BUSULFAN AND RELATED AGENTS

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) Busulfan
2) Bussulfam
3) Busulphan
4) CB-2041
5) GT-41
6) Myelosan
7) NSC-750
8) WR-19508
9) Molecular Formula: C6-H14-O6-S2
10) CAS 55-98-1

1) Dihydroxybusulphan
2) CB 2562
3) NSC-39069
4) L-Threitol 1,4-dimethanesulphonate
5) Treosulphan
6) Treosulfan
7) Tresulfan
8) Molecular Formula: C6-H14-O8-S2
9) CAS 299-75-2

1.2.1) MOLECULAR FORMULA
1) C6-H14-06-S2

Available Forms Sources

1) Busulfan is available as 2 mg tablets and 60 mg in 10 mL vials (6 mg/mL) for intravenous injection (Prod Info BUSULFEX(R) intravenous injection, 2015; Prod Info MYLERAN(R) oral film coated tablets, 2011).

1) Busulfan tablet is indicated as part of a conditioning regimen in combination with cyclophosphamide prior to allogenic hematopoietic progenitor cell transplantation in patients with chronic myelogenous leukemia. Busulfan injection in combination with cyclophosphamide is effective in conditioning regimens prior to bone marrow transplantation for various hematologic malignancies and non-malignant diseases (Prod Info BUSULFEX(R) intravenous injection, 2015; Prod Info MYLERAN(R) oral film coated tablets, 2011).
2) Treosulfan is used palliatively or as an adjunct to surgery primarily for the treatment of ovarian cancer (S Sweetman , 2000).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Busulfan is indicated as part of a conditioning regimen in combination with cyclophosphamide prior to allogenic hematopoietic progenitor cell transplantation in patients with chronic myelogenous leukemia.
B) PHARMACOLOGY: Busulfan is a bifunctional alkylating agent whose chemical structure consists of two labile methanesulfonate groups that are attached to opposite ends of a four carbon alkyl chain. Its cytotoxicity is related to the alkylation of DNA due to the production of reactive carbonium ions caused by the release of the methanesulfonate groups when busulfan is hydrolyzed in an aqueous medium.
C) EPIDEMIOLOGY: Exposure may occur; however, overdose is rare.
D) WITH THERAPEUTIC USE

1) COMMON: Commonly reported adverse reactions, with an incidence of greater than 60%, include myelosuppression (ie, granulocytopenia, thrombocytopenia, anemia), nausea, vomiting, stomatitis, anorexia, diarrhea, abdominal pain, hypomagnesemia, hypokalemia, hyperglycemia, insomnia, fever, anxiety, and headache. Seizures, coma, and veno-occlusive liver disease have been associated, in children and adults, with high-dose therapeutic administration of busulfan.
2) INFREQUENT: Adverse effects, reported less frequently, include tachycardia, hypertension, thrombosis, vasodilation, chest pain, dyspepsia, constipation, dry mouth, hypocalcemia, hyperbilirubinemia, edema, elevated liver enzymes, increased serum creatinine concentration, back pain, asthenia, dizziness, depression, rhinitis, cough, dyspnea, epistaxis, rash, pruritus, injection site reactions, and allergic reactions.
3) RARE: Rare adverse effects, following long-term busulfan administration, include the development of cataracts, pulmonary fibrosis, cardiac toxicity (cardiac tamponade, myocardial fibrosis), cholestasis, hemorrhagic cystitis, and the development of an Addison-like syndrome. Aplastic anemia has been rarely reported with high oral doses of busulfan as well as with chronic oral busulfan therapy at standard therapeutic doses.

E) WITH POISONING/EXPOSURE

1) Busulfan overdose information is limited. Overdose effects are anticipated to be an extension of adverse effects at therapeutic doses. Alopecia nausea, vomiting, stomatitis, anorexia, and pancytopenia were reported in a 4-year-old child following a single dose ingestion of 140 mg. A total oral busulfan dose of 23.3 mg/kg was inadvertently administered to a 2-year-old child who survived without sequelae; however, an acute busulfan dose of 2.4 grams was fatal in a 10-year-old child.

0.2.21)

A) The National Toxicology Program and International Agency for Research on Cancer have classified busulfan as a known carcinogen based on sufficient evidence in humans and limited evidence in experimental animals.
B) Busulfan has been classified as a known carcinogen based on sufficient evidence of carcinogenicity in humans and limited evidence in experimental animals.
C) Leukemia has been associated with the therapeutic use of busulfan.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Treatment is symptomatic and supportive. Treat persistent nausea and vomiting with several antiemetics of different classes. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary.

B) MANAGEMENT OF SEVERE TOXICITY

1) Treatment is symptomatic and supportive. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia, or hemorrhage. Severe nausea and vomiting may respond to a combination of agents from different drug classes. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. For severe hypertension, nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.

C) DECONTAMINATION

1) PREHOSPITAL: Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression or persistent seizures and subsequent aspiration.
2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.

D) AIRWAY MANAGEMENT

1) Ensure adequate ventilation and perform endotracheal intubation early in patients with significant CNS depression, respiratory distress, severe allergic reactions, or severe bleeding.

E) ANTIDOTE

1) There is no specific antidote available.

F) MYELOSUPPRESSION

1) Administer colony stimulating factors following a significant overdose as these patients are at risk for severe neutropenia. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours OR 250 mcg/m(2)/day SubQ once daily. Monitor CBC with differential and platelet count daily for evidence of bone marrow suppression until recovery has occurred. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage. Patients with severe neutropenia should be in protective isolation. Transfer to a bone marrow transplant center should be considered.

G) NEUTROPENIA

1) Prophylactic therapy with a fluoroquinolone should be considered in high risk patients with expected prolonged (more than 7 days), and profound neutropenia (ANC 100 cells/mm(3) or less).

H) FEBRILE NEUTROPENIA

1) If fever (38.3 C) develops during the neutropenic phase (ANC 500 cells/mm(3) or less), cultures should be obtained and empiric antibiotics started. HIGH RISK PATIENT (anticipated neutropenia of 7 days or more; unstable; significant comorbidities): IV monotherapy with either piperacillin-tazobactam; a carbapenem (meropenem or imipenem-cilastatin); or an antipseudomonal beta-lactam agent (eg, ceftazidime or cefepime). LOW RISK PATIENT (anticipated neutropenia of less than 7 days; clinically stable; no comorbidities): oral ciprofloxacin and amoxicillin/clavulanate.

I) NAUSEA AND VOMITING

1) Treat severe nausea and vomiting with agents from several different classes. Agents to consider: dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol, olanzapine).

J) STOMATITIS

K) ENHANCED ELIMINATION PROCEDURE

1) Hemodialysis or hemoperfusion may be useful after overdose.

L) PATIENT DISPOSITION

1) HOME CRITERIA: There is no data to support home management. All exposures should be evaluated in a health care facility.
2) OBSERVATION CRITERIA: All patients should be sent to a healthcare facility for observation. If patients are asymptomatic for 6 hours, they may be sent home. Since toxic effects may be delayed, patients should return to a healthcare provider for any symptoms.
3) ADMISSION CRITERIA: Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), and daily monitoring of CBC with differential until bone marrow suppression is resolved.
4) CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with overdose.
5) TRANSFER CRITERIA: Patients with large overdoses may benefit from early transfer to a cancer treatment or bone marrow transplant center.

M) PITFALLS

1) Symptoms of overdose are similar to reported side effects of the medication. Early symptoms of overdose may be delayed or not evident (ie, particularly myelosuppression), so reliable follow-up is imperative. Patients taking busulfan may have severe co-morbidities and may be receiving other drugs that may produce synergistic effects (ie, myelosuppression).

N) PHARMACOKINETICS

1) Busulfan is approximately 32% protein bound, primarily to albumin. Predominantly metabolized by spontaneous conjugation with glutathione and by glutathione S-transferase catalysis. The glutathione conjugate then undergoes further extensive oxidative metabolism within the liver. Approximately 1% to 2% of busulfan is excreted unchanged in the urine. The plasma elimination half-life of busulfan is approximately 2 to 3 hours.

O) DIFFERENTIAL DIAGNOSIS

1) Includes other agents that may cause myelosuppression.

0.4.6)

A) INTRATHECAL OVERDOSE

1) There are no reports of inadvertent intrathecal injection with busulfan. The following recommendations are based on experience with antineoplastic agents. After an overdose, keep the patient upright and immediately drain at least 20 mL of CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free saline). Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 to 150 mL/hr for 24 hours). Dexamethasone 4 mg IV every 6 hours to prevent arachnoiditis.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Heent

3.4.3)

A) WITH THERAPEUTIC USE

1) CATARACTS: Bilateral cataracts developed in several patients following long- term therapeutic administration of busulfan (Ravindranathan et al, 1972; Akman et al, 1986; Soysal et al, 1993).

3.4.5)

A) WITH THERAPEUTIC USE

1) EPISTAXIS: During a clinical trial, epistaxis was reported in 25% of 61 patients receiving IV busulfan in combination with cyclophosphamide prior to allogeneic hematopoietic cell transplantation (Prod Info BUSULFEX(R) intravenous injection, 2015).

Cardiovascular

3.5.2)

A) TACHYCARDIA

1) WITH THERAPEUTIC USE

a) During a clinical trial, tachycardia was reported in 44% of 61 patients receiving IV busulfan in combination with cyclophosphamide prior to allogeneic hematopoietic cell transplantation (Prod Info BUSULFEX(R) intravenous injection, 2015).

B) HYPERTENSIVE DISORDER

1) WITH THERAPEUTIC USE

a) During a clinical trial, hypertension was reported in 36% of 61 patients receiving IV busulfan in combination with cyclophosphamide prior to allogeneic hematopoietic cell transplantation (Prod Info BUSULFEX(R) intravenous injection, 2015).

C) FIBROSIS

1) WITH THERAPEUTIC USE

a) Pericardial fibrosis and endocardial fibrosis of the left ventricle were reported in 2 patients following prolonged busulfan therapy to treat chronic myeloid leukemia. The fibrosis resolved in one patient following resection of the pericardium. The other patient subsequently developed acute respiratory failure and died. An autopsy revealed fibrosis of the endocardium with abundant collagen fibers (Weinberger et al, 1975; Terpstra & de Maat, 1989).
b) CASE REPORT: A 79-year-old woman, with chronic myelogenous leukemia, developed endocardial fibrosis after receiving a total busulfan dose of 7200 mg over a 9-year period. In addition to the presence of endocardial fibrosis of the left ventricle at autopsy, interstitial pulmonary fibrosis was also detected (Prod Info MYLERAN(R) oral film coated tablets, 2011).

D) CARDIAC TAMPONADE

1) WITH THERAPEUTIC USE

a) Cardiac tamponade was reported in 8 pediatric patients who received high doses of oral busulfan and cyclophosphamide as combination therapy for preparation of bone marrow transplantation, and was fatal in 6 of the 8 patients (Prod Info BUSULFEX(R) intravenous injection, 2015; Prod Info MYLERAN(R) oral film coated tablets, 2011).

E) VASODILATATION

1) WITH THERAPEUTIC USE

a) During a clinical trial, vasodilation was reported in 25% of 61 patients receiving IV busulfan in combination with cyclophosphamide prior to allogeneic hematopoietic cell transplantation (Prod Info BUSULFEX(R) intravenous injection, 2015).

F) CHEST PAIN

1) WITH THERAPEUTIC USE

a) During a clinical trial, chest pain was reported in 26% of 61 patients receiving IV busulfan in combination with cyclophosphamide prior to allogeneic hematopoietic cell transplantation (Prod Info BUSULFEX(R) intravenous injection, 2015).

G) EDEMA

1) WITH THERAPEUTIC USE

a) During a clinical trial, edema was reported in 28% to 36% of 61 patients receiving IV busulfan in combination with cyclophosphamide prior to allogeneic hematopoietic cell transplantation (Prod Info BUSULFEX(R) intravenous injection, 2015).

Respiratory

3.6.2)

A) FIBROSIS OF LUNG

1) WITH THERAPEUTIC USE

a) CHRONIC THERAPY: Interstitial pulmonary fibrosis, characterized by dyspnea, anorexia, cough, and fever, has been reported in children and adults as a result of long- term busulfan therapy. Average onset of symptoms is 4 years post-therapy (range 4 months to 10 years). Chest x-rays confirmed the diagnoses of fibrosis. Death occurred due to acute respiratory failure in many cases (Prod Info BUSULFEX(R) intravenous injection, 2015; Watanabe et al, 1990; Douay & Leduc, 1979) Woodliff & Finlay-Jones, 1972; (Podoll & Winkler, 1974) .
b) CASE REPORT/INFANT: A 16-month-old infant developed interstitial pulmonary fibrosis after receiving busulfan therapy, 65 mg/day orally for 11 months, to treat chronic myelogenous leukemia. The infant developed progressive dyspnea, fever, and a dry cough. Chest x-ray showed a bilateral diffuse interstitial pattern in the lungs. Despite intermittent administration of oxygen and discontinuation of busulfan therapy, death due to respiratory arrest occurred 4 days after hospital admission (Pearl, 1977).
c) CASE REPORT/ADULT: A 34-year-old woman received busulfan therapy, 2 to 6 mg daily for approximately 3 years, and subsequently developed progressive dyspnea and a productive cough. Chest x-ray showed diffuse reticulonodular infiltrates in the upper lung fields with atelectasis of the right middle lobe, and an open lung biopsy revealed pulmonary alveolar proteinosis. Despite supportive care, the patient died due to progressive respiratory failure (Aymard et al, 1984).
d) CASE REPORT: A 79-year-old woman, with chronic myelogenous leukemia, developed endocardial fibrosis after receiving a total busulfan dose of 7200 mg over a 9-year period. In addition to the presence of endocardial fibrosis of the left ventricle at autopsy, interstitial pulmonary fibrosis was also detected (Prod Info MYLERAN(R) oral film coated tablets, 2011).

B) DYSPNEA

1) WITH THERAPEUTIC USE

a) During a clinical trial, dyspnea was reported in 25% of 61 patients receiving IV busulfan in combination with cyclophosphamide prior to allogeneic hematopoietic cell transplantation (Prod Info BUSULFEX(R) intravenous injection, 2015).

C) RHINITIS

1) WITH THERAPEUTIC USE

a) During a clinical trial, rhinitis was reported in 44% of 61 patients receiving IV busulfan in combination with cyclophosphamide prior to allogeneic hematopoietic cell transplantation (Prod Info BUSULFEX(R) intravenous injection, 2015).

D) COUGH

1) WITH THERAPEUTIC USE

a) During a clinical trial, cough was reported in 28% of 61 patients receiving IV busulfan in combination with cyclophosphamide prior to allogeneic hematopoietic cell transplantation (Prod Info BUSULFEX(R) intravenous injection, 2015).

E) PNEUMONIA

1) WITH THERAPEUTIC USE

a) Life-threatening pneumonia was reported in 3% of patients, with death reported in one patient, who were treated with busulfan during a clinical trial (Prod Info BUSULFEX(R) intravenous injection, 2015).

F) PULMONARY HEMORRHAGE

1) WITH THERAPEUTIC USE

a) Fatal alveolar hemorrhage was reported in 3% of patients who received busulfan during a clinical trial (Prod Info BUSULFEX(R) intravenous injection, 2015).

Neurologic

3.7.2)

A) SEIZURE

1) SUMMARY: Generalized tonic-clonic seizures have been reported in adults and children following high-dose busulfan. In many instances, seizures occurred despite prophylaxis with phenytoin. Seizures resolved following supportive care (Prod Info BUSULFEX(R) intravenous injection, 2015; deMagalhaes-Silverman et al, 1996; Murphy et al, 1992) Vassal et al, 1992; (Marcus & Goldman, 1984) De La Camara et al, 1991).

a) Phenytoin serum levels, measured in the patients treated prophylactically, were often discovered to be low or subtherapeutic.

2) CASE REPORT: An 18-year-old man received high-dose oral busulfan, 1 mg/kg 4 times daily for 4 days (total dose of 16 mg/kg) as part of a preparatory regimen for bone marrow transplantation and experienced 2 consecutive episodes of generalized tonic-clonic seizures on the third day of therapy. The patient recovered without further recurrence of seizures following intravenous phenytoin administration (Sureda et al, 1989).
3) Vasta et al (1992) report 3 patients who experienced myoclonic jerking and generalized tonic-clonic seizures after receiving high-dose busulfan therapy for bone-marrow transplantation. Two of the 3 patients also experienced brief episodes of unconsciousness. Neurological deficits persisted in one patient approximately 2 years later (Vasta et al, 1992).
4) CASE REPORT: A 42-year-old woman received high-dose busulfan (60 mg every 6 hr) and, 24 hours later, developed myoclonic jerking that progressed into a generalized tonic-clonic seizure. The myoclonus gradually disappeared following treatment with phenytoin (Martell et al, 1987).

B) COMA

1) WITH THERAPEUTIC USE

a) Several patients experienced brief episodes of unconsciousness with seizures following high-dose busulfan administration in preparation for bone marrow transplantation (Vasta et al, 1992) De La Camara et al, 1991; (Marcus & Goldman, 1984).

C) INSOMNIA

1) WITH THERAPEUTIC USE

a) During a clinical trial, insomnia was reported in 84% of 61 patients receiving IV busulfan in combination with cyclophosphamide prior to allogeneic hematopoietic cell transplantation (Prod Info BUSULFEX(R) intravenous injection, 2015).

D) HEADACHE

1) WITH THERAPEUTIC USE

a) During a clinical trial, headache was reported in 69% of 61 patients receiving IV busulfan in combination with cyclophosphamide prior to allogeneic hematopoietic cell transplantation (Prod Info BUSULFEX(R) intravenous injection, 2015).

E) DIZZINESS

1) WITH THERAPEUTIC USE

a) During a clinical trial, dizziness was reported in 30% of 61 patients receiving IV busulfan in combination with cyclophosphamide prior to allogeneic hematopoietic cell transplantation (Prod Info BUSULFEX(R) intravenous injection, 2015).

F) ANXIETY

1) WITH THERAPEUTIC USE

a) During a clinical trial, anxiety was reported in 72% of 61 patients receiving IV busulfan in combination with cyclophosphamide prior to allogeneic hematopoietic cell transplantation (Prod Info BUSULFEX(R) intravenous injection, 2015).

G) ASTHENIA

1) WITH THERAPEUTIC USE

a) During a clinical trial, asthenia was reported in 51% of 61 patients receiving IV busulfan in combination with cyclophosphamide prior to allogeneic hematopoietic cell transplantation (Prod Info BUSULFEX(R) intravenous injection, 2015).

Gastrointestinal

3.8.2)

A) NAUSEA AND VOMITING

1) WITH THERAPEUTIC USE

a) During a clinical trial, nausea and vomiting were reported in 98% and 95%, respectively, of 61 patients receiving IV busulfan in combination with cyclophosphamide prior to allogeneic hematopoietic cell transplantation (Prod Info BUSULFEX(R) intravenous injection, 2015).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: A 4-year-old girl experienced nausea and vomiting for several hours after ingesting 140 mg of busulfan as a single dose. The patient recovered following supportive care (De Oliveira et al, 1963).

B) DIARRHEA

1) WITH THERAPEUTIC USE

a) During a clinical trial, diarrhea was reported in 84% of 61 patients receiving IV busulfan in combination with cyclophosphamide prior to allogeneic hematopoietic cell transplantation (Prod Info BUSULFEX(R) intravenous injection, 2015).

C) INFLAMMATORY DISEASE OF MUCOUS MEMBRANE

1) WITH THERAPEUTIC USE

a) During a clinical trial, stomatitis was reported in 97% of 61 patients receiving IV busulfan in combination with cyclophosphamide prior to allogeneic hematopoietic cell transplantation (Prod Info BUSULFEX(R) intravenous injection, 2015).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: Stomatitis was reported in a 4-year-old child approximately 1 month after ingesting a single dose of 140 mg of busulfan (De Oliveira et al, 1963).
b) CASE REPORT: Grade III mucositis and lower gastrointestinal tract bleeding developed in an infant who inadvertently received three doses of busulfan 4 mg/kg at 6 hour intervals, total dose 12 mg/kg (intended dose 4 mg/kg daily in divided doses for 4 days, total dose 16 mg/kg) (Stein et al, 2001).

D) ABDOMINAL PAIN

1) WITH THERAPEUTIC USE

a) During a clinical trial, abdominal pain was reported in 72% of 61 patients receiving IV busulfan in combination with cyclophosphamide prior to allogeneic hematopoietic cell transplantation (Prod Info BUSULFEX(R) intravenous injection, 2015).

E) LOSS OF APPETITE

1) WITH THERAPEUTIC USE

a) During a clinical trial, anorexia was reported in 85% of 61 patients receiving IV busulfan in combination with cyclophosphamide prior to allogeneic hematopoietic cell transplantation (Prod Info BUSULFEX(R) intravenous injection, 2015).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: Anorexia has been reported in a 4-year-old child following an overdose ingestion of 140 mg of busulfan (De Oliveira et al, 1963).

F) INDIGESTION

1) WITH THERAPEUTIC USE

a) During a clinical trial, dyspepsia was reported in 44% of 61 patients receiving IV busulfan in combination with cyclophosphamide prior to allogeneic hematopoietic cell transplantation (Prod Info BUSULFEX(R) intravenous injection, 2015).

G) CONSTIPATION

1) WITH THERAPEUTIC USE

a) During a clinical trial, constipation was reported in 38% of 61 patients receiving IV busulfan in combination with cyclophosphamide prior to allogeneic hematopoietic cell transplantation (Prod Info BUSULFEX(R) intravenous injection, 2015).

H) APTYALISM

1) WITH THERAPEUTIC USE

a) During a clinical trial, dry mouth was reported in 26% of 61 patients receiving IV busulfan in combination with cyclophosphamide prior to allogeneic hematopoietic cell transplantation (Prod Info BUSULFEX(R) intravenous injection, 2015).

I) CHOLECYSTITIS

1) WITH THERAPEUTIC USE

a) CASE SERIES: Five of 35 patients who received oral busulfan and intravenous cyclophosphamide as a preparatory regimen for bone marrow transplantation developed acute cholecystitis approximately 18 days after receiving the bone marrow infusion. Ultrasound and CT abdominal scan detected gallbladder abnormalities in all 5 patients, and 3 of the 5 patients underwent cholecystectomies without complications (Kuttah et al, 1995).

Hepatic

3.9.2)

A) VENO-OCCLUSIVE DISEASE OF THE LIVER

1) WITH THERAPEUTIC USE

a) Veno-occlusive disease of the liver (VOD) has been associated with therapeutic administration of high-dose busulfan (total dose greater than 16 mg/kg) in combination therapy with cyclophosphamide as a preparatory regimen for bone marrow transplantation (Prod Info MYLERAN(R) oral film coated tablets, 2011; Ozkaynak et al, 1991). In several instances, fatalities have occurred as a result of VOD (Kasai et al, 1992; Morgan et al, 1991).

1) VOD is characterized by the presence of hyperbilirubinemia, hepatomegaly or upper abdominal pain, and ascites or unexplained weight gain within 4 to 5 weeks of bone marrow transplantation.

b) INCIDENCE: During a clinical trial, hepatic veno-occlusive disease was reported in 5 of 61 patients (8%) who received busulfan, with fatalities occurring in 2 of the 5 patients (Prod Info BUSULFEX(R) intravenous injection, 2015).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: Mild venoocclusive disease of the liver (maximum bilirubin 2.1 mg/dl, maximum weight gain 4.4%) developed in an infant who inadvertently received three doses of busulfan 4 mg/kg at 6 hour intervals, total dose 12 mg/kg (intended dose 4 mg/kg daily in divided doses for 4 days total dose 16 mg/kg) (Stein et al, 2001).

B) LIVER ENZYMES ABNORMAL

1) WITH THERAPEUTIC USE

a) During a clinical trial, elevated ALT (SGPT) enzymes were reported in 31% of 61 patients receiving IV busulfan in combination with cyclophosphamide prior to allogeneic hematopoietic cell transplantation (Prod Info BUSULFEX(R) intravenous injection, 2015).

C) CHOLESTATIC HEPATITIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 61-year-old man developed fever, abdominal pain, and elevated liver enzyme levels after receiving busulfan continuously for 8 years for treatment of chronic myelocytic leukemia. Liver biopsy revealed cellular cholestasis and focal liver cell necrosis. Two weeks after discontinuation of busulfan the patient's liver enzyme levels returned to normal (Morris & Guthrie, 1988).
b) CASE SERIES: Four patients developed elevated serum alkaline phosphatase levels following prolonged busulfan therapy (total dose 1.0 to 2.4 grams). Liver biopsy of 1 of the 4 patients also showed signs of intrahepatic cholestasis (Hast, 1978). It is speculated that the increase in serum alkaline phosphatase levels may be associated with long-term busulfan administration.

Genitourinary

3.10.2)

A) SERUM CREATININE ABNORMAL

1) WITH THERAPEUTIC USE

a) During a clinical trial, an increased creatinine concentration was reported in 21% of 61 patients receiving IV busulfan in combination with cyclophosphamide prior to allogeneic hematopoietic cell transplantation (Prod Info BUSULFEX(R) intravenous injection, 2015).

B) HEMORRHAGIC CYSTITIS

1) WITH THERAPEUTIC USE

a) Hemorrhagic cystitis was reported in association with long-term busulfan therapy. Cystoscopies showed generalized cystitis with an edematous, bleeding mucosa and random biopsies revealed submucosal congestion and inflammation with telangiectatic capillaries. The cystitis resolved in the majority of patients following cessation of busulfan (Angelucci et al, 1993; (Pode et al, 1983; Millard, 1981; Morgan et al, 1991).
b) Hemorrhagic cystitis occurred in approximately 10% of patients (n=52) who received busulfan (16 mg/kg) and cyclophosphamide (60 mg/kg) as a preparatory regimen for bone marrow transplantation (deMagalhaes-Silverman et al, 1996).

Hematologic

3.13.2)

A) PANCYTOPENIA

1) WITH THERAPEUTIC USE

a) Pancytopenia, including anemia, granulocytopenia, and thrombocytopenia, is a very common adverse effect following therapeutic administration of busulfan. Although the bone marrow suppression may be reversible, with granulocyte count nadirs occurring between 10 and 30 days and recovery occurring within 5 months, there have been instances of irreversible or extremely prolonged bone marrow suppression (Prod Info BUSULFEX(R) intravenous injection, 2015; Prod Info MYLERAN(R) oral film coated tablets, 2011; Stuart et al, 1976) .
b) INCIDENCE: During a clinical trial, absolute neutrophil counts decreased to less than 0.5 x 10(9)/L in 100% of patients at a median of 4 days post-transplant, thrombocytopenia of less than 25,000/mm(3) or requiring transplantation, occurred in 98% of patients at a median of 5 to 6 days, and anemia, with a hemoglobin concentration of less than 8 g/dL, occurred in 69% of patients (Prod Info BUSULFEX(R) intravenous injection, 2015).
c) Leukopenia and thrombocytopenia have been reported in patients following ingestion of treosulfan, a derivative of busulfan (Meden et al, 1997; Prior & White, 1978).
d) Shepherd et al (1994) reported 4 patients who developed severe thrombocytopenia following the sequential use of busulfan and interferon-alpha for the treatment of chronic myeloid leukemia. Thrombocytopenia appeared to progress to severe marrow aplasia resulting in the fatalities of 2 of the 4 patients.

1) Due to the association of pancytopenia with busulfan and interferon therapy, it is speculated that the sequential use of busulfan and interferon may increase the risk of development of pancytopenia and may be an additive effect (Shepherd et al, 1994).

e) CASE REPORT: A 36-year-old man developed bone marrow hypoplasia 6 months after receiving busulfan for treatment of chronic myeloid leukemia. The patient recovered, with a bone marrow biopsy showing normocellular marrow approximately 3 months after receiving an infusion of fetal liver cells as an alternative to bone marrow transplantation (Sharma et al, 1998).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: A 4-year-old child ingested 140 mg of busulfan, as a single dose, and, within 4 weeks, developed pancytopenia with aplastic bone marrow. The patient recovered following supportive care (De Oliveira et al, 1963).

B) SIDEROBLASTIC ANEMIA

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 50-year-old woman became pancytopenic with hyperplastic bone marrow showing evidence of ringed sideroblasts 3 months after beginning busulfan therapy. The sideroblastic anemia gradually resolved after beginning treatment with danazol and pyridoxine and discontinuing busulfan therapy (Fernandez & Zayed, 1988).

C) APLASTIC ANEMIA

1) WITH THERAPEUTIC USE

a) Aplastic anemia has been rarely reported with high oral doses of busulfan as well as with chronic oral busulfan therapy at standard therapeutic doses (Prod Info MYLERAN(R) oral film coated tablets, 2011).

Dermatologic

3.14.2)

A) ERUPTION

1) WITH THERAPEUTIC USE

a) During a clinical trial, mild rash and pruritus were reported in 57% and 28%, respectively, of 61 patients receiving IV busulfan in combination with cyclophosphamide prior to allogeneic hematopoietic cell transplantation (Prod Info BUSULFEX(R) intravenous injection, 2015).
b) Leyden & Manoharan (1978) reported 2 patients who developed erythematous maculopapular pruritic rashes approximately 1 week after beginning busulfan and allopurinol therapy. The rashes subsided after discontinuation of both drugs and reappeared after the re-administration of busulfan (Leyden & Manoharan, 1978).

B) ALOPECIA

1) WITH THERAPEUTIC USE

a) Alopecia has been reported with busulfan therapy (Prod Info BUSULFEX(R) intravenous injection, 2015).
b) In a study conducted by Ljungman et al (1995) to determine the relation of busulfan concentration to the development of permanent alopecia in bone marrow transplant recipients, it was shown that the risk of developing permanent alopecia increased as the concentrations of busulfan increased (Ljungman et al, 1995).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: Alopecia occurred in a 4-year-old child approximately 1 month after an overdose ingestion of 140 mg of busulfan as a single dose (De Oliveira et al, 1963).

C) INJECTION SITE REACTION

1) WITH THERAPEUTIC USE

a) During a clinical trial, inflammation at the injection site was reported in 25% of 61 patients receiving IV busulfan in combination with cyclophosphamide prior to allogeneic hematopoietic cell transplantation (Prod Info BUSULFEX(R) intravenous injection, 2015).

D) HYPERPIGMENTATION OF SKIN

1) WITH THERAPEUTIC USE

a) Hyperpigmentation has been reported in 5% to 10% of patients on busulfan therapy. It appears to be more prevalent in patients with a dark complexion (Prod Info MYLERAN(R) oral film coated tablets, 2011).

Musculoskeletal

3.15.2)

A) BACKACHE

1) WITH THERAPEUTIC USE

a) During a clinical trial, back pain was reported in 23% of 61 patients receiving IV busulfan in combination with cyclophosphamide prior to allogeneic hematopoietic cell transplantation (Prod Info BUSULFEX(R) intravenous injection, 2015).

Endocrine

3.16.2)

A) ADRENAL CORTICAL HYPOFUNCTION

1) WITH THERAPEUTIC USE

a) An Addisonian-like syndrome, characterized by skin pigmentation, anorexia, nausea and vomiting, and severe fatigue, has been reported following prolonged or high-dose administration of busulfan and treosulfan. Symptoms may become reversible after withdrawal of the medication (Prod Info MYLERAN(R) oral film coated tablets, 2011; Prior & White, 1978).

B) HYPERGLYCEMIA

1) WITH THERAPEUTIC USE

a) During a clinical trial, hyperglycemia was reported in 66% of 61 patients receiving IV busulfan in combination with cyclophosphamide prior to allogeneic hematopoietic cell transplantation (Prod Info BUSULFEX(R) intravenous injection, 2015).

Immunologic

3.19.2)

A) ALLERGIC REACTION

1) WITH THERAPEUTIC USE

a) During a clinical trial, allergic reaction was reported in 26% of 61 patients receiving IV busulfan in combination with cyclophosphamide prior to allogeneic hematopoietic cell transplantation (Prod Info BUSULFEX(R) intravenous injection, 2015).

Reproductive

3.20.2)

A) BIRTH DEFECTS

1) Busulfan may cause fetal harm if administered to a pregnant woman (Prod Info BUSULFEX(R) intravenous injection, 2015; Prod Info MYLERAN(R) oral film coated tablets, 2011). There are a number of reports of normal infants born after busulfan exposure during pregnancy, however, fetal abnormalities and malformations have also been reported (Prod Info MYLERAN(R) oral film coated tablets, 2011; Boros & Reynolds, 1977; Diamond et al, 1960). Advise patients of reproductive potential to use adequate contraception during and after treatment (Prod Info BUSULFEX(R) intravenous injection, 2015) and to avoid becoming pregnant. If pregnancy occurs, apprise the patient of the potential for fetal harm (Prod Info BUSULFEX(R) intravenous injection, 2015; Prod Info MYLERAN(R) oral film coated tablets, 2011).
2) CASE REPORTS

a) Based on 40 cases involving busulfan use during pregnancy, 3 elective and 1 spontaneous abortions were reported. The remaining 36 pregnancies resulted in 37 offspring (1 set of twins). Four of 37 infants had abnormalities at birth. Busulfan was not the sole agent administered during pregnancy to two of the mothers who had abortions and to two of the mothers who had malformed infants (Bishop & Wassom, 1986).
b) In one compilation of cases, 3 malformed infants were born in 28 total exposed cases, making an apparent risk factor of 1:9 (Schardein, 1993).
c) Multiple birth defects and severe growth retardation have been reported in an infant born to a mother who had been treated with 6-mercaptopurine, irradiation, and busulfan (Diamond et al, 1960a; Schardein, 1993). The teratogenic effects were attributed by the authors to busulfan, since the woman had previously given birth to a normal child after treatment during pregnancy with only 6-mercaptopurine and irradiation (Diamond et al, 1960a). Others have concluded that the effects were due to both busulfan and 6-mercaptopurine (Schardein, 1993).
d) A case of cleft spinal cord resulting from failure of the neural tube to close (spina bifida or myeloschisis) was observed in a six-week-old aborted human embryo (Abramovici et al, 1978). The mother (39 years old) had been treated with busulfan before pregnancy and during the first three months of pregnancy.
e) Apparently normal children have been born to women treated with busulfan during pregnancy (Dugdale & Fort, 1967; Shalev et al, 1987). At least 24 normal infants have been born to mothers exposed to busulfan during the first three months of pregnancy (Schardein, 1985).

B) ANIMAL STUDIES

1) RATS, RABBITS: Administration of busulfan during organogenesis in rats and rabbits resulted in malformations and anomalies including alterations in body weight gain, size, and the musculoskeletal system. An absence of germinal cells in the testes and ovaries was reported resulting in sterility in both the male and female offspring. In rats, administration of the solvent (N,N-dimethylacetamide) at doses of 400 mg/kg/day (approximately 40% of the daily dose) during organogenesis resulted in significant development anomalies including anasarca, cleft palate, vertebral anomalies, rib anomalies, and heart vessel anomalies (Prod Info BUSULFEX(R) intravenous injection, 2015).

3.20.3)

A) PREGNANCY CATEGORY

1) The manufacturer has classified busulfan as FDA pregnancy category D (Prod Info MYLERAN(R) oral film coated tablets, 2011).

3.20.4)

A) BREAST MILK

1) It is not known if busulfan is excreted in human breast milk (Prod Info BUSULFEX(R) intravenous injection, 2015; Prod Info MYLERAN(R) oral film coated tablets, 2011), and the potential for adverse effects in the nursing infant from exposure to the drug is unknown. It is not known if busulfan affects the quantity or composition of breast milk. Even if the drug did not enter the breast milk, the increased energy and nutrient requirements for milk production could negatively impact the mother's recovery (Dillon et al, 1997). Because many drugs are excreted in human milk and due to the potential for tumorigenicity in the nursing infant, a decision should be made to either discontinue nursing(Prod Info BUSULFEX(R) intravenous injection, 2015; Prod Info MYLERAN(R) oral film coated tablets, 2011) or discontinue busulfan taking into account the importance of the drug to the mother (Prod Info MYLERAN(R) oral film coated tablets, 2011).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS55-98-1 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) IARC Classification

a) Listed as: 1,4-Butanediol dimethanesulfonate (Busulphan; Myleran)
b) Carcinogen Rating: 1

1) The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans. This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.

3.21.2)

3.21.3)

A) CARCINOMA

1) The National Toxicology Program and International Agency for Research on Cancer have classified busulfan as a known carcinogen based on sufficient evidence of carcinogenicity in humans and limited evidence of carcinogenicity in experimental animals (NTP, 1992) (IARC, 1987).

B) ENDOMETRIAL CARCINOMA

1) Two cases of endometrial cancer developed after a 2-year course of busulfan administration (Aksoy et al, 1984).

C) LEUKEMIA

1) Four of 243 patients included in a double-blind study developed acute leukemia after receiving busulfan therapy for 5 to 8 years. Those 4 patients were part of a subset of 19 patients who developed pancytopenia during busulfan therapy (Prod Info MYLERAN(R) oral film coated tablets, 2011; Stott et al, 1977).
2) In a series of patients treated for essential thrombocythemia (15 received busulfan and hydroxyurea, 77 received hydroxyurea only, and 20 received neither), treatment with busulfan was associated with the development of secondary malignancies. Malignancies reported in this group included acute myelogenous leukemia (2 cases), refractory anemia, refractory anemia with ringed sideroblasts, B-cell chronic lymphocytic leukemia, and lung carcinoma (2 cases) (Finazzi et al, 2000).

D) MELANOMA

1) Malignant melanoma of the glans penis has been reported in a patient who underwent 13 years of busulfan therapy for the treatment of chronic myeloid leukemia (Sparaventi et al, 1987).

3.21.4)

A) NEOPLASMS

1) Busulfan IV administered at 30% of the total dose on a mg/m(2) basis has been shown to increase the incidence of ovarian and thymic tumors in mice (Prod Info BUSULFEX(R) intravenous injection, 2015).

Genotoxicity

1) Increased rates of sister chromatid exchanges and chromosomal aberrations have been identified in peripheral lymphocytes of patients treated with busulfan for chronic myeloid leukemia (IARC, 1987; Bishop & Wassom, 1986). Some of these studies are confounded by multiple drug therapy and inconsistent dose-response relationships.
2) DNA inhibition has been reported in human HeLa cell cultures (RTECS , 1996).
3) Busulfan has also produced dose-related chromosomal aberrations in cultured human lymphocytes.

1) Busulfan is mutagenic in mice and, possibly, in humans (Prod Info MYLERAN(R) oral film coated tablets, 2011). Busulfan caused mutations in Drosophila melanogaster and Salmonella typhimurium (Prod Info BUSULFEX(R) intravenous injection, 2015)
2) Busulfan has induced DNA damage in rats, mouse leukocytes, and hamster pneumocytes, and has caused unscheduled DNA synthesis in mice injected intraperitoneally (RTECS , 1996). DNA inhibition has been reported in human HeLa cell cultures (RTECS , 1996).
3) Increased rates of sister chromatid exchanges have been induced in bone marrow cells, but not in spermatogonia, of Chinese hamsters injected intraperitoneally with busulfan (Neal & Probst, 1984). Excessive micronuclei have been identified in hamster ovarian cells and mouse cells following intraperitoneal busulfan administration (RTECS , 1996).
4) Chromosomal aberrations have been noted in several animal species treated in vivo with busulfan as well as a variety of cultured animal cells (Bishop & Wassom, 1986).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery. Granulocyte count nadirs may occur between 10 and 30 days with recovery occurring within 5 months. During clinical trials, absolute neutrophil counts decreased to less than 0.5 x 10(9)/L in 100% of patients at a median of 4 days post-transplant, and thrombocytopenia of less than 25,000/mm(3), or requiring platelet transfusion, occurred in 98% of patients at a median of 5 to 6 days.
B) Monitor vital signs and mental status.
C) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
D) Monitor serum electrolytes, renal function, and hepatic enzymes.
E) Monitor pulmonary function tests and obtain a chest x-ray in any patient with respiratory symptoms.
F) Plasma concentrations are not readily available or clinically useful in the management of overdose.

4.1.2)

A) HEMATOLOGIC

1) Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery. Granulocyte count nadirs may occur between 10 and 30 days with recovery occurring within 5 months (Stuart et al, 1976).
2) During clinical trials, absolute neutrophil counts decreased to less than 0.5 x 10(9)/L in 100% of patients at a median of 4 days post-transplant, and thrombocytopenia of less than 25,000/mm(3) or requiring platelet transfusion, occurred in 98% of patients at a median of 5 to 6 days (Prod Info BUSULFEX(R) intravenous injection, 2015).
3) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.

B) BLOOD/SERUM CHEMISTRY

1) Monitor renal and hepatic function as indicated in symptomatic patients.
2) Monitor electrolytes and fluid status as indicated in patients with significant gastrointestinal symptoms following exposure.
3) Plasma concentrations are not readily available or clinically useful in the management of overdose.

4.1.3)

A) URINE

1) Monitor urinalysis for evidence of hemorrhagic cystitis.

4.1.4)

A) OTHER

1) PULMONARY FUNCTION TESTS

a) Monitor pulmonary function tests and obtain a chest x-ray in any patient with respiratory symptoms.

2) MONITORING

a) Monitor vital signs and mental status.

Radiographic Studies

1) Obtain chest radiographs in symptomatic patients. Chronic busulfan therapy has been associated with interstitial pulmonary fibrosis (Prod Info BUSULFEX(R) intravenous injection, 2015).

Methods

1) Rifai et al (1997) and Heggie et al (1997) described a high-performance liquid chromatography method with ultraviolet detection for the determination of busulfan concentrations in human plasma. The limits of detection, for the two different studies, were 0.2 micromol/liter and 0.02 micrograms/milliliter, respectively (Rifai et al, 1997; Heggie et al, 1997).
2) A gas chromatographic-mass spectrometric method was described for the quantification of busulfan in human plasma. The limit of quantification, in this assay, was 20 nanograms/milliliter and the sensitivity of the assay was 10 nanograms/milliliter (Quernin et al, 1998).
3) A method for detecting busulfan in serum employing gas chromatography-mass spectrometry in negative ion-chemical ionization mode has been described (Fukumoto et al, 2001).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), and daily monitoring of CBC with differential until bone marrow suppression is resolved.

6.3.1.2) HOME CRITERIA/ORAL

A) There is no data to support home management. All exposures should be evaluated in a health care facility.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with overdose.

6.3.1.4) PATIENT TRANSFER/ORAL

A) Patients with large overdoses may benefit from early transfer to a cancer treatment or bone marrow transplant center.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) All patients should be sent to a healthcare facility for observation. If patients are asymptomatic for 6 hours, they may be sent home. Since toxic effects may be delayed, patients should return to a healthcare provider for any symptoms.

Monitoring

Oral Exposure

6.5.1)

A) Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression or persistent seizures and subsequent aspiration.

6.5.2)

A) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.3)

A) SUPPORT

1) MANAGEMENT OF MILD TO MODERATE TOXICITY

a) Treatment is symptomatic and supportive. Treat persistent nausea and vomiting with several antiemetics of different classes. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary.

2) MANAGEMENT OF SEVERE TOXICITY

a) Treatment is symptomatic and supportive. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia, or hemorrhage. Severe nausea and vomiting may respond to a combination of agents from different drug classes. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. For severe hypertension, nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.

B) MONITORING OF PATIENT

1) Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery. Granulocyte count nadirs may occur between 10 and 30 days with recovery occurring within 5 months (Stuart et al, 1976). During clinical trials, absolute neutrophil counts decreased to less than 0.5 x 10(9)/L in 100% of patients at a median of 4 days post-transplant, and thrombocytopenia of less than 25,000/mm(3), or requiring platelet transfusion, occurred in 98% of patients at a median of 5 to 6 days (Prod Info BUSULFEX(R) intravenous injection, 2015).
2) Monitor vital signs and mental status.
3) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
4) Monitor serum electrolytes, renal function, and hepatic enzymes.
5) Monitor pulmonary function tests and obtain a chest x-ray in any patient with respiratory symptoms.
6) Plasma concentrations are not readily available or clinically useful in the management of overdose.

C) MYELOSUPPRESSION

1) Severe myelosuppression should be expected after overdose.
2) Monitor CBC with differential daily. If fever or infection develops during leukopenic phase, cultures should be obtained and appropriate antibiotics started. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage.
3) Colony stimulating factors have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Stull et al, 2005; Hartman et al, 1997). They should be administered to any patient who receives a busulfan overdose.
4) Patients with severe neutropenia should be in protective isolation. Monitor CBC with differential daily. If fever or infection develops during leukopenic phase, cultures should be obtained and appropriate antibiotics started. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage.
5) ALTERNATIVE THERAPY: A single fetal liver infusion (total cells of 9.8 x 10(8) per kilogram body weight from a 20-week-old male fetus) was administered to a 36-year-old man as treatment for bone marrow hypoplasia due to busulfan therapy. A bone marrow biopsy three months later showed recovery with normocellular marrow (Sharma et al, 1998).

D) NEUTROPENIA

1) COLONY STIMULATING FACTORS

a) DOSING

1) FILGRASTIM: The recommended starting dose for adults is 5 mcg/kg/day administered as a single daily subQ injection, by short IV infusion (15 to 30 minutes), or continuous IV infusion (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2015). According to the American Society of Clinical Oncology (ASCO), treatment should be continued until the ANC is at least 2 to 3 x 10(9)/L (Smith et al, 2006).
2) SARGRAMOSTIM: The recommended dose is 250 mcg/m(2) day administered intravenously over a 4-hour period OR 250 mcg/m(2)/day SubQ once daily (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2013). Treatment should be continued until the ANC is at least 2 to 3 x 10(9)/L (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2013; Smith et al, 2006).

2) HIGH-DOSE THERAPY

a) Higher doses of filgrastim, such as those used for bone marrow transplant, may be indicated after overdose.
b) FILGRASTIM: In patients receiving bone marrow transplant (BMT), the recommended dose of filgrastim is 10 mcg/kg/day given as an IV infusion no longer than 24 hours. The daily dose of filgrastim should be titrated based on neutrophil response (ie, absolute neutrophil count (ANC)) as follows (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2015):

1) When ANC is greater than 1000/mm(3) for 3 consecutive days; reduce filgrastim to 5 mcg/kg/day.
2) If ANC remains greater than 1000/mm(3) for 3 more consecutive days; discontinue filgrastim.
3) If ANC decreases again to less than 1000/mm(3); resume filgrastim at 5 mcg/kg/day.

c) In BMT studies, patients received up to 138 mcg/kg/day without toxic effects. However, a flattening of the dose response curve occurred at daily doses of greater than 10 mcg/kg/day (Prod Info NEUPOGEN(R) subcutaneous injection, intravenous injection, 2015).
d) SARGRAMOSTIM: This agent has been indicated for the acceleration of myeloid recovery in patients after autologous or allogenic BMT. Usual dosing is 250 mcg/m(2)/day as a 2-hour IV infusion over a 2-hour period. Duration is based on neutrophil recovery (Prod Info LEUKINE(R) subcutaneous injection liquid, intravenous injection liquid, subcutaneous injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, 2013).

3) SPECIAL CONSIDERATIONS

a) In pediatric patients, the use of colony stimulating factors (CSFs) can reduce the risk of febrile neutropenia. However, this therapy should be limited to patients at high risk due to the potential of developing a secondary myeloid leukemia or myelodysplastic syndrome associated with the use of CSFs. Careful consideration is suggested in using CSFs in children with acute lymphocytic leukemia (ALL) (Smith et al, 2006).

4) ANTIBIOTIC PROPHYLAXIS

a) Treat high risk patients with fluoroquinolone prophylaxis, if the patient is expected to have prolonged (more than 7 days), profound neutropenia (ANC 100 cells/mm(3) or less). This has been shown to decrease the relative risk of all cause mortality by 48% and or infection-related mortality by 62% in these patients (most patients in these studies had hematologic malignancies or received hematopoietic stem cell transplant). Low risk patients usually do not routinely require antibacterial prophylaxis (Freifeld et al, 2011).

E) FEBRILE NEUTROPENIA

1) SUMMARY

a) Due to the risk of potentially severe neutropenia following overdose with busulfan, all patients should be monitored for the development of febrile neutropenia.

2) CLINICAL GUIDELINES FOR ANTIMICROBIAL THERAPY IN NEUTROPENIC PATIENTS WITH CANCER

a) SUMMARY: The following are guidelines presented by the Infectious Disease Society of America (IDSA) to manage patients with cancer that may develop chemotherapy-induced fever and neutropenia (Freifeld et al, 2011).
b) DEFINITION: Patients who present with fever and neutropenia should be treated immediately with empiric antibiotic therapy; antibiotic therapy should broadly treat both gram-positive and gram-negative pathogens (Freifeld et al, 2011).
c) CRITERIA: Fever (greater than or equal to 38.3 degrees C) AND neutropenia (an absolute neutrophil count (ANC) of less than or equal to 500 cells/mm(3)). Profound neutropenia has been described as an ANC of less than or equal to 100 cells/mm(3) (Freifeld et al, 2011).
d) ASSESSMENT: HIGH RISK PATIENT: Anticipated neutropenia of greater than 7 days, clinically unstable and significant comorbidities (ie, new onset of hypotension, pneumonia, abdominal pain, neurologic changes). LOW RISK PATIENT: Neutropenia anticipated to last less than 7 days, clinically stable with no comorbidities (Freifeld et al, 2011).
e) LABORATORY ANALYSIS: CBC with differential leukocyte count and platelet count, hepatic and renal function, electrolytes, 2 sets of blood cultures with a least a set from a central and/or peripheral indwelling catheter site, if present. Urinalysis and urine culture (if urinalysis positive, urinary symptoms or indwelling urinary catheter). Chest x-ray, if patient has respiratory symptoms (Freifeld et al, 2011).
f) EMPIRIC ANTIBIOTIC THERAPY: HIGH RISK patients should be admitted to the hospital for IV therapy. Any of the following can be used for empiric antibiotic monotherapy: piperacillin-tazobactam; a carbapenem (meropenem or imipenem-cilastatin); an antipseudomonal beta-lactam agent (eg, ceftazidime or cefepime). LOW RISK patients should be placed on an oral empiric antibiotic therapy (ie, ciprofloxacin plus amoxicillin-clavulanate), if able to tolerate oral therapy and observed for 4 to 24 hours. IV therapy may be indicated, if patient poorly tolerating an oral regimen (Freifeld et al, 2011).

1) ADJUST THERAPY: Adjust therapy based on culture results, clinical assessment (ie, hemodynamic instability or sepsis), catheter-related infections (ie, cellulitis, chills, rigors) and radiographic findings. Suggested therapies may include: vancomycin or linezolid for cellulitis or pneumonia; the addition of an aminoglycoside and switch to carbapenem for pneumonia or gram negative bacteremia; or metronidazole for abdominal symptoms or suspected C. difficile infection (Freifeld et al, 2011).
2) DURATION OF THERAPY: Dependent on the particular organism(s), resolution of neutropenia (until ANC is equal or greater than 500 cells/mm(3)), and clinical evaluation. Ongoing symptoms may require further cultures and diagnostic evaluation, and review of antibiotic therapies. Consider the use of empiric antifungal therapy, broader antimicrobial coverage, if patient hemodynamically unstable. If the patient is stable and responding to therapy, it may be appropriate to switch to outpatient therapy (Freifeld et al, 2011).

g) COMMON PATHOGENS frequently observed in neutropenic patients (Freifeld et al, 2011):

1) GRAM-POSITIVE PATHOGENS: Coagulase-negative staphylococci, S. aureus (including MRSA strains), Enterococcus species (including vancomycin-resistant strains), Viridans group streptococci, Streptococcus pneumoniae and Streptococcus pyrogenes.
2) GRAM NEGATIVE PATHOGENS: Escherichia coli, Klebsiella species, Enterobacter species, Pseudomonas aeruginosa, Citrobacter species, Acinetobacter species, and Stenotrophomonas maltophilia.

h) HEMATOPOIETIC GROWTH FACTORS (G-CSF or GM-CSF): Prophylactic use of these agents should be considered in patients with an anticipated risk of fever and neutropenia of 20% or greater. In general, colony stimulating factors are not recommended for the treatment of established fever and neutropenia (Freifeld et al, 2011).

F) VOMITING

1) TREATMENT OF BREAKTHROUGH NAUSEA AND VOMITING

a) Treat patients with high-dose dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol, olanzapine); diphenhydramine may be required to prevent dystonic reactions from dopamine antagonists, phenothiazines, and antipsychotics. It may be necessary to treat with multiple concomitant agents, from different drug classes, using alternating schedules or alternating routes. In general, rectal medications should be avoided in patients with neutropenia.
b) DOPAMINE RECEPTOR ANTAGONISTS: Metoclopramide: Adult: 10 to 40 mg orally or IV and then every 4 or 6 hours, as needed. Dose of 2 mg/kg IV every 2 to 4 hours for 2 to 5 doses may also be given. Monitor for dystonic reactions; add diphenhydramine 25 to 50 mg orally or IV every 4 to 6 hours as needed for dystonic reactions (None Listed, 1999). Children: 0.1 to 0.2 mg/kg IV every 6 hours; MAX 10 mg/dose (Dupuis & Nathan, 2003).
c) PHENOTHIAZINES: Prochlorperazine: Adult: 25 mg suppository as needed every 12 hours or 10 mg orally every 4 or 6 hours as needed. IV dose: 2.5 to 10 mg by slow IV injection or infusion not to exceed 5 mg per minute (MAX 40 mg/day); Children (2 yrs or older): 20 to 29 pounds: 2.5 mg orally 1 to 2 times daily (MAX 7.5 mg/day); 30 to 39 pounds: 2.5 mg orally 2 to 3 times daily (MAX 10 mg/day); 40 to 85 pounds: 2.5 mg orally 3 times daily or 5 mg orally twice daily (MAX 15 mg/day) OR 2 yrs or older and greater than 20 pounds: 0.06 mg/pound IM as a single dose (Prod Info COMPAZINE(R) oral tablets, 2013; Prod Info prochlorperazine edisylate intramuscular intravenous injection, 2011; Prod Info COMPAZINE(R) rectal suppositories, 2013). Promethazine: Adult: 12.5 to 25 mg orally or IV every 4 to 6 hours; Children (2 yr and older) 12.5 to 25 mg OR 0.5 mg/pound orally every 4 to 6 hours as needed. Monitor children closely for respiratory depression or apnea (Prod Info promethazine HCl oral tablets, 2013). Chlorpromazine: Children: Greater than 6 months of age, 0.55 mg/kg orally every 4 to 6 hours, or IV every 6 to 8 hours; max of 40 mg per dose if age is less than 5 years or weight is less than 22 kg (None Listed, 1999).
d) SEROTONIN 5-HT3 ANTAGONISTS: The following antiemetic dosing is based on high emetic risk. Dolasetron: Adult: 100 mg orally ONLY. Granisetron: Adult: 2 mg orally daily or 1 mg or 0.01 mg/kg (maximum 1 mg) IV. Ondansetron: Adult: 8 mg orally twice daily; 8 mg or 0.15 mg/kg IV. Palonosetron: Adult: 0.5 mg oral; 0.25 mg IV. Tropisetron: Adult: 5 mg oral; 5 mg IV. Ramosetron: 0.3 mg IV (Basch et al, 2011); Ondansetron: Children (older than 3 years of age): 0.15 mg/kg IV 4 and 8 hours after chemotherapy (None Listed, 1999).
e) BENZODIAZEPINES: Lorazepam: Adult: 1 to 2 mg orally or IM/IV every 6 hours; Children: 0.05 mg/kg, up to a maximum of 3 mg, orally or IV every 8 to 12 hours as needed (None Listed, 1999).
f) STEROIDS: Dexamethasone: Adult: 10 to 20 mg orally or IV every 4 to 6 hours; Children: 5 to 10 mg/m(2) orally or IV every 12 hours as needed; methylprednisolone: children: 0.5 to 1 mg/kg orally or IV every 12 hours as needed (None Listed, 1999).
g) ANTIPSYCHOTICS: Haloperidol: Adult: 1 to 4 mg orally or IM/IV every 6 hours as needed (None Listed, 1999).

G) SEIZURE

1) SUMMARY

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

2) DIAZEPAM

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

3) NO INTRAVENOUS ACCESS

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

4) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).

5) PHENOBARBITAL

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

6) OTHER AGENTS

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

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

H) STOMATITIS

1) Treat mild mucositis with bland oral rinses with 0.9% saline, sodium bicarbonate, and water. For moderate cases with pain, consider adding a topical anesthetic (eg, lidocaine, benzocaine, dyclonine, diphenhydramine, or doxepin). Treat moderate to severe mucositis with topical anesthetics and systemic analgesics (eg, morphine, hydrocodone, oxycodone, fentanyl). Patients with mucositis and moderate xerostomia may receive sialagogues (eg, sugarless candy/mints, pilocarpine/cevimeline, or bethanechol) and topical fluorides to stimulate salivary gland function. Patients who are receiving myelosuppressive therapy may receive prophylactic antiviral and antifungal agents to prevent infections. Topical oral antimicrobial mouthwashes, rinses, pastilles, or lozenges may be used to decrease the risk of infection (Bensinger et al, 2008).
2) Palifermin is indicated to reduce the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support. In these patients, palifermin is administered before and after chemotherapy. DOSES: 60 mcg/kg/day IV bolus injection for 3 consecutive days before and 3 consecutive days after myelotoxic therapy for a total of 6 doses (Prod Info Kepivance(R) intravenous injection, 2015). Palifermin should not be given within 24 hours before, during infusion, or within 24 hours after administration of myelotoxic chemotherapy, as this has been shown to increase the severity and duration of mucositis (Hensley et al, 2009; Prod Info KEPIVANCE(TM) IV injection, 2005). It has not been studied in the setting of chemotherapy overdose. In patients with busulfan overdose, consider administering palifermin 60 mcg/kg/day IV bolus injection starting 24 hours after the overdose for 3 consecutive days.
3) Total parenteral nutrition may provide nutritional requirements during the healing phase of drug-induced oral ulceration, mucositis, and esophagitis.

I) HYPERTENSIVE EPISODE

1) Monitor vital signs regularly. For mild/moderate hypertension without evidence of end organ damage, pharmacologic intervention is generally not necessary. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients, especially if a sympathomimetic agent is involved in the poisoning.
2) For hypertensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20% to 25% within one hour), sodium nitroprusside is preferred. Nitroglycerin and phentolamine are possible alternatives.
3) SODIUM NITROPRUSSIDE/INDICATIONS

a) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.

4) SODIUM NITROPRUSSIDE/DOSE

a) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).

5) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION

a) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

6) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS

a) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

7) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS

a) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

8) NITROGLYCERIN/INDICATIONS

a) May be used to control hypertension, and is particularly useful in patients with acute coronary syndromes or acute pulmonary edema (Rhoney & Peacock, 2009).

9) NITROGLYCERIN/ADULT DOSE

a) Begin infusion at 10 to 20 mcg/min and increase by 5 or 10 mcg/min every 5 to 10 minutes until the desired hemodynamic response is achieved (American Heart Association, 2005). Maximum rate 200 mcg/min (Rhoney & Peacock, 2009).

10) NITROGLYCERIN/PEDIATRIC DOSE

a) Usual Dose: 29 days or Older: 1 to 5 mcg/kg/min continuous IV infusion. Maximum 60 mcg/kg/min (Laitinen et al, 1997; Nam et al, 1989; Rasch & Lancaster, 1987; Ilbawi et al, 1985; Friedman & George, 1985).

11) PHENTOLAMINE/INDICATIONS

a) Useful for severe hypertension, particularly if caused by agents with alpha adrenergic agonist effects usually induced by catecholamine excess (Rhoney & Peacock, 2009).

12) PHENTOLAMINE/ADULT DOSE

a) BOLUS DOSE: 5 to 15 mg IV bolus repeated as needed (U.S. Departement of Health and Human Services, National Institutes of Health, and National Heart, Lung, and Blood Institute, 2004). Onset of action is 1 to 2 minutes with a duration of 10 to 30 minutes (Rhoney & Peacock, 2009).
b) CONTINUOUS INFUSION: 1 mg/hr, adjusted hourly to stabilize blood pressure. Prepared by adding 60 mg of phentolamine mesylate to 100 mL of 0.9% sodium chloride injection; continuous infusion ranging from 12 to 52 mg/hr over 4 days has been used in case reports (McMillian et al, 2011).

13) PHENTOLAMINE/PEDIATRIC DOSE

a) 0.05 to 0.1 mg/kg/dose (maximum of 5 mg per dose) intravenously every 5 minutes until hypertension is controlled, then every 2 to 4 hours as needed (Singh et al, 2012; Koch-Weser, 1974).

14) PHENTOLAMINE/ADVERSE EFFECTS

a) Adverse events can include orthostatic or prolonged hypotension, tachycardia, dysrhythmias, angina, flushing, headache, nasal congestion, nausea, vomiting, abdominal pain and diarrhea (Rhoney & Peacock, 2009; Prod Info Phentolamine Mesylate IM, IV injection Sandoz Standard, 2005).

15) CAUTION

a) Phentolamine should be used with caution in patients with coronary artery disease because it may induce angina or myocardial infarction (Rhoney & Peacock, 2009).

16) LABETALOL

a) INTRAVENOUS INDICATIONS

1) Consider if severe hypertension is unresponsive to short acting titratable agents such as sodium nitroprusside. Although labetalol has mixed alpha and beta adrenergic effects (Pearce & Wallin, 1994), it should be used cautiously if sympathomimetic agents are involved in the poisoning, as worsening hypertension may develop from alpha adrenergic effects.

b) ADULT DOSE

1) INTRAVENOUS BOLUS: Initial dose of 20 mg by slow IV injection over 2 minutes. Repeat with 40 to 80 mg at 10 minute intervals. Maximum total dose: 300 mg. Maximum effects on blood pressure usually occur within 5 minutes (Prod Info Trandate(R) IV injection, 2010).
2) INTRAVENOUS INFUSION: Administer infusion after initial bolus, until desired blood pressure is reached. Administer IV at 2 mg/min of diluted labetalol solution (1 mg/mL or 2 mg/3 mL concentrations); adjust as indicated and continue until adequate response is achieved; usual effective IV dose range is 50 to 200 mg total dose; maximum dose: 300 mg. Prepare 1 mg/mL concentration by adding 200 mg labetalol (40 mL) to 160 mL of a compatible solution and administered at a rate of 2 mL/min (2 mg/min); also can be mixed as an approximate 2 mg/3 mL concentration by adding 200 mg labetalol (40 mL) to 250 mL of solution and administered at a rate of 3 mL/min (2 mg/min) (Prod Info Trandate(R) IV injection, 2010). Use of an infusion pump is recommended (Prod Info Trandate(R) IV injection, 2010).

c) PEDIATRIC DOSE

1) INTRAVENOUS: LOADING DOSE: 0.2 to 1 mg/kg, may repeat every 5 to 10 minutes (Hari & Sinha, 2011; Flynn & Tullus, 2009; Temple & Nahata, 2000; Fivush et al, 1997; Fivush et al, 1997; Bunchman et al, 1992). Maximum dose: 40 mg/dose (Hari & Sinha, 2011; Flynn & Tullus, 2009). CONTINUOUS INFUSION: 0.25 to 3 mg/kg/hour IV (Hari & Sinha, 2011; Flynn & Tullus, 2009; Temple & Nahata, 2000; Fivush et al, 1997; Miller, 1994; Deal et al, 1992; Bunchman et al, 1992).

d) ADVERSE REACTIONS

1) Common adverse events include postural hypotension, dizziness; fatigue; nausea; vomiting, sweating, and flushing (Pearce & Wallin, 1994).

e) PRECAUTIONS

1) Contraindicated in patients with bronchial asthma, congestive heart failure, greater than first degree heart block, cardiogenic shock, or severe bradycardia or other conditions associated with prolonged or severe hypotension. In patients with pheochromocytoma, labetalol should be used with caution because it has produced a paradoxical hypertensive response in some patients with this tumor (Prod Info Trandate(R) IV injection, 2010).
2) Use caution in hepatic disease or intermittent claudication; effects of halothane may be enhanced by labetalol (Prod Info Trandate(R) IV injection, 2010). Labetalol should be stopped if there is laboratory evidence of liver injury or jaundice (Prod Info Trandate(R) IV injection, 2010).

f) MONITORING PARAMETER

1) Monitor blood pressure frequently during initial dosing and infusion (Prod Info Trandate(R) IV injection, 2010).

J) ACUTE ALLERGIC REACTION

1) SUMMARY

a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.

2) BRONCHOSPASM

a) ALBUTEROL

1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).

3) CORTICOSTEROIDS

a) Consider systemic corticosteroids in patients with significant bronchospasm.
b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).

4) MILD CASES

a) DIPHENHYDRAMINE

1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).

5) MODERATE CASES

a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).

6) SEVERE CASES

a) EPINEPHRINE

1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).

7) AIRWAY MANAGEMENT

a) OXYGEN: 5 to 10 liters/minute via high flow mask.
b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).

8) MONITORING

a) CARDIAC MONITOR: All complicated cases.
b) IV ACCESS: Routine in all complicated cases.

9) HYPOTENSION

a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.

1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).

10) H1 and H2 ANTIHISTAMINES

a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).

1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).

b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).

11) DYSRHYTHMIAS

a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.

12) OTHER THERAPIES

a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).

K) EXPERIMENTAL THERAPY

1) Animal studies suggest that pretreatment with phenytoin or phenobarbital decreases the mortality from neurotoxicity and myelosuppression after acute busulfan poisoning, probably through anticonvulsant effects and increased busulfan metabolism by cytochrome P-450 induction, respectively (Fitzsimmons et al, 1990). It is not known if treatment with phenobarbital or phenytoin would affect mortality in humans after acute overdose.
2) In a murine model of severe busulfan toxicity, pretreatment with high dose phenytoin (60 milligrams/kilogram/day) or phenobarbital (35 milligrams/kilogram/day) beginning 3 days before treatment with a myeloablative dose of busulfan (135 to 150 milligrams/kilogram divided over 6 days) and continued throughout the 6 days of busulfan treatment was associated with decreased mortality (22% survival in the control group, 85% survival in the high dose phenytoin group, 89% survival in the phenobarbital group). Lower doses of phenytoin (15 milligrams/kilogram/day) did not improve survival (Fitzsimmons et al, 1990).
3) In another study mice received an acutely neurotoxic dose of busulfan (100 milligrams/kilogram) and some received high dose pretreatment with 15 or 60 milligrams/kilogram phenytoin or 70 or 140 milligram/kilogram phenobarbital. None of the control mice survived, compared with 60% of phenytoin treated and 68% of phenobarbital treated mice (Fitzsimmons et al, 1990).

Enhanced Elimination

1) The small volume of distribution (0.6 to 0.7 liters/kilogram) and low degree of protein binding (32%) of busulfan (Prod Info BUSULFEX(R) intravenous injection, 2015; Hassan et al, 1994) suggest that hemodialysis or hemoperfusion might be useful if instituted soon after large overdose.
2) CASE REPORT: Stein et al (2001) report the use of hemodialysis in an infant who inadvertently received three doses of busulfan 4 mg/kg at 6 hour intervals, total dose 12 mg/kg instead of the intended dose of 4 mg/kg daily in divided doses for 4 days (total dose 16 mg/kg). Half-life was 1.64 hours and total clearance was 40.8 ml/min prior to dialysis; half-life decreased to 59 minutes and clearance increased to 60.8 ml/min during dialysis. The patient did not develop severe toxicity and recovered with supportive care (Stein et al, 2001).

Abstracts

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) SPECIFIC SUBSTANCE

1) BUSULFAN

a) ORAL ROUTE

1) REMISSION INDUCTION: 60 mcg/kg or 1.8 mg/m(2) ORALLY every day; usual dose is 4 to 8 mg (Prod Info MYLERAN(R) oral film coated tablets, 2011)
2) MAINTENANCE (if remission is less than 3 months): 1 to 3 mg ORALLY every day (Prod Info MYLERAN(R) oral film coated tablets, 2011)

b) IV ROUTE

1) 0.8 mg/kg of ideal body weight or actual body weight, whichever is lower, administered as a 2 hour IV infusion every 6 hours for 4 days (for a total of 16 doses) (Prod Info BUSULFEX(R) intravenous injection, 2015).

7.2.2)

A) SPECIFIC SUBSTANCE

1) BUSULFAN

a) ORAL ROUTE

1) REMISSION INDUCTION: 60 mcg/kg or 1.8 mg/m(2) ORALLY every day (Prod Info MYLERAN(R) oral film coated tablets, 2011)
2) MAINTENANCE (if remission is less than 3 months): 1 to 3 mg ORALLY every day (Prod Info MYLERAN(R) oral film coated tablets, 2011)

b) IV ROUTE

1) Based on the results of an open-label uncontrolled study involving 24 pediatric patients (ages ranging from 5 months to 16 years) receiving busulfan as part of a conditioning regimen prior to hematopoietic progenitor cell transplantation, the following dosing regimen was suggested:

a) 12 kg or less, 1.1 mg/kg IV every 6 hours as a 2-hour infusion for 4 days (16 total doses), adjust subsequent doses to achieve the desired target AUC (1125 micromol x min); followed by cyclophosphamide 50 mg/kg IV once daily for 4 days; infuse hematopoietic progenitor cells after 1 day of rest; premedicate with phenytoin (study dosing) (Prod Info BUSULFEX(R) intravenous injection, 2015)
b) Greater than 12 kg, 0.8 mg/kg IV every 6 hours as a 2-hour infusion for 4 days (16 total doses), adjust subsequent doses to achieve the desired target AUC (1125 micromol x min); followed by cyclophosphamide 50 mg/kg IV once daily for 4 days; infuse hematopoietic progenitor cells after 1 day of rest; premedicate with phenytoin (study dosing) (Prod Info BUSULFEX(R) intravenous injection, 2015)

Minimum Lethal Exposure

1) An acute busulfan dose of 2.4 grams was fatal in a 10-year-old child (Prod Info BUSULFEX(R) intravenous injection, 2015).

Maximum Tolerated Exposure

1) Seizures with loss of consciousness occurred after receiving 3 to 4 doses of high-dose busulfan therapy, 4 milligrams/kilogram/day. All of the patients recovered following supportive care (Marcus & Goldman, 1984; Vasta et al, 1992).

1) A 4-year-old child ingested 140 milligrams of busulfan, as a single dose, and developed nausea, vomiting, stomatitis, anorexia, pancytopenia, and alopecia. The patient recovered following supportive care (De Oliveira et al, 1963).
2) A 2-year-old child inadvertently received a total oral dose of 23.3 milligrams/kilogram and survived without sequelae (Prod Info BUSULFEX(R) intravenous injection, 2015).

Workplace Standards

1) Not Listed

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 1 ; Listed as: 1,4-Butanediol dimethanesulfonate (Busulphan; Myleran)

a) 1 : The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans. This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.

4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

1) Not Listed

Toxicity Information

7.7.1)

A) BUSULFAN

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 86 mg/kg (RTECS , 2000)

2) LD50- (ORAL)MOUSE:

a) 110 mg/kg (RTECS , 2000)

3) LD50- (SUBCUTANEOUS)MOUSE:

a) 63 mg/kg (RTECS , 2000)

4) LD50- (INTRAPERITONEAL)RAT:

a) 18 mg/kg (RTECS , 2000)

5) LD50- (SUBCUTANEOUS)RAT:

a) 22 mg/kg (RTECS , 2000)

Pharmacology Toxicology

Pharmacologic Mechanism

Physicochemical

Physical Characteristics

Molecular Weight

Animal Toxicology

References

General Bibliography

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FeedBack

BUSULFAN AND RELATED AGENTS

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Hematologic

Dermatologic

Musculoskeletal

Endocrine

Immunologic

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Radiographic Studies

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Enhanced Elimination

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Workplace Standards

Toxicity Information

Pharmacologic Mechanism

Physical Characteristics

Molecular Weight

General Bibliography