenia (Sure et al, 2010).

a) Mild to moderate nausea and vomiting are likely after temozolomide therapy. In some cases, the events can be severe (Prod Info TEMODAR(R) oral capsules, IV injection, 2011; Koukourakis et al, 2009; Brock et al, 1998; Estlin et al, 1998a; Dhodapkar et al, 1997; Bleehan et al, 1995; Woll et al, 1995). In most cases, nausea and vomiting can be managed by standard antiemetics during therapeutic use of temozolomide (Koukourakis et al, 2009).
b) INCIDENCE: Nausea and vomiting occurred in 53% and 42% of adult patients (n=158), respectively, who received temozolomide during an anaplastic astrocytoma clinical efficacy trial. In this trial, 10% and 6% of patients developed severe (grade 3/4) nausea and vomiting, respectively (Prod Info TEMODAR(R) oral capsules, IV injection, 2011). In the Pediatric Cooperative Group Trial (n=122), nausea and vomiting developed in 46% and 51% of children, respectively, who were treated with temozolomide. Severe toxicity (grade 3/4) occurred in 4% or less of children treated (Prod Info TEMODAR(R) oral capsules, IV injection, 2011).

a) Diarrhea has been infrequently reported with temozolomide therapy and is not likely to be severe (grade 3/4) (Prod Info TEMODAR(R) oral capsules, IV injection, 2011; Estlin et al, 1998a).
b) In a study of 213 patients with recurrent malignant glioma treated with standard doses (150 to 200 mg/m(2) daily for 5 days every 28 days) of temozolomide, grade 3 diarrhea occurred in 5 (2%) patients, while there were no episodes of grade 4 toxicity (Chang et al, 2004).

a) Constipation was reported in 33% of patients treated with temozolomide during an anaplastic astrocytoma clinical efficacy trial. Severe toxicity (grade 3/4) was infrequently observed (Prod Info TEMODAR(R) oral capsules, IV injection, 2011).
b) In a study of 213 patients with recurrent malignant glioma treated with standard doses (150 to 200 mg/m(2) daily for 5 days every 28 days) of temozolomide, grade 3 constipation occurred in 5 (2%) patients, while there were no episodes of grade 4 toxicity (Chang et al, 2004).

a) Anorexia is a commonly reported cumulative event of temozolomide therapy (Prod Info TEMODAR(R) oral capsules, IV injection, 2011).
b) Anorexia was reported in 7 of 55 patients following therapeutic administration of temozolomide during a phase II clinical trial (Bleehan et al, 1995).

a) Stomatitis has occurred with therapeutic use of temozolomide. During clinical trials, severe stomatitis (grade 3 or higher) occurred in 1% of all patients treated with temozolomide during the maintenance phase of therapy (Prod Info TEMODAR(R) oral capsules, IV injection, 2011).

a) Gastrointestinal bleeding has occurred in several patients after beginning therapy with temozolomide (Brock et al, 1998; Dhodapkar et al, 1997; Woll et al, 1995).

a) Elevated aminotransferase concentrations have been reported in 4 patients who received temozolomide therapy during phase I and phase II clinical trials (Brock et al, 1998; Bleehan et al, 1995).
b) In a study of 213 patients with recurrent malignant glioma treated with standard doses (150 to 200 mg/m(2) daily for 5 days every 28 days) of temozolomide, grade 3 hepatic toxicity occurred in 3 (1%) patients, while there were no episodes of grade 4 toxicity (Chang et al, 2004).

a) CASE REPORT: A 53-year-old man with glioblastoma multiforme inadvertently received 2750 mg of temozolomide for 2 consecutive days (total dose 5500 mg or 2.8 times the standard dose), instead of 1940 mg over 5 days. He developed mild (grade 1/2) elevation of liver enzymes (AST 106 units/L, ALT 223 units/L, alkaline phosphatase 178 units/L) and bilirubin (2.1 mg/dL), that gradually resolved (Spence et al, 2006).

a) Bone marrow depression, including thrombocytopenia, neutropenia, and leukopenia, occurs frequently with therapeutic administration, and is the major dose-limiting toxicity of temozolomide therapy in adults and children (Prod Info TEMODAR(R) oral capsules, IV injection, 2011; Baruchel et al, 2006; Panetta et al, 2003; Bafaloukos et al, 2002; Brock et al, 1998; Estlin et al, 1998a; Bleehan et al, 1995; Estlin et al, 1992). In clinical trials, myelosuppression (thrombocytopenia and neutropenia) usually occurred within the first few cycles of therapy and appeared to be noncumulative (Prod Info TEMODAR(R) oral capsules, IV injection, 2011; Koukourakis et al, 2009; Mutter & Stupp, 2006; Brada et al, 1999).
b) RISK FACTORS: In clinical trials, elderly (over age 70) patients and women appear to be at greater risk for developing myelosuppression. Grade 4 neutropenia (ANC less than 500 cells/micro/L) or thrombocytopenia (less than 20,000 cells micro/L) was observed more frequently in women and the elderly in the first cycle of therapy (Prod Info TEMODAR(R) oral capsules, IV injection, 2011). In a pediatric study, children treated with temozolomide were found to have a higher frequency and longer duration of myelosuppression compared to adults (Panetta et al, 2003). This was also observed in several pediatric case series with an incidence of grade 3/4 neutropenia, thrombocytopenia, and anemia of 33%, 29% and 7% of all cycles, respectively (Dario & Tomei, 2006).
c) LABORATORY ANALYSIS: The most common grade 3/4 hematologic laboratory abnormalities (10% incidence or greater) reported with temozolomide therapy are lymphopenia, thrombocytopenia, neutropenia and leukopenia (Prod Info TEMODAR(R) oral capsules, IV injection, 2011).
d) MECHANISM: Temozolomide appears to be cytotoxic to stem cell production rather than block stem cell proliferation as might occur with other chemotherapeutic agents (Panetta et al, 2003).
e) Based on therapeutic use, the median nadirs occurred at day 26 for platelets (range 21 to 40 days) and 28 days for neutrophils (range: 1 to 44 days). Myelosuppression was reported late in the treatment cycle and on average returned to normal within 14 days of nadir (Prod Info TEMODAR(R) oral capsules, IV injection, 2011).
f) In the European Organization for Research and Treatment of Cancer - National Cancer Institute of Canada trial (EORTC) the rates of myelosuppression following temozolomide therapy were as follows: lymphopenia (grade 3/4) 55%, thrombocytopenia (grade 3/4) 19%, neutropenia (grade 3/4) 8% to 14%, and leukopenia (grade 3/4) 11% (Villano et al, 2009).
g) In adults treated with temozolomide, grade 3/4 neutrophil abnormalities (including neutropenic reactions) were observed in 8% of patients, and grade 3/4 platelet abnormalities (including thrombocytopenia) occurred in 14% of patients (Prod Info TEMODAR(R) oral capsules, IV injection, 2011).
h) PEDIATRIC TRIAL: In the Pediatric Cooperative Group Trial (n=122) of children treated with temozolomide for various tumors, thrombocytopenia was reported in 58% of patients with 25% of children developing grade 3/4 thrombocytopenia. Lymphopenia, leukopenia and neutropenia occurred in greater than 50% of patients. Grade 3/4 lymphopenia developed in 39% of patients treated (Prod Info TEMODAR(R) oral capsules, IV injection, 2011).
i) In a study of 213 patients with recurrent malignant glioma treated with standard doses (150 to 200 mg/m(2) daily for 5 days every 28 days) of temozolomide alone, hematologic toxicity was the most common event observed. Of the patients developing myelosuppression, 22 (9%) patients developed grade 3, and 40 (16%) patients developed grade 4 toxicity. However, there were no reports of discontinuing therapy due to adverse events (Chang et al, 2004).

a) FATALITY: A temozolomide overdose of 2000 mg/day for 5 days in one patient resulted in pancytopenia, pyrexia, multi-organ failure, and death (Prod Info TEMODAR(R) oral capsules, IV injection, 2011).
b) CASE REPORT: A 53-year-old man with glioblastoma multiforme inadvertently received 2750 mg/day of temozolomide for 2 consecutive days (total dose 5500 mg or 2.8 times the standard dose), instead of 1940 mg over 5 days. The patient complained of grade 2 nausea, vomiting, and diarrhea. Four days after exposure, his WBC was 5.19 THOU/mcL, absolute neutrophil count (ANC) 4.57 THOU/mcL and platelet count 134 THOU/mcL. Granulocyte colony stimulating factor and erythropoietin were started and continued for 23 days, along with prophylactic therapy with fluconazole and acyclovir therapy. On day 16, the patient became febrile with confusion and obtundation and was readmitted. WBC was 0.06, ANC 0.00 and platelets 17 THOU/mcL; bone marrow aspiration was markedly hypocellular on day 21. The patient recovered following supportive care including multiple platelet and several blood transfusions and treatment of secondary infections (ie, Serratia bacteremia and an antecubital cellulitis (treated with vancomycin)). Renal or pulmonary toxicity did not occur. The patient was discharged to home on day 27 with no permanent sequelae; he died 24 months later of disease progression (Spence et al, 2006).
c) CASE REPORT: A 58-year-old man with an anaplastic oligoastrocytoma inadvertently took 200 mg/m(2) daily on days 1 through 5 for 6 consecutive weeks (total dose 12,000 mg) instead of 2000 mg every 28 days. The patient developed grade 4 thrombocytopenia and leukopenia with the effects lasting for 4 weeks and 2 weeks, respectively. No other significant organ toxicities or infection were observed (Koch & Wick, 2006).

a) Febrile neutropenia has been reported rarely following therapeutic use of temozolomide (Singhal et al, 2007).
b) CASE REPORTS: Prolonged and severe pancytopenia (lasting 2 to 6 months) developed in 2 women treated with radiation therapy and temozolomide at a dose of 75 mg/m(2)/day. The first woman was readmitted 5 weeks after therapy with febrile neutropenia and external bleeding. Treatment included antibiotic therapy and blood products; no growth factor support was given. She remained pancytopenic for more than 6 months. The second patient developed pancytopenia 4 weeks after the start of therapy and received a prophylactic platelet transfusion. However, febrile neutropenia occurred 10 days later. Treatment included: blood products, antibiotic and antifungal therapies, and daily colony stimulating factors for one week. She improved, but remained mildly pancytopenic 10 weeks after stopping temozolomide. A bone marrow exam 2 months after stopping therapy was normal. Neither patient was receiving concomitant cotrimoxazole therapy (Singhal et al, 2007).

a) Anemia has been reported following therapeutic administration of temozolomide (Dhodapkar et al, 1997; Brock et al, 1998).
b) A decrease in hemoglobin has been observed in both adults and children treated with temozolomide. During clinical trials, severe (grade 3/4) alterations in hemoglobin were observed in 4% (7/158) of adults and 6% (7/122) of children receiving temozolomide (Prod Info TEMODAR(R) oral capsules, IV injection, 2011).

a) CASE REPORT: A 53-year-old man with glioblastoma multiforme inadvertently received 2750 mg/day of temozolomide for 2 consecutive days (total dose 5500 mg or 2.8 times the standard dose), instead of 1940 mg over 5 days. The patient developed severe pancytopenia and was readmitted 4 days after exposure. Grade 2 anemia (hemoglobin less than 10.0 to 8.0 g/dL) was treated with erythropoietin (10,000 units 3 times weekly on days 4 to 27 and 40,000 units weekly for 8 weeks starting at week 10) and several blood transfusions. The patients developed no permanent sequelae following aggressive supportive management (Spence et al, 2006).

a) In postmarketing experience, prolonged pancytopenia, which can progress to aplastic anemia, has occurred with temozolomide therapy. Concomitant use of other agents (ie, carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim) also known to be associated with aplastic anemia may make the diagnosis difficult (Prod Info TEMODAR(R) oral capsules, IV injection, 2011).
b) INCIDENCE: As of December 2007, 25 cases of aplastic anemia have been reported. According to the manufacturer, the estimated frequency is 10.22 per 100,000 patients exposed to temozolomide (Villano et al, 2009).
c) Based on postmarketing surveillance, 18 cases of aplastic anemia were reported from August 1999 to November 2006 among patients treated with temozolomide. Of these patients, 8 were receiving concurrent radiation therapy. There was no prior history of pancytopenia or aplastic anemia in any case. The median time to onset was 36 days (range: 5 to 578 days). A total of 8 patients died. Three deaths were associated with temozolomide therapy; 2 deaths were secondary to bone marrow transplant complications, and 3 died of disease progression. Five patients recovered following the discontinuation of temozolomide therapy (United States Food and Drug Administration, 2011).
d) CASE REPORT: A 65-year-old woman with glioblastoma multiforme was initially treated with radiation therapy and temozolomide. She was started on adjuvant temozolomide (200 mg/m(2)/day on days 1 to 5) and developed profound fatigue and spontaneous bruising on day 14. Laboratory analysis was consistent with severe pancytopenia and a bone marrow biopsy confirmed the diagnosis of aplastic anemia. The condition was refractory to transfusions and the patient refused further therapy (George et al, 2009).
e) CASE REPORT: A 16-year-old girl with glioblastoma was treated with cranial irradiation with concurrent temozolomide (90 mg/m(2)/day) and became pancytopenic on day 24 of therapy. Temozolomide was discontinued. Bone marrow aspirate showed markedly hypocellular marrow and the patient became red blood cell and platelet transfusion dependent. Filgrastim therapy was given for several months. The patient continued to be transfusion dependent and underwent a successful 8/8 HLA-matched unrelated donor bone marrow transplant over 2 years after developing temozolomide-induced aplastic anemia. The patient continued to require intermittent platelet transfusions, but had an improved quality of life and was able to return home (Morris et al, 2009).

a) Alopecia is more likely to occur when temozolomide is combined with radiation therapy. It has also been observed when temozolomide alone is administered during the maintenance phase of therapy (Prod Info TEMODAR(R) oral capsules, IV injection, 2011). In a study of 61 adults with advanced melanoma, alopecia was reported in 86% of patients (all grades) with 20% experiencing grade 3/4 alopecia (Bafaloukos et al, 2002).

a) Skin rashes and pruritus may develop following therapeutic administration; the events are not anticipated to be severe (grade 3/4) (Prod Info TEMODAR(R) oral capsules, IV injection, 2011; Brock et al, 1998; Estlin et al, 1992).

a) In postmarketing experience, erythema multiforme has been reported during temozolomide therapy. Some patients have reportedly developed a recurrence of symptoms with rechallenge of temozolomide (Prod Info TEMODAR(R) oral capsules, IV injection, 2011).

a) In postmarketing experience, toxic epidermal necrolysis has occurred with temozolomide therapy (Prod Info TEMODAR(R) oral capsules, IV injection, 2011).

a) In postmarketing experience, Stevens-Johnson syndrome has occurred with temozolomide therapy (Prod Info TEMODAR(R) oral capsules, IV injection, 2011).

a) Arthralgia and myalgia are frequently reported with therapeutic use of temozolomide (Rudek et al, 2004).

a) CASE REPORT: A 34-year-old woman, with a past history of amenorrhea for 2.5 years, developed severe hot flashes and ovarian suppression approximately 30 weeks after initiating temozolomide therapy. The patient's hormone concentrations were normal at the beginning of treatment with temozolomide (Brock et al, 1998).

a) Allergic reaction has been reported with temozolomide therapy; severe events (grade 3/4) have not been observed (Prod Info TEMODAR(R) oral capsules, IV injection, 2011).

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.

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).
b) ADVERSE EFFECTS/CONTRAINDICATIONS

a) DOSING

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):
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 OR 250 mcg/m(2)/day SubQ once daily (Prod Info LEUKINE(R) subcutaneous, IV injection, 2008; Smith et al, 2006). Duration is based on neutrophil recovery (Prod Info LEUKINE(R) subcutaneous, IV injection, 2008).

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).

a) There are limited reports of overdose with temozolomide. Due to the risk of potentially severe neutropenia following overdose, all patients should be monitored for the development of febrile neutropenia.
b) CASE REPORT: Based on a single case report, severe pancytopenia (including an absolute neutrophil count (ANC) of less than 500 mm(3)) developed in an adult with glioblastoma multiforme after receiving a temozolomide total dose of 5500 mg over 2 days. Evidence of hematologic toxicity (decreased WBC, ANC and platelet count) was present by day 4 (when the error was found). The patient was immediately admitted to the hospital and started on granulocyte colony stimulating factor for 23 days, and other supportive measures including erythropoietin and prophylactic therapy with fluconazole and acyclovir. Multiple platelet and several red blood cell transfusions were required during the course of hospitalization. Secondary infections (Serratia bacteremia and cellulitis of the antecubital fossa) were treated with several antimicrobial agents and resolved. The patient recovered with aggressive management; he died 24 months later of disease progression (Spence et al, 2006).

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).
g) ANTIBIOTIC PROPHYLAXIS: 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) EMPIRIC ANTIFUNGAL THERAPY: May be considered in patients with persistent or recurrent fever after 4 to 7 days of antimicrobial therapy and duration of neutropenia is expected to be greater than 7 days. A specific agent cannot be recommended; the patient should be evaluated for a specific invasive fungal infection (Freifeld et al, 2011).
i) ANTIVIRAL PROPHYLAXIS: Select patients may require antiviral prophylaxis. If a patient is herpes simplex virus (HSV) seropositive and undergoing allogeneic hematopoietic stem cell transplant or leukemia induction therapy, treat with acyclovir. Antiviral therapy for HSV or varicella-zoster virus is only indicated if there is active disease or laboratory evidence of disease. If a patient has upper respiratory symptoms including a cough, respiratory virus testing (ie, influenza, respiratory syncytial virus (RSV)) may be necessary; treat with neuraminidase inhibitors as indicated (Freifeld et al, 2011).
j) COMMON PATHOGENS frequently observed in neutropenic patients (Freifeld et al, 2011):
k) 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).

a) Based on limited data, nausea and vomiting following a temozolomide overdose is likely to be mild to moderate, and controlled with a combination of antiemetic agents as needed (Tentori & Graziani, 2009; Koukourakis et al, 2009; Spence et al, 2006).
b) TREATMENT OF BREAKTHROUGH NAUSEA AND VOMITING

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):