1) One study suggested that intrathecal methotrexate contributes to the inflammation of the wall of the superior sagittal sinus, subsequent thrombus formation, and swelling of cerebral hemispheres (Enevoldson, 1989).

1) Acute methotrexate neurotoxicity with stroke-like symptoms (eg; aphasia (n=5), facial drooping (n=1), weakness (n=4), left- or right-sided hemiparesis (n=2), sensory loss, and seizures (n=1)) were reported in five children with acute lymphocytic leukemia, treated with intrathecal methotrexate 6 to 11 days before symptom onset. Diffusion-weighted (DW) and conventional MR images of all children within 24 hours of symptom onset were evaluated. The authors concluded that diffusion abnormalities in acute methotrexate neurotoxicity suggested cerebral dysfunction and not overt structural injury to the cerebrum. Diffusion abnormalities could not be used to predict demyelination or gliosis (Rollins et al, 2004).
2) COMBINATION THERAPY WITH CYTARABINE: Neurotoxicity (seizures, encephalopathy, and spinal cord lesions) has been reported in patients receiving combined intrathecal methotrexate and cytarabine. In one study, 28 cases of spinal cord lesions (23 paraplegia (82%), 3 tetraplegia (11%), and 2 cauda equina (7%)) were reported. Six patients received high-dose or slow-release cytarabine. The remaining 22 patients received concomitant or sequential methotrexate and cytarabine intrathecally. Symptoms developed 1 to 91 days (median 10 days) following intrathecal chemotherapy. Patients with spinal cord lesions rarely recover, and are mostly left with residual motor, and bowel or urinary disabilities. Complete recovery was reported in only 3 of the 28 cases (11%) (Kwong et al, 2009).
3) Seizures and headache occurred in a 16-year-old girl with a non-metastatic osteosarcoma who also developed nephrotoxicity, anemia, thrombocytopenia, neutropenia, edema, hypertension, and visual problems after receiving the first course of high-dose methotrexate (HD-methotrexate) (12 g/m(2) IV infusion over 4 hours). She recovered gradually after undergoing hemodialysis and receiving two doses of glucarpidase (CPDG2) (50 Units/kg). On day 47, she received a methotrexate test-dose (50 mg/m(2) IV infusion over 30 min) to determine her elimination pharmacokinetic parameters. She received 16 more courses of HD-methotrexate (10 g or 12 g each course) without any toxicity (Esteve et al, 2007).
4) CHILDREN: Eight children (less than 15 years of age) with brain or cerebellar tumors developed calcification of basal ganglia and dementia after receiving methotrexate and/or radiotherapy. In 2 patients, leukoencephalopathy was also observed. Enlarged ventricles and signs of cerebral and cerebellar atrophy were seen in one patient (Fernandez-Bouzas et al, 1992).
5) CASE REPORT: A 7-year-old girl with B Precursor acute lymphoblastic leukemia (ALL) presented with dysarthria and carpopedal spasms 4 days after receiving the third intrathecal dose of methotrexate, performed under nitrous oxide sedation during induction therapy. Laboratory results revealed neutropenia and slightly elevated c-reactive protein. She received ceftazidime, but her symptoms deteriorated a day later, with somnolence, loss of muscle control, a decreasing Glasgow Coma Scale score of 4 that required intensive care therapy. At this time, she was treated with antiviral and antifungal agents, but these agents were also discontinued after 7 days because all laboratory results were negative. Despite treatment with leucovorin (folinic acid) 15 mg/m(2) for 14 days staring immediately after admission and aminophylline for 3 days (started 7 days after admission), no clinical improvement was observed. MRI images were consistent with severe neurotoxicity. After delaying the consolidation therapy, and the replacement of methotrexate with intrathecal cytarabine and prednisolone, her neurologic symptoms gradually resolved with an intensified rehabilitation program over the next 12 months. However, a year after exposure she continued to have persistent cognitive limitations. The authors suggested a possible synergistic effect of MTX and nitrous oxide (Lobel et al, 2015).
6) CASE REPORT: A 23-year-old woman who suffered from acute myeloid leukemia without cerebral disease experienced cerebral swelling and right frontal hematoma after intrathecal treatment with methotrexate, cytarabine, and hydrocortisone. The authors speculated that the hematoma was incidental to the clinical picture (Hughes & Lane, 1989).

1) Transient leukoencephalopathy that presented with stroke-like symptoms occurred in 2 children after receiving intrathecal methotrexate. MRI results confirmed the diagnosis of leukoencephalopathy. Both patients recovered completely and follow-up MRI results were normal within 1 to 4 weeks (Agarwal et al, 2011).
2) A 19-year-old man with a 5-month history of acute biphenotypic leukemia, presented with sudden-onset dysarthria and weakness of left upper extremity about 3 days after receiving the last intrathecal methotrexate injection. He had difficulty in verbal fluency, dysarthria, left incomplete facial paralysis and ipsilateral upper extremity weakness. A brain diffusion weighted imaging (DWI) MRI of the brain was performed within 6 hours of symptom onset and revealed several areas of restricted diffusion with low apparent diffusion coefficient (ADC) involving the bilateral central semiovale and frontoparietal subcortical white matter. Well-delineated, marked hyperintense abnormalities in the same region of diffusion restriction were observed in T2-weighted image (T2WI) and fluid-attenuated inversion recovery (FLAIR) image. His condition gradually improved without receiving leucovorin, and he recovered completely 10 days later. However, a follow-up MRI 4 weeks later revealed the resolution of the diffusion abnormality and newly developed T2 hyperintensity on FLAIR (Yang et al, 2015).
3) A 10-year-old boy, homozygous for the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, developed toxic encephalopathy after receiving the first high-dose methotrexate infusion (12 g/m(2)/6 hours) for osteosarcoma. The plasma concentrations of methotrexate and 7-OH-methotrexate revealed delayed elimination. Following supportive care which included calcium folinate therapy for 186 hours, he recovered completely. It is suggested that homozygosity for the MTHFR C677T polymorphism can lead to low serum folate concentrations, delayed methotrexate clearance, and prolonged methotrexate exposure (Muller et al, 2008).
4) HIGH-DOSE METHOTREXATE: A 13-year-old girl with osteosarcoma developed severe methotrexate toxicity (plasma methotrexate concentration 446 mcmol/L at 48 hours; target, less than 0.5 mcmol/L), including encephalopathy, liver failure, and renal failure without oliguria, after receiving high-dose methotrexate 12 g/m(2) over 4 hours with standard prehydration, alkalinization, and leucovorin rescue. She gradually recovered over the next 12 days following continuous venovenous hemodialysis, single-pass albumin dialysis (SPAD), continuous venovenous hemodiafiltration, and glucarpidase therapy. CVVHDF achieved the highest clearance rate with an effluent rate of 4950 mL/hr. Glucarpidase therapy resulted in the most rapid percentage (86%) decline in methotrexate concentrations (Vilay et al, 2010).
5) A 12-year-old boy with acute lymphoblastic leukemia developed methotrexate-induced neurotoxicity with cerebral venous sinus thrombosis, and pancytopenia after receiving intrathecal methotrexate (standard dosing) in combination with other chemotherapeutic agents. He developed right hemiparesis, aphasia, altered mental status, persistent seizure activity, and progressive neurological deterioration. An MRI of the brain revealed areas of T2 hyperintensity in the frontoparietal deep cerebral white matter bilaterally. Extensive thrombophilia workup revealed a homozygous methylenetetrahydrofolate reductase C677T mutation and elevated fasting serum homocysteine concentration (13 mcmol/L), but undetectable levels in cerebrospinal fluid. He was treated with enoxaparin, leucovorin, and dextromethorphan for approximately 10 days and his condition improved gradually over the next few weeks (Mahadeo et al, 2010).

1) CASE REPORT: A 30-year-old man with acute lymphoblastic leukemia developed subacute anterior lumbosacral polyradiculopathy 4 days after receiving intrathecal methotrexate (12 mg). He experienced severe motor deficit and double sphincter dysfunction (mild weakness, unstable gait, severe flaccid paraparesis, neurogenic bladder dysfunction, hypopallesthesia from the iliac spine to the foot). CSF examination revealed elevated total protein, mononuclear pleocytosis and immunoglobulin synthesis. He died of respiratory infection and secondary septicemia 15 months after intrathecal chemotherapy (Pascual et al, 2008).
2) CASE SERIES: Three children (22-month-old, 4-year-old, and 5-year-old) developed progressive paraparesis while receiving intrathecal methotrexate as part of a combination regimen for the treatment of acute lymphocytic leukemia. After total doses of 36 to 132 mg, the patients developed symptoms that included leg weakness, areflexia with frequent falling, and flaccid paraplegia. Gadolinium enhancement of the anterior lumbosacral spinal nerve roots was demonstrated on spinal MRI in all 3 patients. All 3 patients received intravenous methylprednisolone 30 mg/kg/day for 3 days. Two patients recovered completely; however, the youngest patient continued to have spastic lower extremities (his muscle strength was improved and he was able to take steps with assistance) (Koh et al, 1999).

1) There were 64 (7%) cases of fibrosis and 1 (0.1%) case of cirrhosis, in 217 rheumatoid arthritis patients with liver biopsies both before and during treatment (after a cumulative dose of at least 1.5 grams), and in 714 patients with biopsy only during treatment. Sixty of the 64 cases of fibrosis were mild. The reticulin stain was more sensitive for early fibrosis (Prod Info RHEUMATREX(R) oral tablets, 2009; Prod Info methotrexate intramuscular, intravenous, intra-arterial injection, 2007).

1) CASE SERIES: In one series, 33 liver biopsy specimens from 25 patients with juvenile rheumatoid arthritis were examined and graded histology to determine the relationship of the Roenigk grade and the presence of liver fibrosis of biopsy specimens with possible risk factors. Similar to patients with rheumatoid arthritis, abnormal liver enzymes were significantly associated with Roenigk grade and the presence of liver fibrosis, which suggested the need for ongoing monitoring for methotrexate hepatotoxicity (Hashkes et al, 1999).
2) CASE REPORT: A patient treated with methotrexate 12 g/m(2) developed elevated liver enzymes, and experienced severe nausea and vomiting. Over the next 20 days, methotrexate was held and her clinical status returned to normal (Banerjee et al, 1988).

1) Anemia, leukopenia, and thrombocytopenia may occur (Prod Info RHEUMATREX(R) oral tablets, 2009; Prod Info methotrexate intramuscular, intravenous, intra-arterial injection, 2007; Esteve et al, 2007; Hansen et al, 1971). These effects typically begin 6 to 9 days after exposure and last for approximately 2 weeks (Hansen et al, 1971).

1) CONCOMITANT RED CELL TRANSFUSION: Methotrexate toxicity was reported in 2 patients administered packed red cell transfusion following high-dose methotrexate infusion 1 gram/m(2) (Yap et al, 1986).
2) CASE REPORT: A rare report of thrombocytopenia (platelet count 25,000/mm(3)) occurred in a 36-year-old woman with sarcoidosis after receiving one oral test dose of 7.5 mg methotrexate. NSAIDS were the only medications the patient was receiving. The platelet count returned to normal 9 days after drug cessation (Jih & Werth, 1998).
3) Three individuals with histories of ESRD treated with hemodialysis secondary to diabetes and hypertension who developed significant toxicity following small doses of methotrexate (e.g., one patient developed pulmonary symptoms following two doses). All developed marrow suppression and one patient died following a total dose of 7.5 mg methotrexate. The patient's course was complicated by ongoing sepsis despite gradual bone marrow recovery (Chatham et al, 2000).
4) PEDIATRIC: A 17-year-old female with osteosarcoma was treated with high-dose methotrexate and developed acute nausea and vomiting approximately 4 hours after the start of therapy (approximately 12 g had been administered). Despite immediate treatment with massive hydration and administration of sodium bicarbonate, acetazolamide and leucovorin her urine output declined to 10 mL/hr and the patient developed acute renal failure, liver dysfunction and a coagulopathy. Severe myelosuppression was reported with leukocytopenia 1,000/mm(3) and thrombocytopenia 10,000/m(3). The patient recovered after 7 days following continuous hemodiafiltration (Goto et al, 2001).
5) CASE REPORT: Grade 3 neutropenia (nadir day 11) and grade 4 thrombocytopenia (nadir day 11) developed in a 54-year-old patient with primary cerebral lymphoma after receiving the first cycle of high-dose intravenous methotrexate (3 g/m(2)) and cytarabine (12 g/m(2)). The patient also developed acute renal failure and grade 3 anemia (nadir day 12) after receiving the second course of therapy. Following intensified rescue therapy, the patient recovered and was discharged on day 21 (vandenBongard et al, 2001).

1) Severe pancytopenia was reported in a 60-year-old woman, with a history of end-stage renal disease secondary to diabetic nephropathy and hypertension, who was receiving methotrexate for painful rheumatoid arthritis. Clinical signs and symptoms resolved after drug discontinuation and treatment with calcium folinate and ongoing hemodialysis (patient already on chronic therapy) (Boulanger et al, 2001).
2) CASE REPORT: A 21-year-old hemodialysis-dependent patient presented with fever (39 degrees C), sore throat and mouth, pruritus, and a diffuse maculopapular rash on her face, a day after receiving methotrexate 100 mg IV, tramadol and dipyrone for ectopic pregnancy. Her rash worsened over the next 3 days and oral thrush, mucositis, and mild trismus were noted during physical examination. At this time, all laboratory results indicated severe pancytopenia. On day 4, her methotrexate blood concentration was higher than 0.12 mcmole/L. Following supportive care, including broad range antibiotics, high-dose steroids, leucovorin (30 mg every 6 hours IV, started on day 5), granulocyte colony stimulating factor (300 mcg/day), repeated 4-hour dialysis with high-flux membrane, and transfusion of packed red blood cells, she gradually recovered and her methotrexate concentrations normalized on day 15 (Willner et al, 2014).
3) CASE REPORT: Two patients with renal dysfunction developed severe pancytopenia after receiving low-dose methotrexate therapy for rheumatoid arthritis. The first patient was taking 7.5 mg/wk of methotrexate (total cumulative dose 15 mg) started 10 days before admission. Despite supportive treatment, he developed multiple-organ failure due to probable sepsis and died 30 hours after admission. The second patient was taking 10 mg/wk of methotrexate (total cumulative dose 1030 mg), started 23 months before admission. She also was taking diclofenac, which can affect renal function. She recovered completely and was discharged 14 days after admission. Bone marrow biopsy of both patients showed hypoplasia (Calvo-Romero, 2001).
4) CASE REPORT: A 12-year-old boy with acute lymphoblastic leukemia developed methotrexate-induced neurotoxicity with cerebral venous sinus thrombosis, and pancytopenia after receiving intrathecal methotrexate (standard dosing) in combination with other chemotherapeutic agents. Extensive thrombophilia workup revealed a homozygous methylenetetrahydrofolate reductase C677T mutation and elevated fasting serum homocysteine concentration (13 mcmol/L), but undetectable levels in cerebrospinal fluid. He was treated with enoxaparin, leucovorin, and dextromethorphan for approximately 10 days and his condition improved gradually over the next few weeks (Mahadeo et al, 2010)

1) Although rare, pancytopenia with severe mucositis has been reported following methotrexate overdose (Ozkol et al, 2015; Fridlington et al, 2011; Brown & Corrigan, 1991).
2) Pancytopenia with severe mucositis was reported following an unintentional overdose of 10 mg/day for 4 days in an 80-year-old woman (Brown & Corrigan, 1991).
3) Pancytopenia developed in a 72-year-old woman 9 days after overdose with an unknown amount of methotrexate (Steger et al, 1993).
4) In a series of 5 patients with fatal subacute methotrexate overdose (duration 6 to 23 days), pancytopenia developed in 4(Sinicina et al, 2005).
5) CASE SERIES: Four adult patients with rheumatoid arthritis developed severe pancytopenia after taking methotrexate 10 to 20 mg/day (instead of weekly) for 7 to 9 days. Despite treatment with leucovorin (in 3 cases) and filgrastim (in 2 cases), all 4 patients died 2 to 2.5 weeks later (Moisa et al, 2006).

1) CASE REPORT: A 67-year-old man with a history of seronegative polyarthritis was treated with methotrexate 5 mg daily for 3 years and developed recurrent ulcer of the skin (upper and lower extremities) and oral mucosa. Symptoms resolved and the ulcers healed within 5 weeks of drug cessation (Ben-Amitai et al, 1998).

1) Another case was reported with a dose of only 2.5 mg/day for 5 days (HSDB , 1995).

1) One 18-year-old patient with acute lymphocytic leukemia developed severe oligospermia, but subsequently fathered a normal child. Mercaptopurine, cyclophosphamide, and prednisone were administered in addition to methotrexate (Hinkes & Plotkin, 1973).
2) Patients with seminomas treated with methotrexate had a greatly reduced sperm count compared with normal controls; sperm morphology and motility did not appear to be affected (Weissbach et al, 1974).
3) In a group of men who had received methotrexate in combination with nitrogen mustard, vincristine, and prednisone for treatment of lymphoma, some were completely azoospermic, but some had recovered sperm production. Individuals who had been in remission for a longer time tended to have recovered sperm production (Sherins & DeVita, 1973).
4) In a group of 3 adult men and 7 boys (1 in puberty and 6 prepubertal) in remission from acute lymphoblastic leukemia and who had been treated with methotrexate in combination with radiation, reduced sperm production was observed in 2 of 3 men and azoospermia in the third. Unexpected stimulation of sperm production was seen in 3 of 4 of the prepubertal boys (Pasqualini et al, 1981).
5) A leukemia patient fathered a normal child while receiving methotrexate therapy. Prior courses of treatment had included daunorubicin, cytarabine, thioguanine, and radiation (Matthews & Wood, 1980).
6) A group of 6 male patients with acute lymphocytic leukemia recovered sperm counts after cessation of the L-10 treatment protocol (cyclophosphamide, BCNU, vincristine, actinomycin D, methotrexate, cytosine arabinoside, thioguanine, and asparaginase). Treatment had been for a minimum of 3.5 years. Of the 2 men who fathered children after recovery, one had a child with multiple malformations then subsequently fathered a normal child (Evenson et al, 1984).
7) Male psoriasis patients receiving methotrexate therapy at varying doses had increased numbers of abnormal sperm and some reduction of sperm counts (Rytter, 1970). Reversible severe oligospermia was seen in one psoriasis patient during methotrexate treatment (Sussman & Leonard, 1980).

1) The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.

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).

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).

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).

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).

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).

1) In one study, early intervention with leucovorin and glucarpidase was highly effective in patients with high-dose methotrexate-induced renal dysfunction. Patients (n=100; median age, 17 years; range, 0.3 to 82 years) with methotrexate-induced nephrotoxicity and delayed methotrexate excretion received glucarpidase 50 Units/kg/dose for 5 minutes given by one of three regimens: a single dose, 2 doses 24 hours apart, or 3 doses every 4 hours. Patients had to meet either of the two eligibility criteria: plasma methotrexate concentration of at least 10 mcmol/L at least 42 hours after the start of high-dose methotrexate infusion OR serum creatinine of at least 1.5 times the upper limit of normal or creatinine clearance of 60 mL/min/m(2) or less and plasma methotrexate concentration of at least 2 standard deviations above the mean at 12 hours or greater after methotrexate administration. Leucovorin doses 1 g/m(2) IV every 6 hours (or per institutional guidelines) before glucarpidase and 250 mg/m(2) IV every 6 hours after the last dose of glucarpidase was given. In the first 35 patients, thymidine (8 g/m(2)/day) IV continuous infusion was administered for at least 48 hours after the last dose of glucarpidase. In patients receiving thymidine, glucarpidase was administered at a median of 96 hours (range, 22 to 294 hours) after the start of methotrexate infusion. Overall, glucarpidase was given at a median of 96 hours (range, 22 to 294 hours; receiving thymidine, n=44) and 66 hours (range, 22 to 192 hours; not receiving thymidine, n=56). Within 15 minutes after the first dose of glucarpidase, plasma methotrexate concentration decreased by 98.7% (range, 84% to 99.5%). Patients who received glucarpidase more than 96 hours after the start of the methotrexate developed more grade 4 and 5 toxicity compared with those patients who received glucarpidase earlier (Widemann et al, 2010).
2) CASE REPORT: A 13-year-old girl with osteosarcoma developed severe methotrexate toxicity (plasma methotrexate concentration 446 mcmol/L at 48 hours; target, less than 0.5 mcmol/L), including encephalopathy, liver failure, and renal failure after receiving high-dose methotrexate 12 g/m(2) over 4 hours with standard prehydration, alkalinization, and leucovorin rescue. Initially, she was treated with continuous venovenous hemodialysis (CVVHD) for 9 hours and then with single-pass albumin dialysis (SPAD) for 23.9 hours. Despite an immediate decline in concentration and half-life (before: 14.8 hours; after: 6.5 hours with CVVHD and 7.4 hours with SPAD) with the start of both therapies, glucarpidase therapy (2000 Units IV infusion) and then continuous venovenous hemodiafiltration (CVVHDF) were required. CVVHDF achieved the highest clearance rate with an effluent rate of 4950 mL/hr. Glucarpidase therapy resulted in the most rapid percentage (86%) decline in methotrexate concentrations. The patient's condition improved gradually (Vilay et al, 2010).
3) In a study of 43 adult cancer patients (median age 54; range 18 to 78 years) with delayed methotrexate elimination, the effects of glucarpidase were evaluated. Patients with a methotrexate concentration of 1 to 1,187 micromol/L received glucarpidase, leucovorin rescue, daily monitoring and supportive care. Although glucarpidase was well tolerated and produced a rapid reduction of circulating methotrexate, 10 (23%) patients died of complications (ie, infection (n=7), uremia and seizures (n=1), methotrexate neurotoxicity (n=1), and peritonitis with multiorgan failure (n=1)) associated with high dose methotrexate therapy. Of note, all the patients in this study had evidence of delayed elimination of methotrexate, which may have contributed to the high case fatality rate, as compared to two previous trials with rates </= to 7%; the authors suggested that a higher median age may have been a contributing factor (Schwartz et al, 2007).
4) CASE SERIES: In one study, cancer patients were treated with methotrexate-induced renal dysfunction with a combination therapy of CPDG2, thymidine, and leucovorin. Of note, patients who had adequate urine output continued to receive IV hydration undergo alkalinization (Widemann et al, 1997).
5) CASE REPORT: A 16-year-old girl with a non-metastatic osteosarcoma developed severe acute toxicity after receiving the first course of high-dose methotrexate (HD-methotrexate) (12 g/m(2) IV infusion over 4 hours). She recovered gradually after receiving two doses of glucarpidase (CPDG2) (50 Units/kg). On day 47, she received a methotrexate test-dose (50 mg/m(2) IV infusion over 30 min) to determine her elimination pharmacokinetic parameters. She received 16 more courses of HD-methotrexate (10 g or 12 g each course) without any toxicity. In this case, fluorescence polarization immunoassay (FPIA) was found unreliable for determining methotrexate concentration after the first dose of CPDG2, due to a cross-reaction between methotrexate and its non-toxic metabolite, 2,4-diamino-N10-methylpteroic acid (DAMPA). However, HPLC was effective in determining the true remaining serum methotrexate level and to evaluate the necessity for a second dose of CPDG2 (Esteve et al, 2007).
6) CASE REPORT/GLUCARPIDASE and AMINOPHYLLINE: A 14-year-old boy with nonmetastatic osteosarcoma of the tibia developed acute renal failure after the sixth cycle of high-dose methotrexate and was initially treated with leucovorin and urine alkalinization. CPDG2 (50 units/kilogram) and aminophylline were started later as a second-intention rescue strategy. Sixteen hours after the first infusion of CPDG2, the methotrexate plasma concentration decreased from 614 to 24.1 mcmol/L. A second dose of CPDG2 was given approximately 5 days later for persistent renal failure. Aminophylline, an adenosine antagonist, was also given to minimize renal dysfunction. Within 2 weeks, the patient had complete recovery of clinical signs and symptoms and went on to have limb salvage surgery (Peyriere et al, 2004).

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).

1) Higher doses of filgrastim, such as those used for bone marrow transplant, may be indicated after overdose.
2) 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):
3) 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).
4) 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).

1) 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).

1) 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).

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).