Clinical Management of Cytotoxic Drug Overdoses in Companion
Valerie Wiebe and Eric Simonson

In general, companion animals tolerate chemotherapy exceptionally well, with far fewer side effects than their human counterparts. This is primarily due to the lower doses used in veterinary species (well below the maximum tolerated dose in people) and the less frequent use of multimodality therapies. Since most cytotoxic effects on bone marrow, heart, nervous system, and gastrointestinal tract are dose related, the moderate doses used in companion animals typically result in only mild side effects, including nausea, vomiting, diarrhea, and inappetence. It is estimated that less than 5% of animals require hospitalization for chemotherapy-related toxicities and that less than 1% may actually die as a result of chemotherapy-related toxicity.1 Typically most morbidity noted in veterinary patients following chemotherapy is related to poor tolerance to standard cytotoxic drug doses. In these patients, many factors may contribute to the increased incidence of side effects, including (1) reduced or delayed elimination of the drug because of limited liver metabolism or renal excretion, (2) geriatric alterations in drug pharmacodynamics, (3) pre-existing cardiac, pulmonary, or bone marrow disease, (4) prior chemotherapy and/or radiation exposure, or (5) breed differences in drug tolerance (MDR1 gene deletion mutation: reducing elimination of drugs such as vincristine, vinblastine, and doxorubicin).2 Unfortunately, accidental ingestion of owner’s medications (e.g., fluorouracil ointment) has contributed significantly to the veterinary chemotherapy overdose literature. On rare occasion, inadvertent administration of large or inappropriate doses, the wrong drug, or an incorrect schedule of administration has also lead to significant morbidity or mortality in veterinary species as well as humans Many errors noted in the literature are frequently caused by drugs that are spelled similarly (carboplatin instead of cisplatin or vincristine in place of vinblastine). Errors are also due to poor handwriting skills or failure to place a leading zero before a decimal point (i.e., a volume of .1 ml should be written as 0.1 ml). Miscalculation of infusion rates (over hours rather than days) and provision of more than a cycle’s worth of drug at one time has also lead to serious overdoses. Miscalculation of doses based on weight conversions between kilograms (kg), pounds (lb)lb, and square meters (M2) contribute significantly to error rates. Client misinterpretation of directions on outpatient prescription labels has also resulted in overdoses. Clients frequently misinterpret “Take one tablet weekly” as “Take one tablet daily,” or “Take one tablet every Monday” as “Take one tablet every morning.” In these cases, dose-related side effects should be anticipated to occur and prophylactic intervention may be required to limit the severity of morbidity incurred. Although chemotherapeutic accidents are believed extremely rare in veterinary medicine, it is difficult to assess the exact incidence since most incidences probably go unreported. Although chemotherapeutic “mishaps” are currently considered rare in veterinary medicine, as the practice of veterinary oncology grows, the number of patients undergoing chemotherapy increases, and the number of large clinics doing multiple chemotherapeutic treatments concurrently continues to expand, the incidence of misfilled cytotoxic drug orders and accidental overdoses is likely to increase in number. Unfortunately, limited data are available even in the human literature on the prophylactic management of cytotoxic drug overdoses. Because of the unethical nature of conducting toxicologic studies in humans, most data on cytotoxic drug toxicities come from original toxicologic studies in research animals or from published human case reports on inadvertent overdoses. Although many cases often go unreported, little to no information is often available on how to best manage drug overdoses when they occur. Drug Information and Poison Control frequently offer no more advice than what is available on the manufacturer’s package insert or a Physicians Desk Reference. Advice is typically to provide “supportive care” rather than prophylactic intervention. In order to best treat patients following an overdose, defined treatment protocols should be readily available. The provision of aggressive prophylactic measures (hospitalization, decontamination, hydration, anecdotes, hematopoietic growth factors, prophylactic gastrointestinal protectants, and antibiotics) and prompt supportive care for serious adverse side effects following an overdose may lessen the likelihood of irreversible harm (Table 1). In this chapter, the pharmacological management of accidental chemotherapeutic overdoses is discussed. Current data from the human literature are presented as well as the few case reports and anecdotal information found in the veterinary literature. Clinical management of accidental overdoses of the more common cytotoxic agents used in companion animals are proposed based on available clinical data and speculation in some instances, where no data are available. Management of l-Asparaginase (Elspar) Overdoses L-Asparaginase is very different than most other chemotherapeutic agents in that most of its fatal toxicities are not dose dependent, but are typically due to hypersensitivity
reactions or rapid reduction of large tumor burdens. Currently, no documented clinical
case reports of L-asparaginase overdoses were noted in the veterinary literature.
Manufacturer animal toxicology data suggest that intravenous administration of L-
asparaginase in dogs at doses of 250, 1000, and 2000 IU/Kg/day revealed only decreased
serum albumin, protein, and body weight at the highest dose. Anorexia, emesis, and
diarrhea occurred at all doses. In humans, only one case of L-asparaginase overdose (ten-
fold) was located in the literature. A 3-year-old boy with acute lymphoblastic leukemia
was administered chemotherapy consisting of L-asparaginase, vincristine, daunorubicin
and dexamethasone. He inadvertently received a ten-fold overdose of L-asparaginase.
Despite very high plasma ammonia levels, he remained well clinically, with normal
laboratory parameters.3

Maximum Subcutaneous or Intramuscular Dosages*
400 IU/kg to a maximum of 10,000 IU
400 IU/kg
*Dosage adjustments (reductions) may be required in geriatric animals who are more sensitive to this drug or when using in combination with other cytotoxic drugs. Toxicities Associated with Overdoses Gastrointestinal Toxicity Nausea and vomiting are common at standard doses of L-asparaginase and should be anticipated. Anorexia, weight loss, diarrhea, and ulcers (oral and intestinal) may also occur. Hypersensitivity Reactions Hypotension, bronchospasm, laryngeal edema, erythema, urticaria, wheals, hives, fever, and dyspnea occur rarely at normal doses (<10%–25%) and are not dose dependent. Hypersensitivity reactions typically are not observed until after the second dose. In humans, test doses are given before administration. Hepatic Toxicity Elevated liver enzymes (bilirubin, aspartate aminotransferase [AST], alkaline phosphatase), decreased albumin, edema, and fatty changes to the liver occur in humans following high doses. Liver toxicity may be fatal. Reduced serum albumin was noted in manufacturer toxicology studies in dogs with high-dose L-asparaginase (>1000 IU/kg). Pancreatitis Pancreatitis is reported in dogs following standard treatment and may be severe following high doses.4,5 Pancreatitis may be hyperosmolar, with non-ketotic hyperglycemia, glycosuria, and polyuria. Inflammation and necrosis of the pancreas is reported in humans despite normal amylase concentrations. Fulminant and fatal pancreatitis may occur more frequently with overdoses. Hematologic Toxicity Bone marrow suppression is uncommon at normal doses but may increase in incidence with an overdose. Decreased fibrinogen, clotting factors, platelets, leukopenia and an increased prothrombin time have been reported in humans with high doses. Coagulopathies and thrombosis of large vessels may also occur. Nervous System Hyperexcitation, lethargy, agitation, convulsions, and seizures may occur with large doses. Hypocalcemia associated with necrosis of the parathyroid cells and seizures has been reported in rabbits receiving 1000 IU/kg/day (Merck-Preclinical toxicology data). Hypertriglyceridemia and hyperlipidemia-associated hyperviscosity syndrome have occurred in pediatric and adult human populations that may result in CNS syndrome.6 It is unknown if this side effect is dose dependent. Renal System Azotemia (pre-renal) with increased calcium and phosphorus excretion may occur more frequently at high doses because of protein degradation. Proteinuria and acute renal shut down may also occur with high doses. Miscellaneous Increased plasma concentrations of ammonia are anticipated as a result of breakdown product from asparagine. Very high ammonia concentrations are reported following at
least one ten-fold overdose in a human patient.3

Treatment of L-Asparaginase Overdoses
Gastrointestinal System
Both acute and delayed nausea, vomiting, and diarrhea are anticipated. Delayed gastrointestinal upset may be the result of hyperammonemia. Selective inhibitors of type 3 (5-HT-3) serotonergic receptors (granisetron, ondansetron, dolasetron) or substituted benzamides (metoclopramide) may be effective. For nausea and vomiting refractory to these, a combination of both, with or without a corticosteroid (dexamethasone, methylprednisolone) should be considered. Give antiemetic therapy for at least 24 hours or longer if high ammonia levels persist. Hypersensitivity Reactions Anaphylaxis precautions should be observed. Hypersensitivity reactions are typically not seen on the first dose but may occur with subsequent doses. Although rare (<10%–25%), be prepared to treat hypersensitivity reactions with epinephrine, antihistamine, corticosteroids, and airway maintenance if necessary. The incidence should not be greater with overdoses but has caused significant morbidity and mortality following L-asparaginase administration. Hepatotoxicity Monitor LFTs, clotting factors, triglycerides, and cholesterol. Lipolytic therapy may be required to reduce serum lipid levels that may cause hyperviscosity, resulting in central nervous system (CNS) syndrome. In humans, the lipolytic agent atorvastatin (Lipitor) has been used to reduce cholesterol following L-asparaginase, but its efficacy and safety are not established in dogs. A low-fat diet may be helpful for continuous reduction in serum lipids. Pancreatitis Assess patient for hyperglycemia and pancreatitis. Monitor blood and urine glucose. Administer insulin and IV fluids to prevent diabetic ketoacidosis. Hematologic System Monitor for myelosuppression, which is rare following standard doses in companion animals but may increase with high doses. Patients’ clotting function should be monitored because of the potential for decreased clotting factors. Nervous System Hypertriglyceridemia, hyperlipidemia, hyperammonemia, and hyperglycemia may all contribute to the CNS syndrome and should be monitored carefully. Hypocalcemia associated with necrosis of the parathyroid cells and seizures has been reported in rabbits receiving 1000 IU/kg/day of L-asparaginase. Supplementation with calcium gluconate was beneficial in this setting (manufacturer’s data). Renal Failure For severe renal failure, dialysis should be considered. Hyperammonemia has also been managed with sodium benzoate. Sodium benzoate (206 mg/kg/day plus low protein diet for 2 days) for ammonia-trapping therapy has been effective in humans.6,7 Drug Removal No reports were noted at this time for the use of dialysis in L-asparaginase overdoses. In general, overdoses may be managed without experiencing significant morbidity. Dialysis may be beneficial in the case of severe hyperammonemia or renal failure. Management of Carboplatin (Paraplatin) Overdoses Cisplatin and carboplatin have similar mechanisms of action but differ in their side effect profile. The dose-limiting side effects of carboplatin typically involve bone marrow suppression and hepatotoxicity. This is in contrast to cisplatin, which is associated with sometimes severe nephrotoxicity, ototoxicity, and neurotoxicity even at therapeutic doses. In general, carboplatin is better tolerated than cisplatin unless a patient has impaired renal function. The incidence of severe leukopenia, neutropenia, and thrombocytopenia for both drugs is significantly increased in patients with renal failure.
Toxicologic studies done with platinum-containing agents in dogs suggest that dogs are
highly predictive of toxicities seen in humans.16 Therefore, toxicologic data obtained
from human overdoses may be predictive of those in animals. Human literature suggests
that most platinum-related overdoses have involved the inadvertent substitution of
cisplatin for carboplatin. Because carboplatin is substantially less toxic than cisplatin on a
milligram-for-milligram basis, and higher doses are used for carboplatin, substitution
with cisplatin has resulted in massive overdoses with significant morbidity and mortality.

Maximum Intravenous Dosages*
Small dogs (<15 kg): 10 mg/kg; large dogs (>15 Kg): 300 mg/m2 *Dose reduction is required with renal insufficiency
Toxicities Associated with Carboplatin Overdoses
Hypersensitivity reactions
Hypersensitivity reactions (anaphylactoid, edema, wheezing, dyspnea, tachycardia, hypotension) urticaria, rashes, dermatitis, or erythema may occur following carboplatin treatment, but they are not dose related. Hypersensitivity reactions are frequency delayed and may be seen after multiple doses. Patients with a history of cisplatin hypersensitivity reactions may cross react. Hematologic Bone marrow suppression (thrombocytopenia, leukopenia, neutropenia, and/or anemia) is dose dependent and may be severe at high doses. This is typically the dose-limiting side effect in humans. Gastrointestinal Nausea, vomiting, and anorexia—both acute and delayed—should be anticipated in overdoses. Symptoms may continue for days and are believed mediated via both local and central mechanisms involving serotonin. Nervous System Peripheral neuropathies (paresthesias) are reported rarely with carboplatin at standard doses but may occur more frequently with overdoses. Ototoxicity has been reported at doses of ≥2 g/m2 in adults and at higher than recommended doses in pediatric patients. A reversible loss of vision is also noted at high doses in humans, which may be complete for light and color. Renal Toxicity Elevations of serum creatinine and BUN would be expected at high doses. Renal failure is not normally witnessed at the low doses used in animals but may be seen following overdoses, since this side effect is a result of cumulative or high total dose effects. Electrolyte Effects Hyponatremia, hypokalemia, hypocalcemia, and hypomagnesemia have all been reported in humans with high doses and should be carefully monitored. Hepatic System Elevations in serum alkaline phosphatase, aspartate aminotransferase (AST), serum glutamic-oxaloacetic transaminase (SGOT), or bilirubin concentrations have been reported in human patients receiving high-dose carboplatin. This may be severe in large overdoses. Treatment of Carboplatin Overdoses There are no established guidelines for treating human or animal overdoses of carboplatin. Since many of the side effects of carboplatin are concentration dependent and hemodialysis and plasmapheresis have been shown to effectively remove the drug, these measures may be beneficial in a severe overdose, if available. Alternatively, intravenous hydration and diuresis may speed drug elimination and reduce overall morbidity. At normal doses in humans, plasma platinum terminal half-lives are on the order of 4 to 6 days so that even delayed measures in reduction of carboplatin plasma concentrations may be of some benefit. Hematologic Neupogen (G-CSF) should be started prophylactically in the case of an overdose to prevent potentially severe neutropenia. In humans, G-CSF reduces the incidence, severity, and duration of Grade IV neutropenia following high-dose carboplatin.17 Blood transfusions may also be required. Antibiotics should be started prophylactically. Gastrointestinal Serotonergic receptor antagonists in combination with a metoclopramide CRI may be effective. For nausea and vomiting refractory to these, a combination of both, with or without a corticosteroid (dexamethasone, methylprednisolone), should be considered. Both acute and chronic treatment may be required. Nervous/Hepatic System Because these are concentration-dependent side effects, any reduction in carboplatin concentrations may be beneficial. Intravenous hydration and diuresis may assist in the elimination of carboplatin from the plasma. Renal Intravenous normal saline given at twice the maintenance rate and mannitol (0.25–0.5 g/kg IV q 4–6 hr) and/or furosemide (1–2 mg/kg IV q 6–12 hr) may help to maintain renal function and assist in drug elimination. Electrolytes Monitor closely and replace if necessary. Carboplatin is removed by hemodialysis and plasmapheresis, but the clinical efficacy of these procedures in carboplatin overdose has not been proven. Other platinum-containing products are removed by dialysis but cause secondary rebound spikes in plasma platinum concentrations as drug leaves the tissues. Plasmapheresis has been effective clinically following cisplatin overdoses as described below. Management of Chlorambucil (Leukeran) Overdoses Chlorambucil is an alkylating agent similar to nitrogen mustard. It is available in tablet form for outpatient therapy, making it easier to overdose because of client confusion with directions for use or inadequate “animal/child proofing” of the household. As a result, multiple reports are available in the human literature concerning chlorambucil overdoses. In one case, a 22-month-old child ingested 32 mg (3.2 mg/kg) of chlorambucil tablets prescribed for a family member. She was seen in the emergency room within 1 hour of ingestion. Treatment with gastric lavage, activated charcoal, and magnesium sulfate as a cathartic was initiated. The patient developed irritability, myoclonic-like muscle jerks, an exaggerated startle reflex, vomiting, and EEG changes (epileptiform) within a few hours. The patient was discharged 28 hours after ingestion. A mild bone marrow suppression (leukopenia) was noted on follow-up 7 days after ingestion, which normalized by 23 days. An EEG performed 33 weeks after ingestion was normal.7 Ataxia, coma, grand mal seizures, lethargy, staring gaze, tonic movements, and vomiting have been reported in other human patients following overdoses.8 In humans, the risk of seizures increases with dose, with prior seizure history, and in very young children.9 At least one case report exists in the veterinary literature that describes an inadvertent overdose of a cat given chlorambucil orally. The 9.5-year-old cat was given a prescription of chlorambucil (15 mg/m2 or 4 mg total) every 24 hours for 4 days, followed by 17 days of rest. The owner gave the first evening dose and repeated the dose in the morning. Two days later the cat presented with neurologic signs consisting of twitching and agitation, which began a few hours after the second dose was administered. Severe facial twitching, myoclonus, tonic-clonic seizures, hyperesthesia, and extreme agitation continued until the second day of admission. The cat had mild alterations in its CBC (normocytic, normochromic, non-regenerative anemia), WBC (leukocytosis), and biochemistry (hypocalcemia, hypercholesterolemia), which was attributed to the cats underlying lymphoma and stress. The cat was anorexic, which may have also been a result of the underlying intestinal lymphoma. Treatment consisted of intravenous crystalloids, potassium chloride, vitamin B complex, diazepam, ranitidine, and cefazolin for a brief febrile episode. Nasogastric and PEG tube feedings were instituted for nutritional support. The cat continued to improve clinically and was neurologically normal by day 4. He was discharged on day 7.10 Experiments performed with high-dose, intravenous chlorambucil in cats demonstrated that neurologic toxicity was often the dose-limiting side effect. Following doses of 15 to
40 mg/kg, bilateral discharges similar to petite mal epilepsy were noted on EEG. EEG
changes were reversed with phenobarbital sodium. Age-related CNS changes were also
noted in the study and suggested that young kittens (25–30 days old) had massive
myoclonic flexor spasms, whereas older kittens (3 months) had more typical grand mal
seizures or pure tonic seizures. The threshold for chlorambucil-induced seizures also
appeared to be higher in more mature animals.11

Maximum Oral Dosage*
2 mg once q 4 days. Tabs should not be split, so an alternative is 2 mg PO twice. 2 to 6 mg/m2 q 24 hours (dependent on neoplasia type); may also be used as a *Dose reduction required with renal insufficiency. Prior seizures or CNS disease may increase risk of chlorambucil neurologic toxicities. Toxicities Associated with Chlorambucil Overdoses Hematologic Leukopenia, neutropenia, progressive lymphopenia, thrombocytopenia, and anemia have all been reported in humans following high doses of chlorambucil. Hematologic side effects are dose limiting in humans and are dose dependent. Excessive doses and prolonged therapy may result in irreversible bone marrow damage. In most overdose cases, only mild bone marrow suppression was noted, but depressive effects were highly variable in time of onset (2 days to 41 days after ingestion). Following overdoses, pancytopenia nadirs may occur 1 to 6 weeks after ingestion and not recover for 3 to 7 weeks. Gastrointestinal The gastrointestinal side effects of chlorambucil are also dose dependent. Nausea, vomiting, abdominal pain, discomfort, anorexia, and diarrhea have all occurred in human overdose cases. Gastrointestinal effects may only last for 24 hours, but nausea can persist for up to 7 days. Neurologic Tremors, muscle twitching, myoclonia, confusion, agitation, ataxia, flaccid paralysis, peripheral neuropathy, and hallucinations have all been reported in human cases. Focal and/or generalized seizures occur commonly with high doses or overdoses of drug. Seizures may occur very early after ingestion (2 hours) or be delayed (6–90 days). Focal seizures may progress to become generalized. Seizures are typically reversible. EEG changes may occur within 1 to 6 hours after ingestion or can be delayed (90 days).12-14 Younger animals may be more susceptible to neurologic toxicity. Pulmonary In rare cases, a syndrome of bronchopulmonary dysplasia, interstitial pneumonitis, and pulmonary fibrosis has been reported in humans with prolonged continuous chlorambucil dosing. Fever, cough, rales, dyspnea, respiratory distress, hypoxia, and death have resulted. Miscellaneous In humans, at least one case of acute renal failure was reported following an overdose.15 Dermatologic reactions may occur but are not dose related. Hypersensitivity
reactions including rashes, urticaria, toxic epidermal necrolysis, and periorbital edema
have all been reported. Hyperuricemia, hepatoxicity, and drug fever may also occur.

Treatment of Chlorambucil Overdoses
Excessive doses may result in pancytopenia and irreversible bone marrow damage. The manufacturer suggests that this may occur when the total dose in humans approaches 6.5 mg/kg in one course of therapy. Following large overdoses, treatment initiated 24 hours after ingestion with Neupogen may help to prevent severe myelosuppression. Transfusions with blood components may also be required. Antibiotic prophylaxis should be initiated if myelosuppression becomes severe. Complete blood counts should be measured at least three times weekly for 3 to 4 weeks. Gastrointestinal The adverse gastrointestinal effects of chlorambucil are typically mild and last less than 24 hours. These effects can be treated with anti-emetics. Serotonergic receptor antagonists or metoclopramide should be sufficient to control nausea and vomiting. Neurologic Seizures and other CNS side effects are seen frequently in human patients following overdoses. Seizures may occur early, within hours after ingestion, and generally disappear within 24 to 48 hours. No apparent residual neurologic damage has occurred in humans to date. Phenobarbital sodium was shown to be of benefit in controlling EEG changes after chlorambucil in experimental treatment of cats receiving high intravenous doses of chlorambucil.11 Miscellaneous In humans, pulmonary side effects have resulted in a discontinuation of chlorambucil. Steroids may be of some benefit. Allergic reactions may require antihistamines and steroids if severe. Drug Removal Chlorambucil is not significantly removed by dialysis. Absorption from the gastrointestinal tract is rapid (1 hour) and complete. Emesis may be induced only if the patient just recently ingested chlorambucil and if the patient is not comatose, vomiting, having seizures, or has lost gag reflex. Gastric lavage with activated charcoal may also be useful. Management of Cisplatin (Platinol) Overdoses Cisplatin, as discussed under carboplatin, is more frequently overdosed than carboplatin because of inadvertent name interchange with carboplatin. In general, the
dose-limiting toxicities for cisplatin are typically non-hematologic and include
nephrotoxicity, ototoxicity, neurotoxicity, and emesis. At high doses of cisplatin, bone
marrow suppression is more common and has been noted in multiple cases of cisplatin
overdose. As stated under carboplatin, human toxicologic data may be useful in
determining toxicities witnessed in dogs. Multiple cases of cisplatin overdoses have been
reported in the human literature. An accidental cisplatin overdose (300 mg/m2) in a 59-
year-old male induced severe emesis, myelosuppression, renal failure, mental
deterioration with hallucinations, dim vision, and hepatotoxicity. The patient was
successfully managed with plasmapheresis and G-CSF. The renal function was restored
after 3 months.18 Similar side effects were also reported in a 68-year-old woman with a
massive cisplatin overdose. In this case, the patient also experienced deafness (non-
reversible) and seizures. Plasmapheresis was effective and reduced platinum
concentrations from 2900 to 200 ng/ml. Further hydration, even after the onset of renal
failure, resulted in increased urinary excretion of platinum.19

Maximum Intravenous Dosages*
70 mg/m2 *Dose reduction required with renal insufficiency
Toxicities Associated with Cisplatin Overdoses
Hypersensitivity Reactions
Anaphylactoid reactions, edema, wheezing, dyspnea, tachycardia, hypotension, urticaria, rashes, dermatitis, or erythema may occur following cisplatin treatment at any dose. Hematologic Bone marrow suppression (thrombocytopenia, leukopenia, neutropenia, and/or anemia), which is typically rare with cisplatin, is expected at higher doses and has been reported in human overdose cases. Myelosuppression may be severe. Gastrointestinal Severe nausea, vomiting, and anorexia are reported in humans following overdoses.18,19 Both acute and delayed gastrointestinal symptoms should be anticipated in overdoses. Symptoms may continue for weeks and are believed mediated via both local and central mechanisms involving serotonin. Nervous System Peripheral neuropathies (reversible and non-reversible) are a dose-dependent toxicity in humans and may occur acutely or may be delayed following high doses of drug. Dorsal column myelopathy and autonomic neuropathy may also occur. Both partial and tonic-clonic seizures, slurred speech, loss of taste, mental deterioration, hallucinations, and tremors have also been described. Ototoxicity (non-reversible), loss of vision (cortical blindness), optic neuritis, and papilledema is also noted following overdoses of cisplatin in humans. Renal Toxicity Cisplatin is an extremely nephrotoxic heavy metal. Nephrotoxicosis is characterized by reduced glomerular filtration and renal tubular damage. Patients with prior renal impairment, hypertension, or diabetes, or those on other nephrotoxic drugs may be at increased risk of renal failure, particularly when high doses of cisplatin are used. At high doses, nephrotoxicity may be severe and result in irreversible renal damage, which may be fatal. Focal acute tubular necrosis and degeneration have been described. Electrolyte Effects Severe and prolonged hypophosphatemia, hypokalemia, hypocalcemia, and hypomagnesemia have all been reported in humans and should be carefully monitored. Cisplatin has caused significant hypomagnesemia and hypocalcemia in children at high doses resulting in cramps, clonus, tremor, carpopedal spasm, and tetany. Hepatic System Hepatotoxicity has been described following human cisplatin overdoses. Elevated liver enzymes (serum alkaline phosphatase, AST, bilirubin) have been reported in human
patients receiving high dose regimens as well as cisplatin overdoses.18

Treatment of Cisplatin Overdoses
Overdoses of cisplatin typically result in severe toxicities. Prior experience with human overdoses suggests a number of effective but costly treatments. Plasmapheresis is considered the therapy of choice in humans following platinum overdoses but is not readily available in veterinary medicine. In humans, amifostine (Ethyol or WR-2721) has been given to reduce the severity and incidence of cisplatin-induced side effects (neurotoxicity, nephrotoxicity, hypomagnesemia, bone marrow toxicity). This agent works as a cytoprotective pro-drug that releases free thiol groups that can act to detoxify reactive nucleophiles generated by alkylating agents and platinum-containing agents. Amifostine has been shown to be effective in human cisplatin overdoses and appears to be well tolerated in dogs.20,21 In humans, amifostine may contribute to cisplatin-induced nausea and hypotension. Hematologic Neupogen (G-CSF) should be started prophylactically following severe overdoses. Blood transfusions may also be required. Amifostine has been shown to reduce cisplatin-induced bone marrow toxicity in humans. Antibiotics should also be started prophylactically. Gastrointestinal A selective serotonergic receptor antagonist in combination with a metoclopramide CRI may be effective. For nausea and vomiting refractory to these, a combination of both, with or without a corticosteroid, should be considered. Both acute and chronic treatment may be required. Nervous/Hepatic Because neurotoxicity and hepatic toxicity are concentration-dependent side effects, reduction in cisplatin tissue concentrations via plasmapheresis, hydration, and diuresis may be beneficial. Amifostine has also been shown to reduce cisplatin-induced neurotoxicity. Renal Cisplatin has been demonstrated to be less toxic in a high-chloride environment.22 Intravenous normal saline given at twice the maintenance rate and mannitol (0.25–0.5 g/kg IV q 4–6 hr) and/or furosemide (1–2 mg/kg IV q 6–12 hr) may also be effective. Following cisplatin overdoses in humans, hydration, even after the onset of renal failure, has resulted in significant increased urinary excretion of platinum.19 Ideally, hydration should be aimed at induction of a brisk diuresis, particularly after an overdose has occurred. Many substances have been evaluated in an attempt to minimize cisplatin=-induced nephrotoxicity, including sodium thiosulfate, glutathione, superoxide dismutase, MESNA, probenecid, and amifostine. Sodium thiosulfate (4 g/m2) loading dose over 15 minutes to decrease hypotension, then 2.7 g/m2 in three divided doses, has been administered to pediatric patients.23 Amifostine has been administered to humans at a dose of 740 to 910 mg/m2 (up to three doses in 24 hr) administered as a 15-minute intravenous infusion. Longer infusions may cause hypotension. Monitor for hypotension and give fluid boluses if needed. If blood pressure returns to normal within 5 minutes, infusion may be restarted (Micromedex Healthcare Services). Amifostine has had proven efficacy in human patients.24 Electrolyte Effects Monitor closely and replace if necessary. Potassium chloride should be added to intravenous fluids to replace losses. Magnesium sulfate should be given intravenously if required. Drug Removal Hemodialysis is not effective because of rapid release of secondary platinum species from tissues causing a rebound effect.23 Plasmapheresis is effective in reducing plasma platinum concentrations following human overdoses. Concentrations have been reduced from 2979 ng/ml to 185 ng/ml following plasmapheresis in at least one human patient.18 Management of Cyclophosphamide (Cytoxan) Overdoses The toxicity of high-dose cyclophosphamide is perhaps better known than any drug since it is a frequent drug of choice for bone marrow ablation, prior to bone marrow
transplantation in humans. Acute toxicity from overdoses produces extensions of
common adverse reactions such as leukopenia and thrombocytopenia. Cardiotoxic effects
may occur and are dose dependent. Extreme overdoses in humans (4 g/m2/day, four times
per day) have resulted in fatal cardiotoxicity. The urinary system is also a target for
toxicity because it is low in thiols (i.e., glutathione) that bind acrolein and other
cytotoxic-active metabolites. Prolonged exposure of bladder mucosa to high
concentrations of cytotoxic metabolites results in sometimes severe hemorrhagic cystitis.

Maximum Intravenous Dosages*
250 mg/m2 IV or PO *Tablets should not be split! *Dose reduction (33%–50%) is required in patients with compromised bone marrow function.

Toxicities Associated with Cyclophosphamide Overdoses
One of the major dose-limiting side effects of cyclophosphamide is hematologic toxicity. Leukopenia, thrombocytopenia, hypothrombinemia, and anemia would be expected to be severe following an overdose. Cardiac Cardiac toxicity is expected following extremely high doses. In humans, this has resulted in hemorrhagic myocardial necrosis, acute myocarditis, and fatal congestive heart failure within days of an overdose. Indicators may include sudden weight gain, ECG abnormalities, and dyspnea. Gastrointestinal Nausea, vomiting, and anorexia are dose related and may be severe following an overdose. Nausea may be delayed for up to 12 to 24 hours. Although rare with smaller doses, diarrhea, hemorrhagic colitis, mucosal irritation, and oral ulceration may occur more frequently with overdoses. Genitourinary Sterile hemorrhagic cystitis (hematuria, hemorrhagic cystitis) caused by chemical irritation of the bladder by active metabolites (acrolein) is noted at low doses, and its incidence may be increased in an overdose. Typically it is seen more frequently in dogs on chronic therapy but has been reported acutely with high doses and can also occur in cats.25 Following standard oral doses, sterile hemorrhagic cystitis is reported to occur in 7% (14/203) of dogs and 3% (1/52) of cats.26 Bladder fibrosis may occur with or without cystitis and is also a dose-related side effect. Obstruction may occur from clots and cause significant pain on urination. Metabolic As a result of extensive purine catabolism, hyperuricemia may result and may be more prevalent at high doses with significant cellular destruction. Hyperkalemia resulting from rapid tumor lysis may also occur. In humans, hyponatremia resulting from impaired water excretion (SIADH) has also been reported and should be monitored. SIADH appears to be dose dependent in humans receiving cyclophosphamide. Miscellaneous At high doses over prolonged periods, human patients have developed interstitial pulmonary fibrosis, which has been fatal and non-responsive to corticosteroids. Other
side effects may include hepatotoxicity, alopecia, anaphylactic reactions, skin
pigmentation, and the development of secondary cancers (bladder, leukemia).

Treatment of Cyclophosphamide Overdoses
Neupogen (G-CSF) should be started prophylactically (24 hr after chemotherapy overdose) in the case of a severe overdose. Blood transfusions may also be required. Anti-infectives should be started prophylactically. Drugs that interact with the P-450 enzyme system should be avoided. P-450 inducers (barbiturates) may increase formation of cyclophosphamide toxic metabolites, and P-450 inhibitors (cimetidine) may delay drug accumulation, leading to increased bone marrow suppression. Cardiac Cardiac toxicity is dose and concentration related so that any process to expedite drug clearance may reduce the potential for toxicity. Hemodialysis, if available, should be performed after extremely large overdoses. Hydration with forced diuresis may be of some help. Assess patient frequently for signs and symptoms of cardiac dysfunction. Gastrointestinal Emesis should be minimal following cyclophosphamide, even when administered to cats.27 If vomiting and nausea are severe, a selective serotonergic receptor antagonist or metoclopramide may be effective. If gastrointestinal irritation or mucositis is evident, a proton pump inhibitor with or without sucralfate may be useful. Genitourinary In veterinary medicine, a variety of treatments have been tried to minimize bladder toxicity. Prednisone (0.5–1.0 mg/kg) PO once daily has been given to reduce bladder inflammation and promote diuresis.4 Intravesicular administration of formulin (1%) or DMSO (25%–50%) has also been given with some success in dogs.28,29 In humans, the mainstay of treatment is diuresis, bladder irrigation with aluminum sulfate (alum), and MESNA. In general, hyper-hydration with bladder irrigation may be equivalent to MESNA at reducing bladder toxicity. Therefore, patients with asymptomatic hematuria and/or minimal symptoms can be managed with fluid diuresis. Hydration is key to the prevention of cystitis, particularly in the first 72 hours. Frequent voiding of urine to eliminate accumulation of toxic metabolites in the bladder may also be helpful in reduction of hemorrhagic cystitis. More aggressive therapy may be necessary for symptomatic patients. In pediatric patients, MESNA (12 mg/kg IV at hours 0, 3, 6, 9, and 12)30 and fluids (1.5–2.0 maintenance rate) are suggested if there is evidence of hemorrhagic cystitis.31 In dogs, the recommended dose of MESNA is based on the dose of cyclophosphamide used (20%). MESNA is given as an IV bolus followed by a 0.9% NaCl diuresis. Two additional doses can be given at 2 and 5 hours during the diuresis period.32,33 Benzyl alcohol is used as a preservative in MESNA, which may be toxic to animals. However, cats have been given MESNA apparently without problems.34 Metabolic If hyperuricemia is present, fluid therapy should be initiated. In pediatric patients, D5W (3000 ml/m2/day with 40 mEq/L NaHCO3) is used in combination with allopurinol. If SIADH is present, treatment should involve fluid restriction and furosemide. Hypertonic crystalloids may be given to increase sodium solutes. Hyponatremia can lead to seizures or coma and should be frequently monitored. Slowly increase the sodium concentration at a rate of 0.5 to 1.0 mmol/L/hr, so that central pontine myelinolysis is not induced. Aggressive intravenous potassium supplementation may also be required. Miscellaneous Pulmonary fibrosis from cyclophosphamide is not reversed by corticosteroids. Hemodialysis is effective at reducing cyclophosphamide plasma concentrations and is suggested following large overdoses if available.35,36 For orally administered overdoses, emesis may be suggested if noted early after ingestion. Activated charcoal may also be effective. Management of Cytarabine (Cytosar) Overdoses High-dose regimens of cytarabine are associated with many severe toxicities not frequently seen with standard doses. Severe and sometimes fatal CNS, gastrointestinal, cardiac, and pulmonary toxicity may occur. Toxicity studies in dogs have shown that toxicity is influenced by the schedule of administration. Total doses given to beagle dogs of 1920 mg/m2 every 6 hours for 12 doses was lethal (causing bone marrow hypoplasia, liver, and kidney damage), but the same dose (1920 mg/m2) every 6 hours for 8 doses produced only minimal toxicity (elevated transaminases). In general, the dose-limiting side effects in dogs are bone marrow suppression with leukopenia and reversible cerebellar dysfunction (manufacturer’s toxicologic data). Maximum Intravenous Dosages* Cats 300 mg/m2 or CRI: 100 mg/m2 6- to 8-hour infusions. 400 mg/m2 or CRI: 100 mg/m2 6- to 8-hour infusions. *Dose reductions should be made in the case of severe hepatic or renal dysfunction or if severe myelosuppression is present.

Toxicities Associated with Cytarabine Overdoses
1. Hematologic
Bone marrow suppression is frequently seen at standard doses of cytarabine and would be expected to be severe following overdoses. Myelosuppression is manifested by reticulocytopenia, leukopenia, thrombocytopenia, anemia, and megaloblastosis. Generally there is a biphasic drop in white blood cell count regardless of the dose or schedule. This may begin within 24 hours, followed by another nadir after 2 weeks. Gastrointestinal Whereas nausea and vomiting are encountered at standard doses, severe ulceration, bowel necrosis, and necrotizing colitis have been reported in humans following high doses. Diarrhea, ileus, abdominal pain, hematemesis, melena, hypokalemia, hypocalcemia, protein-losing enteropathy, and intestinal infections have also been reported. Hepatic Liver damage with increased hyperbilirubinemia, elevated transaminases, and alkaline phosphatases has been reported in humans. Liver abscesses and veno-occlusive disease have also been reported. Nervous System High doses of cytarabine are associated with sometimes very severe neurotoxicity, including cerebral and cerebellar dysfunction (ataxia, dysarthria, nystagmus, tremor). This is typically reversible. Peripheral motor and sensory neuropathies may also occur. The drug is a direct neurotoxin and reduced renal clearance may further increase neurotoxicity. Pulmonary/Cardiac Pericarditis with tamponade, cardiomyopathy, pulmonary edema, and sudden respiratory distress has been reported following high doses in humans. Ophthalmic Hemorrhagic conjunctivitis and keratitis may occur with very large doses. The drug is excreted into tears and may block corneal DNA synthesis. Hyperuricemia Extensive purine catabolism may occur at high doses and result in hyperuricemia. Serum uric acid concentrations should be monitored. Rapid cell kill with large tumor burden may also result in tumor lysis syndrome. Treatment of Cytarabine Overdoses Hematologic Neupogen (G-CSF) should be started prophylactically in the case of a severe overdose (approximately 24 hours after chemotherapy, until counts return to normal). Blood transfusions may also be required. Antibacterials should also be started prophylactically. Gastrointestinal Selective serotonergic receptor inhibitors in combination with a metoclopramide CRI may be effective. For nausea and vomiting refractory to these, a combination of both, with or without a corticosteroid, should be considered. Both acute and chronic treatment may be required. Proton pump inhibitors may be useful in the prevention of severe ulceration. Prophylactic antibiotics should also be prescribed. Hepatic/Nervous System There is no known effective treatment for hepatic and nervous system side effects. Since the parent drug and its active metabolite (ara-CTP) are primarily cleared via renal elimination, intravenous hydration and diuresis may assist in the elimination of drug from the plasma. The efficacy of hepatoprotective agents such as milk thistle and SAM-E has not been evaluated. Frequent neurologic examinations should be performed. Concurrent use of renal toxic drugs (aminoglycosides) should be avoided to prevent drug accumulation. Pulmonary/Cardiac Supportive care, for non-cardiac pulmonary edema (pressors and positive-pressure ventilation) may be required. Corticosteroids may be useful for chronic or hypersensitivity pneumonitis (should not be used if gastrointestinal ulceration is present). Ophthalmic This may be prevented by prophylaxis with ophthalmic corticosteroids. Steroid eye drops with dexamethasone or prednisolone should be given for at least 72 hours to prevent conjunctivitis. Hyperuricemia Hydration and alkalinization of urine may minimize or prevent hyperuricemia. Hemodialysis does not remove cytarabine from plasma.35 Management of Dacarbazine (DTIC) Overdoses Manufacturer toxicology studies in dogs, rats, and mice suggest that the primary toxicities seen in all species at the maximum tolerated dose were bone marrow
suppression, lymphoid, and gastrointestinal toxicity. No published dacarbazine overdoses
were noted in the veterinary literature. Multiple reports suggest that its use in
combination with other cytotoxic agents significantly increases the toxicity of
dacarbazine. No antidote exists for most of the side effects associated with dacarbazine.
The severity of hematologic and hepatic effects noted even at standard doses in humans
suggests that overdoses may result in extreme morbidity and mortality. Although there is
no confirmed treatment of dacarbazine overdoses, any process that increases drug
elimination may be of benefit. In vitro studies suggest that it may be effective.35
Approximately 46% to 52% of the parent drug is eliminated in the urine as well as 9% to
18% of its active metabolite (5-aminoimidazole-4-carboxamide (AIC).37 Early hydration
and forced diuresis to expedite renal clearance may be beneficial.

Maximum Intravenous Dosages*
1000 mg/m2 as a 4-hour infusion or 200 mg/m2 given once daily for 5 days. Not used *Dose reduction should be considered in animals with limited hepatic function and renal function.

Toxicities Associated with Dacarbazine Overdoses
Acute nausea, vomiting, loss of appetite, and anorexia occur in most patients treated with dacarbazine and would be expected to be severe with overdoses. Vomiting is believed to be due to a centrally mediated mechanism. At high doses, stomatitis and diarrhea may also occur. Hematologic Both leukopenia and thrombocytopenia are frequently seen at standard doses and would be expected in dogs at high doses. Hepatic Hepatic toxicity is rare but may be severe with standard doses of dacarbazine and is seen more frequently at high doses or with combination therapy. Severe hepatotoxicity, including hepatic vein thrombosis and fatal hepatocellular necrosis, has been reported. Flu-Like Syndrome Fever, malaise, and myalgia are reported in humans after large single doses of dacarbazine and may occur in dogs following high doses. Miscellaneous Effects Flushing, rashes, renal failure (elevated BUN, renal impairment), anaphylactic reactions, paresthesia, blurred vision, seizures, and photosensitivity have also been

Treatment of Dacarbazine Overdoses
Patients may have severe and protracted vomiting and diarrhea. Hydration, gut rest, and TPN or PPN may be required. Selective serotonergic receptor inhibitors with a metoclopramide CRI and potentially a corticosteroid may be required to inhibit the severe nausea and vomiting expected acutely. Metoclopramide may be effective for delayed emesis. Both acute and chronic treatment may be required. To prevent ulceration, a proton pump inhibitor such as oral omeprazole may be advised; if oral agents cannot be administered, intravenous Prevacid or Nexium may be beneficial. Hematologic Assess blood counts frequently. Neupogen (G-CSF) should be started prophylactically in the case of a severe overdose (approximately 24 hr after chemotherapy, until counts return to normal). Blood transfusions may also be required. Anti-infectives should be started prophylactically. Hepatic Liver function may be significantly altered and should be assessed frequently. Other hepatotoxic agents should be avoided. Few drugs are effective for treating frank liver disease in people or animals. Ursodeoxycholic acid (Ursodiol) has been given to humans as a hepatoprotective agent where it decreases hydrophobic bile acids that act to damage hepatocytes. Dog doses are approximately 10 to 15 mg/kg every 24 hours or divided and given every 12 hours. However, ursodeoxycholic acid may be less effective in dogs, since their primary circulating bile acid is taurocholate. Oral cholestyramine was recently reported to reduce taurine plasma concentrations in dogs and may have potential for binding taurocholate.38 Flu-Like Syndrome The exact mechanism of flu-like syndrome is unknown and there is no suggested supportive care noted. It does appear to be dose related and may be seen more frequently with overdoses. Miscellaneous Effects Local application of hot packs may help pain and burning at the injection site. CSF concentrations are approximately 14% of the plasma concentration, so seizures may occur at very high doses and should be treated appropriately. Phenobarbital has been demonstrated in human medicine to enhance metabolism of dacarbazine significantly, but its acute effects are unknown. Drug Removal The efficacy of hemodialysis for dacarbazine overdoses in vivo is unknown. However, in vitro studies suggest that hemodialysis may be effective.35 Management of Dactinomycin (Actinomycin-D) Overdoses Reports of actinomycin-D overdoses are uncommon in the literature. A number of reports are available in the human literature. Errors have primarily involved mistakes in
verbal orders being misinterpreted, such as a verbal order called in by an oncologist for
actinomycin-D 4 mg over 4 days that was incorrectly filled as actinomycin-D 4 mg daily
for 4 days. The patient died 6 days after completing the course of actinomycin-D.
Manifestations of overdoses in humans have typically included nausea, vomiting,
diarrhea, mucositis, stomatitis, gastrointestinal ulceration, skin disorders (including
exanthema), desquamation, epidermolysis, severe bone marrow suppression, veno-
occlusive disease, and hepatic failure. Choonara et al.39 described a case of a 17-year-old
boy who received a total dose of 3.3 mg/m2 (0.1 mg/kg) who had severe and prolonged
electrolyte abnormalities, generalized seizures, and skin rashes. Brogan et al.40 further
described an 18-month-old boy who received a massive overdose of actinomycin-D that
developed severe, acute toxicity affecting many organ systems and had multiple
prolonged complications. A ten-fold overdose (0.15 mg/kg/day) was given for the first 3
days of the induction phase of chemotherapy. By day 5 after initiation of therapy, the
patient presented with respiratory distress, oliguria, severe mucositis, hepatic
insufficiency, pancreatitis, hyponatremia, hypocalcemia, melena, and pancytopenia. On
day 6 the patient was febrile and irritable and had extensive alveolar-interstitial
infiltrates. He subsequently developed pneumomediastinum with subcutaneous
emphysema, coagulopathies, anuria, hypotension, a lesion of the cerebral cortex,
choreoathetosis, and dysarthria. He was discharged 50 days following the overdose with
minimal neurologic dysfunction.

Maximum Intravenous Dosage*
Not used *Dosage adjustments (reductions) may be required in geriatric patients who are more sensitive to this drug or when using in combination with other cytotoxic drugs. Doses should be based on body surface area in obese or edematous patients. Toxicities Associated with Dactinomycin Overdoses Hematologic Hematologic toxicity is dose dependent following actinomycin D. Anemia, pancytopenia, reticulopenia, agranulocytosis, and aplastic anemia are commonly seen with high-dose therapy. A decrease in platelet counts may be observed first followed by a total myelosuppression. Leukocyte and nadirs may be delayed for 14 to 21 days, and may not return to normal for 3 to 4 weeks. Following severe overdoses in humans, pancytopenia is noted as early as 5 days following the overdose.40 Gastrointestinal Gastrointestinal side effects are considered dose dependent following actinomycin D. Nausea and vomiting are acute following large doses of actinomycin-D (1–2 hr). Later effects may be severe stomatitis, dysphagia, esophagitis, ulcers, and pharyngitis. Severe stomatitis may occur as early as 5 days after overdose.40 Liver Dysfunction Ascites, hepatotoxicity, hepatitis, hepatic failure resulting in death, veno-occlusive disease (mainly hepatic), intravascular clotting, and hepatomegaly have all been reported with actinomycin- D. Hepatotoxicity appears to be dose related. The risk of veno-occlusive disease is greater in children (<4 years old) and may be greater following overdoses in animals. Dermatologic Alopecia, skin eruptions, and flare-up of erythema occur commonly with the drug, but large doses may involve more serious skin disorders including exanthema, desquamation, and epidermolysis. Other Electrolyte abnormalities, malaise, lethargy, growth retardation, fever, myalgia, pneumonitis, and anaphylactoid reactions are reported in patients following actinomycin
D treatment. Overdoses appear to have a higher risk of hypocalcemia, hyponatremia,
pancreatitis, respiratory distress, renal failure, hypotension, and neurologic dysfunction.
Neurologic impairment may be severe and has included hyperintense regions of the
cerebellar white matter and lesions of the cerebral cortex consistent with an infarct in the
area of the left middle cerebral artery. Dysarthria and choreoathetoid movements of all
extremities and weakness in one extremity have been reported.

Treatment of Dactinomycin Overdoses
Neupogen (G-CSF) should be started prophylactically (day 2–3) in the case of an overdose to prevent potentially severe neutropenia. Blood transfusions may also be required. Broad spectrum antibiotics should be started prophylactically. Blood cultures should be done if possible. Gastrointestinal Acute nausea, vomiting, and diarrhea are anticipated. Delayed gastrointestinal upset may be the result of hyperammonemia if renal failure occurs. Selective inhibitors of type 3 (5-HT-3) serotonergic receptors (granisetron, ondansetron, dolasetron) or a substituted benzamide (metoclopramide) may be effective. For nausea and vomiting refractory to these, a combination of both, with or without a corticosteroid (dexamethasone, methylprednisolone) should be considered. Liver Dysfunction Liver enzymes must be monitored carefully. Hepatic toxicity may be severe to fatal following an overdose. Hepatic veno-occlusive disease associated with intravascular clotting disorder may also occur and should be monitored closely. There is no antidote, and hepatoprotective agents such as milk thistle and SAM-E remain to be evaluated for efficacy. Avoidance of other hepatotoxic agents (cimetidine, antifungals, TMS, etc.) may be of some benefit. Dermatologic Dermatologic side effects following actinomycin-D overdoses may be severe. Patients should be evaluated closely and supportive care given if required. Other Supportive care is required with severe respiratory distress. Mechanical ventilation may be required. Continuous veno-venous hemofiltration has been useful in human patients with severe overdoses.40 Hypotension refractory to dopamine and epinephrine was successfully treated with norepinephrine and stress doses of hydrocortisone in at least one case.40 Renal failure may resolve within 3 to 4 weeks if the patient has good supportive care. Intravenous normal saline given at twice the maintenance rate and mannitol (0.25–0.5 g/kg IV q 4–6 hr) and/or furosemide (1–2 mg/kg IV q 6–12 hr) may help to maintain renal function and assist in drug elimination. Drug Removal Dialysis has not been proven to be effective. Many of the side effects of actinomycin- D are dose related and may benefit by improved clearance of drug. Approximately 30% of the drug is excreted in the urine and feces in 9 days in humans. The drug is excreted primarily as unchanged drug in urine so that hydration and diuresis may be of some benefit in increasing renal clearance of drugs. Management of Doxorubicin (Adriamycin) Overdoses Overdoses from doxorubicin are reported in the human literature, and most cases have involved severe bone marrow depression and cardiac failure. Both acute and latent
reactions have been severe. Doxorubicin toxicity has also been reported more commonly
in geriatric patients, particularly with pre-existing cardiac disease. Its use in breeds that
have MDR-1 gene mutations may also be a predisposing factor for toxicity. Latent
cardiac failure has been significantly decreased with prophylactic use of dexrazoxane, but
its efficacy remains to be evaluated in overdoses. There are few reports in the literature
describing overdoses of doxorubicin in veterinary medicine. We described at least one
case of doxorubicin toxicity in a 5-year-old, spayed English Springer Spaniel that
inadvertently received twice (60 mg/m2) its normal dose (30 mg/m2) of doxorubicin. The
animal developed hemorrhagic gastroenterocolitis, leukopenia, absolute neutropenia,
thrombocytopenia, anemia, and elevated liver enzymes. The animal recovered fully with
blood transfusions and supportive care that included fluids, antibiotics, iron, and
gastrointestinal protectants (cimetidine, misoprostol).

Maximum Intravenous Dosages*
Small (<15 kg): 1 mg/kg; large (>15 kg): 30 mg/m2 *Dose reductions should be considered in the case of existing neutropenia and renal failure. In patients with abnormal fluid retention, doses should be based on the ideal body weight.
Toxicities Associated with Doxorubicin Overdoses
Leukopenia (primarily granulocytopenia) is the primary dose-limiting side effect of standard doses. Deaths may occur from severe leukopenia at high doses from septicemia. Anemia and thrombocytopenia may also occur. Cardiac At least three types of cardiac toxicity occur following standard doxorubicin treatments: (1) transient (abnormal ECG findings, S-T wave changes, prolonged Q-T, and arrhythmias), (2) chronic: related to cumulative dose (progressive loss of cardiac myocytes, thinning of ventricular walls, decreased systolic performance), and (3) subacute: latent onset from prior exposure in juveniles. Cardiotoxicity has been related to peak drug concentrations in humans so that cardiotoxicity may be more prevalent with overdoses. Animals with an increased risk of cardiomyopathy such as Dobermans, boxers and other giant breeds or those with prior cardiac disease may be at much higher risk. Following standard doses to the maximum dose (240 mg/m2 over eight cycles), the incidence of cardiotoxicity is between 4% and 16%.41,42 However, it has also been noted following only two cycles of 30 mg/m2.43 Gastrointestinal Stomatitis and esophagitis (mucositis) would be expected to occur with high doses. Gastrointestinal toxicity (nausea, vomiting, anorexia, diarrhea), which is only moderate following standard doses, may be severe with overdoses. Following the two-fold overdose in the case described above, severe hemorrhagic gastroenterocolitis was noted. Ulceration and necrosis of the colon and cecum have occurred in humans and dogs that can lead to fatal infections. Dermatologic In humans, palmar-plantar erythrodysesthesia (swelling, pain, erythema, and desquamation of the hands and feet) has been reported with the liposomal product (Doxil) and appears dose related. It is also a dose-limiting toxicity of dogs treated with Doxil. Nervous System Peripheral neuropathy (sensory and/or motor) and seizures have been reported with high doses of doxorubicin in humans. Hyperuricemia Extensive purine catabolism may occur at high doses and result in hyperuricemia. Serum uric acid concentrations should be monitored. Nephrotoxicity Nephrotoxicity (azotemia, reduced specific gravity) has been noted with high cumulative doses (300 mg/m2) of doxorubicin in two of six cats and may be seen following high acute doses.44,45 Miscellaneous Hypersensitivity reactions (fever, chills, urticaria, anaphylaxis) may occur but are not dose related. Elevated liver enzymes were also noted following the two-fold overdose
noted previously.

Treatment of Doxorubicin Overdoses
Neupogen (G-CSF) should be started prophylactically in the case of a severe overdose (approximately 24 hours after chemotherapy, until counts return to normal). Blood transfusions may also be required. Antibiotics should also be started prophylactically. Cardiac Dexrazoxane (Zinecard) is typically given just prior to doxorubicin to reduce the risks of cardiotoxicity. Its efficacy in overdoses has not been proven. It is an effective cardioprotectant for cumulative cardiotoxicity and helps to neutralize doxorubicin extravasations. Suggested dosing for cardiotoxicity is a 10:1 ratio of dexrazoxane to doxorubicin (or 300 mg/m2 of dexrazoxane for a 30 mg/m2 dose of doxorubicin). Supportive care using digoxin, diuretics, and after-load reducers may also be beneficial. Gastrointestinal Selective serotonergic receptor inhibitors or metoclopramide CRI may be effective for nausea and vomiting. Typically doxorubicin gastrointestinal side effects are seen a few days after chemotherapy with standard doses. This is frequently treatable with both metoclopramide and sucralfate. However, following overdoses, severe nausea, vomiting, and gastroenteritis may occur. Intravenous proton pump inhibitors may be required for the prevention of severe ulceration. Prophylactic antibiotics should also be prescribed. Nervous System Since neurotoxicity is dose related, any reduction in doxorubicin plasma concentration will potentially reduce neurologic complications. Dermatologic The use of oral pyridoxine (vitamin B6) to prevent cutaneous reactions (palmer-plantar erythrodysesthesia [PPES]) from Doxil has been evaluated in dogs. Pyridoxine (50 mg/kg po TID) was reported to delay the onset and severity of PPES from Doxil, which permitted dogs to have fewer delays and discontinuations in treatment.46 Following overdoses of Doxil and possibly doxorubicin pyridoxine may have some benefit. Nephrotoxicity/Hyperuricemia Hydration and alkalinization of urine may minimize or prevent hyperuricemia and Hemodialysis does not effectively reduce plasma concentrations of doxorubicin.35 Hemoprofusion using a charcoal filter (1.5–4 hr) or Amberlite filter has been successful if initiated early (<18 hr) after the overdose. Amberlite hemoprofusion (2 x 4-hour) was also successful if performed early after overdoses in humans.47,48 Management of 5-Fluorouracil (5-FU) Overdoses There are few documented cases of 5-fluorouracil (5-FU) overdoses in the human literature. However, because of the frequent side effects of this agent even at standard doses, much is known about its toxicities. A single case report of a woman receiving an accidental intravenous overdose of 5-FU (infusion of 4000 mg/m2 over 4 hours vs. 4 days) was reported to be due to the incorrect programming of an infusion pump. The woman developed nausea, vomiting, and throat discomfort 2 days after infusion and then went on to develop mucositis, pancytopenia, hemodynamic collapse, and multi-organ failure. She died 22 days after the event.49 Severe and toxic reactions have also been attributed to deficiency of dipyrimidine dehydrogenase activity in some human patients, which prolongs the clearance of 5-FU. Typically more than 90% of the 5-FU dose is accounted for by either excretion in urine or expired CO2 within 24 hours in humans, so removal of drug (emesis, gastric lavage) following overdoses should be done rapidly if possible. Although little information exists in the veterinary literature on 5-FU overdoses with intravenous administration, there are multiple reports of oral ingestion of human-labeled commercial ointment and solutions used by the owners. Most ointments and solutions contain 2% to 5% 5-FU, which is 20 to 50 mg of 5-FU per gram or milliliter of product. The minimum toxic dose of 5-FU according to manufacturer data is 8.6 mg/kg and the lethal dose is 20 mg/kg. If a 55-lb dog were to ingest a 30-g tube of the 5% Ont., then 30 g × 50 mg 5-FU/1 g Ont. = 1500 mg 5-FU. Therefore 1500 mg/25 kg dog = 60 mg/kg. This is three times the lethal dose. Unfortunately, toxicity from ingestion of 5-FU is fairly common in dogs.50 One survey suggests that of 72 dogs ingesting 5-FU, 63% died or were euthanized because of poor treatment response. Various anecdotes to 5-FU have been studied experimentally, but their efficacy in clinical overdoses is still being investigated. New drugs that may prove effective against 5-FU overdoses include agents such as triacetyluridine (Wellstat Therapeutics Corp. Gaithersburg, MD). This is an oral pro-drug of uridine that is orally more bioavailable than uridine itself. Uridine itself is poorly absorbed orally and results in osmotic diarrhea at the doses required to achieve effective plasma concentrations as an antidote. When uridine is given intravenously in large doses, it may also result in hyperthermia and phlebitis. Triacetyluridine may be effective even up to 48 hours following an overdose.51 The enzyme inhibitor 5-(phenylthio) acyclouridine (PTAU), a uridine phosphorylase inhibitor also shows promise when used in combination with uridine in the rescue of mice treated with lethal overdoses of 5-FU.52 Although these agents may be very promising, their current availability is limited to investigational use only. LETHAL: Not given because of neurotoxicity
150 mg/m2 *Dose reductions should be considered in the case of existing renal or liver failure or with pre-existing bone marrow suppression. Doses should be based on the patient’s lean body weight if obese or if serious weight gain from edema, ascites, etc. is present. Toxicities Associated with 5-Fluorouracil Overdoses Hematologic Thrombocytopenia, leukopenia, agranulocytosis, pancytopenia, and hemolytic anemia may occur. Leukopenia and neutropenia may occur between 7 and 14 days, but the maximum depression may be delayed for up to 20 days. Myelosuppression is noted to be concentration and time dependent in humans with bolus administration resulting in the most severe myelosuppression. Cardiac Cardiac arrhythmias, myocardial ischemia, angina, and ischemic heart failure have all Nausea, vomiting, diarrhea, ulceration, stomatitis, mucositis, esophagopharyngitis, and anorexia can occur. Gastrointestinal toxicity is due to damage to rapidly dividing cells and is worse with continuous infusions. Diarrhea may be severe and life threatening. Animals surviving seizures may be at risk for gastrointestinal necrosis. Oral and esophageal ulcers can occur as well as severe hemorrhagic gastritis. Nervous System Lethargy, tremors, ataxia, nystagmus, and seizures may develop within a few hours of oral ingestion of 5-FU in animals. Severe seizures may result in death. Acute neurotoxicity presents as encephalopathy or cerebellar syndrome. Delayed neurotoxicity has been associated with multi-focal leukoencephalopathy. Extrapyramidal and cortical dysfunction may also occur but is typically reversible. Human patients with dihydropyridine dehydrogenase deficiencies are at higher risk of 5-FU neurologic and cardiac toxicities. To date, no such correlation has been reported in animals. Other Rashes, dry skin, fissures, anaphylaxis, thrombophlebitis, epistaxis, loss of nails, photosensitivity, pigmentation, palmer-plantar erythrodysesthesia syndrome, oculomotor disturbances, optic neuritis, and lacrimal duct stenosis have all been reported in humans. Treatment of 5-Fluorouracil Overdoses Hematologic Bone marrow suppression should be monitored every 3 to 4 days for at least 2 weeks. Blood transfusions, platelets, and anti-infective therapy should be initiated if suppression occurs. Neupogen should be initiated prophylactically prior to severe suppression. In severe overdoses, it may be started as soon as 5 to 6 days. Cardiac Myocardial toxicity has been associated with the active 5-FU monofluorinated, organic metabolites. Myocardial toxicity in humans has been treated with supportive care, including morphine, oral nitrates, and calcium channel blockers. Gastrointestinal Gastrointestinal protectants including proton acid pump inhibitors, metoclopramide, and sucralfate should be initiated prior to the occurrence of gastritis. Metoclopramide should be used with caution since it may also contribute to neurologic signs. Vomiting may occur within hours of ingestion and require intravenous CRI of metoclopramide and intravenous administration of pump inhibitors. Hypovolemic shock may result from blood and fluid loss from the gastrointestinal tract and should be closely monitored. Nervous System Both acute and chronic neurotoxicity of 5-FU has been associated with its monofluorinated organic metabolites: monofluoroacetic acid (FA) and alpha-fluoro-beta-alanine (FBAL). Seizures following oral ingestion of 5-FU in animals may occur within hours of ingestion and have been difficult to control. Benzodiazepams may not control seizures alone. Seizures may require constant rate infusions with propofol, diazepam, and/or pentobarbital. Animals with severe seizures may have a worse prognosis. Acute encephalopathies following 5-FU in humans have been treated with thiamine infusions with various degrees of success.53 Delayed leukoencephalopathy may respond to steroids.54 Drug Removal Studies evaluating the pharmacokinetics of 5-FU in humans with chronic renal failure receiving dialysis suggest that the parent drug does not accumulate in renal failure. Although the parent drug does not accumulate, the active metabolites that are mainly excreted in urine do accumulate and are responsible for the majority of toxicities seen. The final 5-FU catabolite FBAL in humans has been shown to accumulate in renal failure and may be removed by hemodialysis (extraction ratio of 0.6–0.85 over the filter membrane).55 Therefore, hemodialysis may be useful in reducing the concentrations of active metabolites and reduce their associated toxicities after overdoses. Management of Lomustine (CCNU or CeeNU) Overdoses Lomustine is given as oral therapy and is only available in 10, 40, and 100 mg (CeeNu) capsules. Overdoses have frequently occurred in human medicine when they are
supplied with more than one treatment course at a time. Directions are frequently
misinterpreted as one capsule daily rather than one capsule on day 1 of each treatment
cycle. Overdoses in humans have resulted in multi-organ failure, including severe
pancytopenia and liver, brain, and lung toxicities.56 Because of the relatively high
incidence of overdoses with this very potent drug, it is generally recommended that no
more than one dose is prescribed and filled for each treatment cycle. Ideally, this drug
should be administered in the clinic with each dose adjusted based on the animal’s nadir
from the prior dose. If administered at home, clients should be clearly instructed on exact
dosing instructions and on the proper handling of cytotoxic drugs. If the animal vomits
within 30 minutes after dosing, it is unlikely to have absorbed the drug. If vomiting
occurs between 30 and 60 minutes, it is most likely due to the absorbed drug, and re-
dosing should not be considered since this may inadvertently overdose the animal.

Maximum Oral Dosages
10 mg/cat or 50 mg/m2 PO q 3 to 4 weeks *Dose reductions should be considered in patients with compromised bone marrow function or with renal insufficency.

Toxicities Associated with Lomustine Overdoses
Bone marrow suppression is cumulative with CCNU and may be both acute and delayed with overdoses (4–5 weeks). In dogs, the acute dose-limiting toxicity is neutropenia approximately 7 days after CCNU administration.57 Thrombocytopenia is less common but appears to be a cumulative toxicity in dogs. In rare cases, thrombocytopenia can also be progressive and irreversible.57,58 In humans, a case report on lomustine overdose (four-fold) resulted in grade 4 neutropenia and thrombocytopenia.59 Neutropenia is noted even after standard doses of lomustine in dogs and cats and appears dose related in cats.60,61 Nervous System CCNU is highly lipophilic and non-ionized at physiologic pH, so it readily crosses into the CNS where levels are reported to be approximately 50% of plasma levels (manufacturer’s label). High CNS concentrations of CCNU following overdoses may result in seizures. Generalized convulsions have been reported in humans at four-fold the standard dose of CCNU and would be expected in animals following overdoses.59 Disorientation, lethargy, ataxia, dysarthria, optic atrophy, and visual disturbances may also occur at high doses. Pulmonary Pulmonary toxicity is dose related and may be severe following CCNU overdoses. Toxicity is typically seen with large cumulative doses and may be delayed in nature but has been reported acutely with overdoses.59 Infiltrates and/or fibrosis have occurred in humans from 6 months to 17 years after treatment. Lung fibrosis has been progressive and fatal in humans. Gastrointestinal Nausea and vomiting occur early after oral dosing (3–6 hr) and appear to be lessened by fasting patients. Vomiting typically only lasts for 24 hours in humans. If the patients vomit 30 to 45 min after dosing, do not repeat the dose. This may be more severe and protracted in animals receiving overdoses. Stomatitis may also occur. Renal Progressive azotemia and reduced kidney size and function may occur following large cumulative doses of CCNU but may occur acutely in animals with large overdoses. Hepatic A reversible hepatic toxicity is reported in humans following overdoses and is manifested by increased transaminases, alkaline phosphatase, and bilirubin. In dogs, a delayed, cumulative, dose-related, and irreversible hepatotoxicity is associated with CCNU even at standard doses.58,62,63 Liver enzymes should be monitored for weeks to months following overdoses.58,62 The median duration to detection of hepatic toxicity following CCNU is 11 weeks (range, 2–49 weeks).62 Treatment of Lomustine Overdoses Hematologic side effects are the primary dose-limiting side effect of lomustine and may be very severe following overdoses of the drug. Delayed thrombocytopenia and leukopenia are the primary concern. Hematologic Grade 4 neutropenia and thrombocytopenia have been reported even at standard doses of lomustine in companion animals, and the incidence is expected to be much higher with overdoses.60,61 Myelosuppression has typically been noted a week or so after inadvertent daily doses of lomustine in human patients. Careful monitoring following an overdose is required since many of the toxicities of lomustine may be somewhat delayed. Neupogen (G-CSF) and blood transfusions will most likely be required and should be initiated prior to severe bone marrow suppression. Antibiotics should also be started prophylactically (avoid the use of TMS, which may have combined hepatic toxicity with lomustine). Nervous System There is no antidote to lomustine-induced neurotoxicities. Because it is dose related and may be severe, any reduction in plasma lomustine concentrations may be of benefit. Although the initial half-life of lomustine is short (6 hr), the second phase may take days (5–6 days) and active metabolites may remain in the system much longer than that. Appropriate anticonvulsants may be required if seizures occur. Pulmonary Pulmonary fibrosis is not easily treated and the treatment course may be very prolonged. The use of corticosteroids may be of some benefit. Gastrointestinal Nausea and vomiting will be severe if the patient has had a single high dose of lomustine or a high cumulative dose (over days). In general, nausea and vomiting start early after dosing (45 minutes to 6 hr) and may last for days; at high doses this may continue for longer periods and be much more severe. Selective serotonergic receptor inhibitors in combination with a metoclopramide CRI may be effective. This has been combined further with corticosteroids for treatment of acute emesis. Hepatic Hepatic toxicity is common even at standard doses of lomustine and may be severe to fatal following an overdose. There is no antidote, and hepatoprotective agents such as SAM-E and milk thistle remain to be evaluated for efficacy. Avoidance of other hepatotoxic agents (cimetidine, antifungals, TMS, etc.) may be of some benefit. Although not proven clinically, the use of phenobarbital prior to CCNU was noted to prevent CCNU hepatotoxicity in laboratory rats.64 The mechanism was believed related to the altered metabolism of CCNU, shifting the metabolic profile to a less toxic species as well as reversing cholestasis and enhancing biliary excretion and washout of toxic metabolites. Other antioxidants (butylated hydroxyanisole, alpha-tocopherol) or iron chelators (deferoxamine) have been studied in vitro with some success.65 The use of bile acid sequestrants (cholestyramine, colestipol) that alter biliary bile acid secretion or products that increase bile flow similar to phenobarbital (theophylline) may reduce exposure to toxic metabolites as well as reduce the high serum bile acid concentrations noted in dogs with CCNU-induced hepatotoxicity.62,66 Drug Removal Following known oral overdoses of CCNU, emesis and gastric lavage may be performed if soon after ingestion. There is no information concerning dialysis of lomustine, but the majority of the drug is excreted via the kidneys (75%). Another alkylating agent (BCNU), which is structurally similar, is removed from plasma by dialysis; this suggests that lomustine may be at least partially removed by dialysis. The prolonged secondary half-life of lomustine is believed to be related to enterohepatic circulation of drug and protein binding. Gastrointestinal lavage with charcoal and potentially cholestyramine resin may also help to reduce plasma levels of drug over time. Management of Melphalan (Alkeran) Overdoses Overdoses caused by melphalan have been reported in the human literature. Patients receiving melphalan doses of more than 100 mg/m2 intravenously have developed severe mucositis, stomatitis, colitis, diarrhea, and GI bleeding. Bone marrow aplasia was noted but reversed within 3 weeks. Larger intravenous overdoses of melphalan (290 mg/m2) have resulted in severe nausea, vomiting, ulceration of the mouth, decreased consciousness, seizures, muscular paralysis, and cholinomimetic effects. Elevations in liver enzymes, hepatic veno-occlusive disease, adult respiratory distress syndrome, nephrotoxicity, and severe hyponatremia from SIADH have all been noted. Reports in
animals receiving high doses of melphalan suggest that bone marrow suppression and
gastrointestinal toxicities are the primary dose-limiting toxicities.

Maximum Oral Dosages*
0.1 mg/kg PO once daily. For cytoxan, substitute 20 mg/m2 * Doses should be reduced in patients with pre-existing renal failure. Studies indicate that the dose should be reduced in proportion to the degree of renal failure (i.e., 50%
reduction in dose with 50% reduction in renal function).

Toxicities Associated with Melphalan Overdoses
Hematologic toxicity is the primary dose-limiting toxicity of melphalan. Leukopenia and thrombocytopenia are the primary hematologic toxicities seen with high doses. Studies looking at dose escalation in dogs have shown that small dogs may have a disproportionately greater risk of severe myelosuppression when dosed on a milligram-per-square-meter (mg/m2) basis. Myelosuppression may be delayed (1–3 weeks), but leukopenia may occur much sooner (3–5 days) and last for several weeks.67 Anemia, hemolytic anemia, pancytopenia, and agranulocytosis may also occur. Cardiovascular Arterial or venous thrombosis and pulmonary emboli have been noted in humans. Hepatic veno-occlusive disease has also been reported. At least one human patient developed cardiac arrhythmias, which resulted in death following an overdose of 290 mg/m2 of melphalan.68 Gastrointestinal Nausea and vomiting may occur after high doses of melphalan. Diarrhea, stomatitis, and ulceration may also occur. Intravenous doses of more than 125 mg/m2 have resulted in severe gastrointestinal side effects in humans, including hemorrhagic diarrhea and bowel perforation.68 Hypersensitivity Reactions Rashes, dermatitis, anaphylaxis, edema, tachycardia, bronchospasm, and dyspnea have occurred in human patients receiving melphalan intravenously. Other Toxicities A syndrome of inadequate ADH secretion and electrolyte disturbances has been reported in the human literature following melphalan overdoses.68

Treatment of Melphalan Overdoses
Neupogen (G-CSF) should be started prophylactically in the case of a severe overdose. Leukopenia may be absolute even with G-CSF. Because of the early occurrence of leukopenia, G-CSF should be started at least 48 hours following the overdose. Blood transfusions may also be required. Antibiotics should also be started prophylactically. Hematologic parameters should be monitored for at least 3 weeks following the overdose. Patients should be monitored closely for signs or symptoms of cardiac arrhythmias and Selective serotonergic receptor inhibitors or metoclopramide may be effective. Typically gastrointestinal side effects are mild with standard doses. However, following overdoses frank ulceration may be more common. Proton pump inhibitors may be useful in the prevention of severe ulceration. Prophylactic antibiotics should also be prescribed. Hypersensitivity Reactions This is typically only after repeat doses of intravenous melphalan and should not be at any greater frequency following overdoses. Other Toxicities If SIADH is present, treatment should involve fluid restriction (urine output plus insensible loss) and the use of furosemide for diuresis. Hypertonic crystalloids may be given to increase sodium solutes. Hyponatremia can lead to seizures or coma and should be monitored frequently. Slowly increase the sodium concentration at a rate of 0.5 to 1.0 mmol/L/hr, so that central pontine myelinolysis is not induced. Drug Removal Hemodialysis and hemoprofusion do not alter the clearance of melphalan from plasma. If melphalan has been given orally and the overdose is recognized immediately, emesis may be induced. Administration of activated charcoal via gastric lavage may be useful. The drug is incompletely absorbed and is extremely variable in absorption. Melphalan is eliminated by chemical hydrolysis in plasma, and its metabolites may accumulate in renal failure. In humans, 50% of the dose is excreted into feces within 6 days, suggesting that continued presence of activated charcoal or cholestyramine could reduce the total amount of drug absorbed. Management of Methotrexate (MTX) Overdoses Most cases involving MTX overdoses in the literature are accidental human overdoses with either oral or intrathecal MTX. Many are related to accidental daily, instead of
weekly, administration of MTX.69 In general, MTX oral absorption and clearance rates
vary widely and toxicity is believed dependent on the duration of exposure to drug, rather
then high peak levels. MTX appears to be better tolerated in cats than in dogs.

Maximum Intravenous Dosages*
0.5 mg/kg IV or SQ *Doses should be reduced in patients with renal or hepatic failure as well as in geriatric patients or patients with a high degree of third spacing.

Toxicities Associated with MTX Overdoses
Leukopenia, thrombocytopenia, anemia, hemorrhage, aplastic anemia, granulocytopenia, hypergammaglobulinemia, and pancytopenia have all been reported in humans and animals and would be expected from high-dose therapy or overdoses. Bone marrow suppression may occur rapidly (2–7 days) after large doses. Gastrointestinal Glossitis, pharyngitis, stomatitis, enteritis, ulcerations, bleeding of the mucous membranes, anorexia, nausea, vomiting, hematemesis, diarrhea, melena, hemorrhagic enteritis, and intestinal perforation leading to death can occur. Gastrointestinal side effects are very common with high doses and overdoses in humans. Hepatic Both acute (elevated transaminases) and chronic (potentially fatal fibrosis and cirrhosis) hepatotoxicity can occur. Hepatotoxicity in humans is correlated to high cumulative or total doses of MTX. Hepatotoxicity from MTX is difficult to diagnosis, since fibrosis and cirrhosis may develop without alterations in liver function tests. Biopsies may be required for assessment of the degree of toxicity here. Neurologic Acute chemical arachnoiditis and subacute and chronic leukoencephalopathy may occur and can result in fatalities. Ataxia, dementia, elevated CSF pressure, seizures, and coma have been reported in pediatric patients at high doses and adult humans following overdoses. Although MTX does not cross the blood–brain barrier significantly, high doses of drug in the presence of inflammation after radiation or with large tumor burdens may increase penetration into the blood–brain barrier. Intrathecal administration of large doses of MTX in cats and in people appears to produce “multifocal axonopathy” without necrotizing lesions. Axonal degeneration and fibrin exudation in the walls of vessels occur, suggesting that a toxic effect on blood vessels is another mechanism of MTX-induced neurotoxicity.70 In cases of large overdoses, seizures are frequently seen.71 Respiratory Pulmonary toxicity is rare and does not appear to be dose related. Symptoms may be vague or extreme. Typically human patients present with a dry cough, fever, dyspnea, hypoxemia, and pulmonary infiltrates on x-rays. Fibrosis and acute or chronic interstitial pneumonitis may occur at any time. Pulmonary toxicity may not be reversible and can be fatal. Cardiovascular Pericarditis, pericardial effusions, hypotension, and thrombotic complications may Severe nephrotoxicity occurs in humans and animals and further predisposes them to other toxicities. Azotemia, hematuria, renal failure, and necrosis of the epithelium of the renal tubules may all occur. Fatalities resulting from renal failure have been reported in humans. Other Rashes, exfoliative dermatitis, skin necrosis, elevated serum uric acid, tumor lysis syndrome, visual changes, conjunctivitis, and stress fractures have been rarely reported in humans. Treatment of MTX Overdoses In cases in which the overdose is identified early, leucovorin is indicated to prevent toxicity. Leucovorin calcium is a potent folic acid antagonist commonly used as an antidote to MTX toxicity. Leucovorin is most effective if administered within 4 hours of MTX administration. Beyond 6 to 12 hours, the efficacy decreases substantially with time. A minimum of 72 hours of leucovorin rescue are suggested. Ideally the dose of leucovorin should be determined by obtaining serum MTX levels. Toxicities (mucositis, bone marrow suppression) are correlated with MTX concentrations (>1 uM) (1 × 10-6 M) for more than 48 hours. Leucovorin rescue should continue until MTX serum concentrations are <0.1 to 0.01 uM. Alternatively, the dose of leucovorin should be equal to or greater than that of MTX.72 Hydration and urinary alkalization may also be needed to prevent precipitation of the drug or metabolites in the renal tubules. Intermittent high-flux polysulfone dialyzer systems are effective at reducing MTX serum concentrations but may not be readily available. Other agents may also be of benefit, including oral cholestyramine, which actively binds the parent MTX compound in the gastrointestinal system and prevents further enterohepatic recirculation of MTX and its active metabolites that get converted back to MTX.73-75 In humans, carboxypeptidase G2 (CPDG2, glucarpidase)—a recombinant form of the bacterial enzyme CPG2, cloned from Pseudomonas strain RS-16—has recently become available for compassionate human use (developed by CTEP and Protherics Inc, Brentwood, TN). The enzyme rapidly hydrolyzes the glutamine residue from circulating MTX and inactivates it. The inactive metabolite DAMPA is then excreted non-renally. Clinical studies in humans suggest that in patients with MTX-induced renal failure, MTX concentrations are reduced by 98% within 15 minutes.76-79 Studies suggest that carboxypeptidase G2 can be administered up to 96 hours after MTX infusion and can be given with leucovorin.76 Current human recommendations are to administer CPDG2 to patients with sustained MTX concentrations greater than 10 uM at 42 to 48 hours after the MTX infusion.76 Hematologic Bone marrow suppression may occur rapidly and should be monitored for closely. In cats, neutropenia is witnessed even at standard doses. Leukopenia, thrombocytopenia, anemia, and pancytopenia have been seen with human MTX overdoses. The use of leucovorin and other agents to improve MTX clearance (cholestyramine, CPDG2) will help to prevent bone marrow suppression. Blood counts should be assessed frequently. Neupogen (G-CSF) should be started prophylactically in the case of a severe overdose (approximately 24 hours after chemotherapy, until counts return to normal).80 Blood transfusions may also be required. Anti-infectives should be started prophylactically. Gastrointestinal Gastrointestinal side effects caused by MTX are dose related and caused by direct mucosal injury. Selective serotonergic receptor inhibitors or metoclopramide may be effective. Typically gastrointestinal side effects are seen a few days after chemotherapy with standard doses. This is frequently treatable with both metoclopramide and sucralfate. However, following overdoses, frank ulceration may be more common. Proton pump inhibitors may be useful in the prevention of severe ulceration and hemorrhagic enteritis. Prophylactic antibiotics should also be prescribed to prevent bacterial invasion. Diets enriched with glutamine, short-chain fatty acids, and transforming growth factors (TGF)–β have demonstrated decreased weight loss, acidosis, and hypoalbuminemia in rats treated with MTX.81 Hepatic/Cardiovascular There are no treatments for either hepatic or cardiac side effects of MTX. Liver function tests may not always be indicative of developing liver disease, and liver biopsies would be contraindicated after overdoses. Hepatitis and cardiac side effects are related to delayed elimination of MTX, so all interventions to increase MTX elimination are beneficial here. Avoid all other hepatotoxic drugs. Neurologic High-dose leucovorin should be administered within the first hour after MTX if possible. Corticosteroids may help to minimize CNS inflammation. If available, CPDG2, an enzyme that rapidly hydrolyzes MTX, may also be used and can be administered up to 96 hours after MTX administration. Following an overdose of MTX administered intrathecally to a child, CSF drainage, ventricular-lumbar perfusion, intravenous dexamethasone and leucovorin, CPDG2, hydration, and alkalinization successfully rescued the patient. Seizures following overdoses may not be controlled with benzodiazepines. Phenobarbital-induced coma may be required in some overdose circumstances.82 Intravenous thymidine continuous infusions have also been recommended in humans until plasma MTX concentrations are less than 0.5 μm.31 Respiratory Treatment of MTX-induced pulmonary toxicity is primarily supportive in nature and may require mechanical ventilation if severe. Corticosteroids may provide some benefit. Renal Nephrotoxicity is primarily due to precipitation of MTX and 7-hydroxymethotrexate in the renal tubules. Early leucovorin administration, hydration, and urine alkalization with D5W, and sodium bicarbonate (pH >7.0) are recommended. Measurements of serum MTX and creatinine concentrations are essential to avoid further MTX-induced toxicities. Other Administration of large volumes of fluids and alkalinization of the urine may be of benefit if serum uric acid levels are high. Drugs that decrease the renal excretion of MTX (cisplatin, salicylates, sulfas, probenecid, and penicillins) should be avoided. Drug Removal Hemodialysis does not effectively alter MTX elimination. Alternatively, acute intermittent hemodialysis with a high-flux polysulfone dialyzer (F-80-B Fresenius dialyzer) has been shown to be effective at increasing MTX clearance in acute renal failure resulting from MTX.83 MTX is primarily metabolized in the liver. However, intracellular metabolism and bacterial degradation in the gastrointestinal tract also play a role. Metabolism results in MTX polyglutamates that can then undergo hydrolysis back to MTX. Metabolites remain in tissues for extended periods and prolong cytotoxicity. Following intravenous doses, MTX is primarily excreted via the kidneys, and MTX clearance is directly associated with creatinine clearance in humans. Following oral dosing, a large amount is excreted via feces. Enterohepatic recirculation is believed to occur for both the MTX parent compound and its metabolites. The use of adsorbents (cholestyramine, activated charcoal) to bind MTX and metabolites from being reabsorbed may therefore be very useful. MTX is an anionic drug, and anion-exchange resins accelerate the excretion of drug. Following high-dose MTX in an 11-year-old girl, serum MTX concentrations 24 hours after MTX infusion with cholestyramine were about 50% of the concentrations measured after the first course of MTX given without cholestyramine. Cholestyramine appears to bind MTX and its active metabolites better than activated charcoal. The binding capacity of MTX to cholestyramine exceeds that of activated charcoal by a factor of 5.4.75 Management of Mitoxantrone (Novantrone) Overdoses Mitoxantrone overdoses are frequently reported in the human literature. Most overdoses have been due to misinterpretation of the shorthand use of “MTX” for
methotrexate, which inadvertently gets filled for mitoxantrone. Because doses of MTX
are often very large in human medicine compared with mitoxantrone, this typically
results in a significant overdose. As a result, the side effects of mitoxantrone overdoses
are fairly well understood in people. No veterinary overdoses were found in the literature
at this time. Animal toxicology studies report that mitoxantrone has a spectrum of activity
and toxicity similar to other anthracyclines but is much less toxic. In beagles, safety
assessment studies using mitoxantrone (2.58 or 5.15 mg/m2 q 3 weeks × 30 weeks)
resulted in gastrointestinal toxicity and marrow suppression, but much less cardiotoxicity
than doxorubicin.84 Myocardial changes as measured by sequential endocardial biopsies
were also shown to be unrelated to dose or time at the maximum tolerated dose of 0.25
mg/kg or 5.15 mg/m2.85 In mouse studies, animals were noted to have severe bone
marrow suppression starting on day 4 after an LD50 dose of 6.6 mg/kg/day for 21 days.
Myocardial changes (mitochondria swelling, vacuoles) also appeared starting on day 4.
At extremely high doses (5–10 mg/kg), dogs were noted to have a rapid drop in blood
pressure and slowing of heart rate.86 Cardiotoxicity and bone marrow suppression have
been the two primary established side effects following toxic doses of mitoxantrone.

Maximum Intravenous Dosages*
5.5 mg/m2 *Doses should be reduced in patients with severe hepatic disease.
Toxicities Associated with Mitoxantrone Overdoses
Immediate onset of nausea and vomiting would be expected in an overdose. Stomatitis, mucositis, and diarrhea may also occur. Cardiovascular Cardiovascular side effects are more rare with mitoxantrone then doxorubicin, but it remains the dose-limiting side effect in humans. Transient arrhythmias, congestive heart failure, and cardiomyopathy may occur. A rapid drop in blood pressure and slowing of the heart rate may also occur. Following mitoxantrone overdose (100 mg/m2) in a 9-year-old girl, echocardiograms demonstrated a reversible decrease of the shortening fraction of the left ventricle.87 In three patients overdosed with mitoxantrone (2 × 100 mg/m2) and another receiving 183 mg/m2, acute cardiotoxicity was not evident.88 Severe bone marrow suppression should be expected after an overdose and has been witnessed in human case reports of overdoses and in animal toxicity studies. The primary toxicity has been a profound but reversible neutropenia and thrombocytopenia in all human overdose case reports. Hepatic Elevated liver enzymes have been reported in humans at standard doses and may be more frequent in overdoses. Frequent assessment should be made. Avoid using other hepatotoxic drugs (TMS). Miscellaneous Renal failure, urinary tract infections, blue-green urine/skin, and toxic leukemias have also been reported.89 Hypersensitivity reactions have been reported but are rare and not
concentration dependent.

Treatment of Mitoxantrone Overdoses
Selective inhibitors of serotonergic receptors or metoclopramide may be effective. For nausea and vomiting refractory to these, a combination of both, with or without a corticosteroid, should be considered. Both acute and chronic treatment may be required. To prevent severe gastroenteritis, a proton pump inhibitor should be initiated. Cardiovascular Dexrazoxane (Zinecard) has recently been studied in the prevention of mitoxantrone- induced cardiotoxicity in humans and appears to be very effective.90 It is an effective cardioprotectant for cumulative cardiotoxicity of mitoxantrone in patients with multiple sclerosis. Its efficacy in overdoses has not been proved. Suggested dosing for cardiotoxicity is a 10:1 ratio of intravenous dexrazoxane to anthracycline (or 300 mg/m2 of dexrazoxane for a 30-mg/m2 dose of anthracycline) just prior to chemotherapy. Supportive care using digoxin, diuretics, and after-load reducers may also be of benefit. Hematologic



Journal of the Korean Magnetic Resonance Society 2006 , 10, 126 - 140 Quantification of Metabolic Alterations of Dorsolateral Pre-Frontal Cortex in Depression SD Rat by MR Spectroscopy Sung-Tak Hong1, Bo-Young Choe1*, Chi-Bong Choi1, 1Department of Biomedical Engineering, College of Medicine, The Catholic University of Korea, 505 Banpo-Dong, Seocho-Gu, Seoul 137-040, Korea 2MRI


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