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NITROSOUREAS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Nitrosoureas are bifunctional alkylating antitumor agents with activity against a wide range of human malignancies. Nitrosoureas have a high degree of lipid solubility that allows penetration of the blood-brain barrier.
    B) Nitrosoureas may inhibit several enzymes by carbamoylation of amino acids. Nitrosoureas are cell cycle-nonspecific and are dose-dependent.

Specific Substances

    A) BENDAMUSTINE
    1) Bendamustina hidrocloruro de
    2) Bendamustine hydrochloride
    3) Bendamustine, Chlorhydrate de
    4) Bendamustine hydrochloridum
    5) Hidrocloruor de bendamustina
    6) IMET-3393
    7) SDX-105
    8) Molecular Formula: C(16)H(21)Cl(2)N(3)O(2), HCl
    9) CAS 16506-27-7 (bendamustine)
    10) CAS 3543-75-7 (bendamustine hydrochloride)
    CARMUSTINE
    1) 1,3-Bis(2-chloroethyl)-1-nitrosourea
    2) BCNU
    3) N,N-Bis(2-chloroethyl)-N-nitrosourea
    4) NSC 409962
    5) WR 139021
    6) CAS 154-93-8
    CHLOROZOTOCIN
    1) 2-((((2-chloroethyl)nitrosoamino)-
    2) carbonyl)amino)-deoxy-d-glucose
    3) 2-(3-(2-chloroethyl)-3-nitroso ureido)-
    4) 2-deoxy-D-glucopyranose
    5) 2-Chloroethyl analog of streptozocin
    6) DCNU
    7) NSC 178248
    8) CAS 54749-90-5
    FOTEMUSTINE
    1) (1-((((2-chloroethyl-3-nitrosoamino)- carbonyl)amino)ethyl)phosphonic acid diethyl ester
    2) diethyl[1-[3-(2-chloroethyl)-30nitrosoureido]- ethylphosphonate
    3) 1-[N-(2-chloroethyl)-N-nitrosoureido]- ethylphosphonic acid diethyl ester
    4) S-10036
    5) Muphoran
    6) CAS 92118-27-9
    LOMUSTINE
    1) 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea
    2) CCNU
    3) N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosourea
    4) NSC 79037
    5) RB 1509
    6) WR 139017
    7) CAS 13010-47-4
    PCNU
    1) 1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea
    2) N-(2-chloroethyl)-N'-(2,6-dioxo-3-piperidinyl)-N-nitrosourea
    3) NSC 95466
    4) CAS 13909-02-9
    RANIMUSTINE
    1) MCNU
    2) alpha-D-glucopyranoside
    3) Glucopyranoside, methyl-6-((((2-chloroethyl)nitrosoamino)carbonyl)amino)-6-deoxy-,alpha-D-
    4) Methyl-6-(3-(2-chloroethyl)-3-nitrosoureido)-6-deoxy-alpha-D-glucopyranoside
    5) NSC-0270516
    6) CAS 58994-96-0
    SEMUSTINE
    1) 1-(2-chloroethyl)-3-(4-met-hylcyclo-hexyl)-1-nitrosourea
    2) Methyl-CCNU
    3) Methyl lomustine
    4) NSC 95441
    5) WR 220076
    6) CAS 13909-09-6
    STREPTOZOCIN
    1) 2-Deoxy-2-[[(methylnitrosoamino)- carbonyl]amino]-D-glucopyranose
    2) 2-deoxy-2-(3-methyl-3-nitrosoureido)- D-glucopyranose
    3) NSC-85998
    4) U-9889
    5) Zanosar
    6) CAS 18883-66-4
    TAUROMUSTINE
    1) 1-(2-chloroethyl)-3-(2-(dimethylaminosulfonyl)ethyl)-1-nitrosourea
    2) TCNU

    1.2.1) MOLECULAR FORMULA
    1) BENDAMUSTINE HYDROCHLORIDE: C16H21Cl2N3O2.HCl (Prod Info TREANDA(R) intravenous injection, 2013)
    2) LOMUSTINE: C9-H16-Cl-N3-O2 (Prod Info CeeNU(R) oral capsules, 2010)

Available Forms Sources

    A) FORMS
    1) BENDAMUSTINE: Available for injection in 25 mg or 100 mg per use single-vials of white to off-white lyophilized powder (Prod Info TREANDA(R) IV injection, 2010).
    2) CARMUSTINE: Available in a package containing 100 mg carmustine and an ampule containing 3 mL sterile diluent (Prod Info BICNU(R) IV injection, 2007).
    3) CHLOROZOTOCIN: An investigational agent available as a lyophilized powder for reconstitution for injection containing 50 mg per vial with citric acid and sodium hydroxide.
    4) LOMUSTINE: Available as capsules for oral use in 10 mg, 40 mg and 100 mg strengths (Prod Info CeeNU(R) oral capsules, 2009).
    5) SEMUSTINE: An investigational agent available from National Institutes of Health as 100 mg, 50 mg, and 1 mg capsules.
    6) STREPTOZOCIN: Available in 1 gram vials for intravenous use (Prod Info ZANOSAR(R) powder for IV solution, 2003).
    7) TAUROMUSTINE: No longer available.
    B) USES
    1) The nitrosoureas are cell-cycle nonspecific alkylating agents indicated for the treatment of various carcinomas and are used as single agents or in combination therapy with other antineoplastic agents (Prod Info TREANDA(R) IV injection, 2010; Prod Info BICNU(R) IV injection, 2007; Prod Info ZANOSAR(R) powder for IV solution, 2003).
    a) Bendamustine is indicated for the treatment of chronic lymphocytic leukemia (CLL) and for indolent B-cell non-Hodgkin's Lymphoma that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen (Prod Info TREANDA(R) IV injection, 2010).
    b) Carmustine is used for the palliative therapy, as a single agent or in combination therapy in the following conditions: brain tumors, multiple myeloma (combined with prednisone), Hodgkin's disease (secondary therapy) and Non-hodgkin's lymphoma (secondary therapy) (Prod Info BICNU(R) IV injection, 2007).
    c) Lomustine is indicated for both primary and metastatic brain tumors in patients who have undergone appropriate surgical or radiotherapeutic therapies. It is also indicated as a secondary therapy for Hodgkin's disease in combination with other agents (Prod Info CeeNU(R) oral capsules, 2009).
    d) Streptozocin is indicated for the treatment of metastatic islet cell carcinoma of the pancreas. Due to the risk of renal toxicity, this agent is limited to patients with symptomatic or progressive metastatic disease (Prod Info ZANOSAR(R) powder for IV solution, 2003).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH THERAPEUTIC USE
    1) Hypotension, tachycardia and myocardial ischemia have been reported with high dose carmustine infusion. Thrombocytopenia and granulocytopenia are common. Infrequent reports of hypotension and tachycardia have also been reported with bendamustine.
    2) Pulmonary toxicity may develop after carmustine and lomustine therapy. It appears to be dose related, more common in women, and may present years after therapy.
    3) Hypersensitivity reactions (fever, chills, pruritus and rash) have occurred with bendamustine therapy, but severe anaphylactoid reactions have been reported rarely. Myelosuppression is common, tumor lysis syndrome may cause renal failure. Rashes are common.
    4) Renal toxicity is common and may be severe following therapy with streptozocin.
    B) WITH POISONING/EXPOSURE
    1) Limited data. It is anticipated that overdose events are likely an extension of the toxicity reported with the therapeutic use of these agents (ie, myelosuppression, nephrotoxicity, hepatotoxicity). Clinical effects information is based primarily on two case reports of lomustine (CCNU) overdose, and on adverse effects from high-dose therapy.
    2) Effects reported following lomustine overdose included severe delayed bone marrow depression. In one case the nadir for thrombocytes occurred about 4 weeks after exposure, and for leukocytes about one week after the nadir for the thrombocytes; both normalized over 2 weeks. In the other case neutropenia developed 7 days after the last dose of lomustine and persisted for more than 40 days. Thrombocytopenia also developed.
    3) Delayed liver and lymph node enlargement, abdominal pain, ileitis, elevated liver enzymes, mental status changes and tachypnea have been reported after lomustine overdose.
    0.2.3) VITAL SIGNS
    A) Patients may present with hypotension and tachycardia.
    0.2.5) CARDIOVASCULAR
    A) Hypotension and tachycardia have been reported with bendamustine and carmustine therapeutic use; myocardial ischemia has also occurred with carmustine.
    0.2.6) RESPIRATORY
    A) Dose related pulmonary infiltration or fibrosis has been reported as a delayed adverse effect.
    0.2.7) NEUROLOGIC
    A) CNS depression may occur.
    0.2.8) GASTROINTESTINAL
    A) Nausea and vomiting commonly occur with these agents. Diarrhea is also frequently reported with bendamustine use.
    0.2.9) HEPATIC
    A) A reversible, transient hepatotoxicity has been reported with therapeutic doses as well as after overdose.
    0.2.10) GENITOURINARY
    A) Progressive azotemia and renal failure have been reported with therapeutic doses. Renal toxicity is common with streptozocin therapy.
    0.2.13) HEMATOLOGIC
    A) Thrombocytopenia usually occurs in 4 to 5 weeks.
    B) Leukocytopenia usually occurs in 5 to 6 weeks.
    C) Polycythemia vera has been reported following treatment with ranimustine.
    0.2.14) DERMATOLOGIC
    A) Skin irritation may occur.
    0.2.20) REPRODUCTIVE
    A) Use of these agents during pregnancy or while breast feeding is not recommended. Bendamustine and carmustine are classified as FDA pregnancy category D. These agents are reported to be teratogenic and embryotoxic in animals. Studies of bendamustine in pregnant women have not been conducted; however, fetal malformations as well as embryofetal lethality have been observed in animals administered bendamustine intraperitoneally. Studies of carmustine or lomustine in pregnant women have not been conducted; however, fetal malformations including anophthalmia, micrognathia, and omphalocele were observed in rats administered intraperitoneal carmustine. Increased embryofetal deaths, reduced numbers of litters, and reduced litter size were observed in rabbits administered intravenous carmustine. Embryonic resorption, post-implantation loss, and a number of malformations were noted after the administration of lomustine in rats.
    0.2.21) CARCINOGENICITY
    A) Carcinogenic potential has been reported in humans following the use of nitrosourea therapy.

Laboratory Monitoring

    A) Monitor hematocrit, platelet count, total leukocyte count with a differential, and renal function and hepatic enzymes.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    B) Follow hematologic parameters, renal function, and liver enzymes for 4 to 6 weeks postexposure.
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    0.4.6) PARENTERAL EXPOSURE
    A) INTRATHECAL INJECTION
    1) No clinical reports of intrathecal nitrosoureas injection are available. This information was derived from experience with other antineoplastics. Keep the patient upright if possible. Immediately drain at least 20 mL 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 normal saline or lactated ringers). Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative-free normal saline or LR through ventricular catheter, drain fluid from lumbar catheter; typical volumes are 80 to 150 mL/hr for 18 to 24 hours). Fresh frozen plasma (25 mL FFP per liter NS or LR) or albumin 5% have been used for perfusion. Dexamethasone 4 mg IV every 6 hours to prevent arachnoiditis.

Range Of Toxicity

    A) The range of toxicity is not well defined for these agents.
    B) A patient survived an overdose of 600 mg lomustine ingested over 15 days. Delayed bone marrow toxicity was reported. Two patients survived after taking 800 mg of lomustine over 5 days. Both patients experienced severe myelosuppression. An adult died of multiorgan system failure after ingesting 1400 milligrams of lomustine.

Clinical Effects

Summary Of Exposure

    A) WITH THERAPEUTIC USE
    1) Hypotension, tachycardia and myocardial ischemia have been reported with high dose carmustine infusion. Thrombocytopenia and granulocytopenia are common. Infrequent reports of hypotension and tachycardia have also been reported with bendamustine.
    2) Pulmonary toxicity may develop after carmustine and lomustine therapy. It appears to be dose related, more common in women, and may present years after therapy.
    3) Hypersensitivity reactions (fever, chills, pruritus and rash) have occurred with bendamustine therapy, but severe anaphylactoid reactions have been reported rarely. Myelosuppression is common, tumor lysis syndrome may cause renal failure. Rashes are common.
    4) Renal toxicity is common and may be severe following therapy with streptozocin.
    B) WITH POISONING/EXPOSURE
    1) Limited data. It is anticipated that overdose events are likely an extension of the toxicity reported with the therapeutic use of these agents (ie, myelosuppression, nephrotoxicity, hepatotoxicity). Clinical effects information is based primarily on two case reports of lomustine (CCNU) overdose, and on adverse effects from high-dose therapy.
    2) Effects reported following lomustine overdose included severe delayed bone marrow depression. In one case the nadir for thrombocytes occurred about 4 weeks after exposure, and for leukocytes about one week after the nadir for the thrombocytes; both normalized over 2 weeks. In the other case neutropenia developed 7 days after the last dose of lomustine and persisted for more than 40 days. Thrombocytopenia also developed.
    3) Delayed liver and lymph node enlargement, abdominal pain, ileitis, elevated liver enzymes, mental status changes and tachypnea have been reported after lomustine overdose.

Vital Signs

    3.3.1) SUMMARY
    A) Patients may present with hypotension and tachycardia.
    3.3.3) TEMPERATURE
    A) CASE REPORT: A mild FEVER of a few days duration was reported following the granulocyte nadir from an overdose of CCNU. No other signs of infection occurred (Hornsten et al, 1983).
    3.3.4) BLOOD PRESSURE
    A) CASE REPORT: HYPOTENSION was noted as an acute effect of high-dose BCNU (up to 6.25 mg/m(2)/minute) by intravenous infusion (Henner et al, 1986).

Heent

    3.4.3) EYES
    A) Neuroretinitis has been associated with use of carmustine (Prod Info BICNU(R) IV injection, 2007) and procarbazine together and intra-arterial and intravenous carmustine therapy (McLellan & Taylor, 1978; Shingleton et al, 1983; Pickrell & Purvin, 1987).
    B) BLINDNESS has been reported in patients treated with intravenous, intra-arterial, and oral carmustine therapy (McLellan & Taylor, 1978; Pickrell & Purvin, 1987; Wilson et al, 1987).
    3.4.5) NOSE
    A) Some nosebleeds were reported while a patient was thrombocytopenic following an overdose of CCNU (Hornsten et al, 1983).

Cardiovascular

    3.5.1) SUMMARY
    A) Hypotension and tachycardia have been reported with bendamustine and carmustine therapeutic use; myocardial ischemia has also occurred with carmustine.
    3.5.2) CLINICAL EFFECTS
    A) TACHYARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) Tachycardia has been associated with therapeutic use of bendamustine (infrequently) and carmustine (Prod Info TREANDA(R) IV injection, 2010; Prod Info BICNU(R) IV injection, 2007).
    b) CASE REPORT: Hypotension and tachycardia were reported during an infusion of carmustine 600 mg/m(2) infused at a rate of 5 mg/m(2)/minute and were associated with intense flushing of skin of the upper chest and face (Henner et al, 1986). This reaction may be secondary to the ethanol used to dissolve the dose of BCNU (Higby, 1987).
    c) CASE REPORTS: Two patients receiving high dose carmustine infusion developed tachycardia and hypotension which responded to intravenous fluids and dopamine (Iliadis et al, 1991).
    B) ANGINA
    1) WITH THERAPEUTIC USE
    a) CASE SERIES: Three cases of angina pectoris during and after carmustine (BCNU) infusion have been reported in middle-aged women with few or no cardiac risk factors (Iliadis et al, 1991):
    1) All three were cancer patients with normal ECG and cardiac function parameters prior to treatment. All patients had previously received other therapy including cyclophosphamide, doxorubicin, 5-fluorouracil, and Calmette-Guerin vaccine.
    2) All three experienced tachycardia and ST segment depression during BCNU infusions of unknown rate and dose, two became hypotensive. These effects responded to treatment (intravenous fluids, nitroglycerin, morphine) and did not reoccur.
    C) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension has been associated with therapeutic use of bendamustine (infrequently) and carmustine (Prod Info TREANDA(R) IV injection, 2010; Prod Info BICNU(R) IV injection, 2007).
    b) Two women developed hypotension responsive to intravenous fluid and dopamine during high dose carmustine infusion (Iliadis et al, 1991).
    D) ELECTROCARDIOGRAM ABNORMAL
    1) WITH THERAPEUTIC USE
    a) BENDAMUSTINE: Three of 4 patients who received 280 mg/m(2) developed ECG changes at 7 and 21 days post dosing. Observed ECG changes included one case of QTc prolongation, one patient with sinus tachycardia, two patients with ST and T wave changes, and one patient with a lead anterior fascicular block. Cardiac enzymes and ejection fraction remained normal in these patients (Prod Info TREANDA(R) IV injection, 2008).

Respiratory

    3.6.1) SUMMARY
    A) Dose related pulmonary infiltration or fibrosis has been reported as a delayed adverse effect.
    3.6.2) CLINICAL EFFECTS
    A) FIBROSIS OF LUNG
    1) WITH THERAPEUTIC USE
    a) Pulmonary infiltration or fibrosis have been reported in patients receiving chronic carmustine therapy and in patients receiving high dose therapy occurring up to 17 years after treatment (Prod Info BICNU(R) IV injection, 2007; Prod Info TREANDA(R) IV injection, 2010; Schmitz & Diehl, 1997).
    1) Pulmonary toxicity occurrence risk may be associated with a total dose greater than 902 mg/m(2), although it has been reported with as little as 300 mg/m(2) (Weinstein et al, 1986; Weiss et al, 1981; Schmitz & Diehl, 1997).
    b) INCIDENCE: In lymphoma patients receiving carmustine as part of a high dose chemotherapy regimen, the incidence of idiopathic pneumonia syndrome (IPS) was 0% to 17% for patients receiving 300 mg/m(2) carmustine and 16% to 40% in patients receiving 500 to 600 mg/m(2) (Schmitz & Diehl, 1997).
    1) In another study of lymphoma patients receiving high dose carmustine, cyclophosphamide and etoposide 5% of patients receiving 450 mg/m(2) carmustine developed IPS compared with 28% of those receiving 600 mg/m(2) carmustine (Schmitz & Diehl, 1997).
    2) In a study of patients with Hodgkin's disease treated with carmustine, melphalan and etoposide, 15% of patients who received less than 475 mg/m(2) carmustine developed IPS, compared with 32% of those who received 475 to 525 mg/m(2) and 47% of those who received more than 525 mg/m(2) carmustine (Schmitz & Diehl, 1997).
    c) RISK FACTORS: Women appear to be more susceptible than men (Schmitz & Diehl, 1997).
    d) ONSET: High dose carmustine usually causes onset of IPS within months of therapy (Schmitz & Diehl, 1997). Symptoms may be delayed for years in patients who have received chronic carmustine therapy (O'Driscoll et al, 1990).
    e) FINDINGS: May include upper lobe fibrotic changes on chest radiograph or CT, restrictive lung defects on spirometry, and interstitial fibrosis and elastosis on biopsy (O'Driscoll et al, 1990). Patients may be asymptomatic or may complain of shortness of breath or cough.
    f) Pulmonary toxicity may occur with other nitrosoureas (Smith, 1989; Stone & Richardson, 1987).
    g) Two patients developed pulmonary toxicity after receiving the third cycle of chemotherapy with carmustine and streptozocin for treatment of refractory melanoma. Both patients subsequently died with the autopsy of one of the patients showing pulmonary fibrosis and hyaline membrane disease (Smith et al, 1996).
    B) RESPIRATORY FAILURE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 28-year-old woman mistakenly took 200 mg of lomustine daily for 7 consecutive days (825 mg/m(2)). She developed tachypnea 50 days after her first lomustine dose followed 6 days later by respiratory decompensation. The woman died on hospital day number 45 (Trent et al, 1995).

Neurologic

    3.7.1) SUMMARY
    A) CNS depression may occur.
    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH THERAPEUTIC USE
    a) Disorientation, lethargy, ataxia, and dysarthria have been reported with some patients receiving lomustine; however, the relationship to the medication remains unclear (Prod Info CeeNU(R) oral capsules, 2010).
    B) TOXIC ENCEPHALOPATHY
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 60-year-old woman with metastatic melanoma developed neurological impairment after receiving polychemotherapy with fotemustine (10 courses, 100 mg/m(2); total dose received 2340 mg), eldisine 1.5 mg/m(2) and dacarbazine 250 mg/m(2) (an initial course followed by 3 supportive courses). She experienced headaches, body instability, and cognitive, thinking and speaking impairment. In addition, she developed a sudden loss of vision of the left eye; however, doppler revealed only a decrease in the right ophthalmic artery flow. The clinical and radiological patterns suggested a fotemustine-related toxic encephalopathy. An initial brain MRI showed an already known right retro-orbital lesion. However, a second brain MRI revealed a mild hypersignal in T2 mode of the periventricular white substance with a 'glove finger' pattern, indicating a toxic chemotherapy-related lesion rather than a tumor or vascular lesion. Three months later, another lesion on the right caudate nucleus was discovered; however, the pattern of periventricular leuco-encephalopathy was still observed. She subsequently died several months later with prominent neurological symptoms (Khalil et al, 2005).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 28-year-old woman mistakenly took 200 mg of lomustine daily for 7 consecutive days (825 mg/m(2)). She developed mental status changes including intermittent confusion 44 days after her first lomustine dose, which progressed to persistent disorientation (Trent et al, 1995).

Gastrointestinal

    3.8.1) SUMMARY
    A) Nausea and vomiting commonly occur with these agents. Diarrhea is also frequently reported with bendamustine use.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting are commonly reported following administration of nitrosoureas (Prod Info TREANDA(R) IV injection, 2010; Prod Info CeeNU(R) oral capsules, 2009; Prod Info BICNU(R) IV injection, 2007).
    b) The onset of vomiting for carmustine is usually within 2 hours and lasts for about 4 to 6 hours (Prod Info BICNU(R) IV injection, 2007).
    c) Onset of vomiting for lomustine may be delayed up to 3 to 6 hours following exposure and may last for up to 24 hours (Prod Info CeeNU(R) oral capsules, 2009).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea is a common adverse event reported with bendamustine therapy (Prod Info TREANDA(R) IV injection, 2010).

Hepatic

    3.9.1) SUMMARY
    A) A reversible, transient hepatotoxicity has been reported with therapeutic doses as well as after overdose.
    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) A reversible transient rise in aminotransferases, alkaline phosphatase, and bilirubin has been reported in a small number of patients treated therapeutically with high doses of carmustine (Smith et al, 1996).
    b) Transient rises of AST and ALT have been reported for chlorozotocin with some evidence of cumulative effects (Hoth et al, 1978).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 28-year-old woman mistakenly took 200 mg of lomustine daily for 7 consecutive days (825 mg/m(2)). She developed elevations in bilirubin and alkaline phosphatase concentrations 29 days after her first dose of lomustine. There was no significant increase in aminotransferases concentrations. Liver biopsy revealed centrilobular and canalicular cholestasis, lipofuscin accumulation and extensive hepatocellular ballooning (Trent et al, 1995).

Genitourinary

    3.10.1) SUMMARY
    A) Progressive azotemia and renal failure have been reported with therapeutic doses. Renal toxicity is common with streptozocin therapy.
    3.10.2) CLINICAL EFFECTS
    A) RENAL FAILURE SYNDROME
    1) WITH THERAPEUTIC USE
    a) Progressive azotemia and renal failure have been reported with the therapeutic use of carmustine, lomustine and streptozocin (Prod Info ZANOSAR(R) powder for IV solution, 2003; Prod Info CeeNU(R) oral capsules, 2009; Prod Info BICNU(R) IV injection, 2007).
    b) Renal toxicity is common and appears to be dose-related and cumulative with streptozocin therapy (Prod Info ZANOSAR(R) powder for IV solution, 2003).

Hematologic

    3.13.1) SUMMARY
    A) Thrombocytopenia usually occurs in 4 to 5 weeks.
    B) Leukocytopenia usually occurs in 5 to 6 weeks.
    C) Polycythemia vera has been reported following treatment with ranimustine.
    3.13.2) CLINICAL EFFECTS
    A) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Delayed thrombocytopenia is a dose-related toxicity of nitrosoureas. The nadir or minimum count occurs at 4 to 5 weeks postexposure and persists for 1 to 2 weeks (Prod Info CeeNU(R) oral capsules, 2009; Prod Info BICNU(R) IV injection, 2007).
    b) Sustained thrombocytopenia lasting for longer than 10 weeks developed in some patients receiving the investigational agent, PCNU (Mitchell et al, 1981).
    2) WITH POISONING/EXPOSURE
    a) LOMUSTINE: Two patients with high-grade gliomas (one with a grade IV astrocytoma and the other with a glioblastoma multiforme) developed grade 4 neutropenia and thrombocytopenia approximately 2 weeks after taking lomustine at an oral dose of 800 mg over 4 to 5 days instead of their regular doses of 200 and 240 mg. One patient required 8 packs of thrombocyte suspension because of severe thrombocytopenia on the fourth day of hospitalization. Following supportive therapy, they recovered from the severe myelosuppression (Buyukcelik et al, 2004).
    B) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Delayed leukopenia is a dose-related toxicity of nitrosoureas. The nadir or minimum count occurs 5 to 6 weeks postexposure and persists 1 to 2 weeks (Prod Info BICNU(R) IV injection, 2007; Hornsten et al, 1983). The granulocyte nadir occurs about 3 weeks after administration of bendamustine (Prod Info TREANDA(R) IV injection, 2008).
    2) WITH POISONING/EXPOSURE
    a) LOMUSTINE
    1) CASE REPORT: A 28-year-old woman mistakenly took 200 mg of lomustine daily for 7 consecutive days (825 mg/m(2)). She developed neutropenia 7 days after the last lomustine dose. She received filgrastim and transfusion of leukophoresed cells and her granulocyte count recovered 50 days after her first lomustine dose (Trent et al, 1995).
    2) CASE REPORTS: Two patients with high-grade gliomas (one with a grade IV astrocytoma and the other with a glioblastoma multiforme) developed grade 4 neutropenia and thrombocytopenia approximately 2 weeks after taking lomustine at an oral dose of 800 mg over 4 to 5 days instead of their regular doses of 200 and 240 mg. Following supportive therapy, they recovered from the severe myelosuppression (Buyukcelik et al, 2004).
    C) MYELOSUPPRESSION
    1) WITH THERAPEUTIC USE
    a) SUMMARY: Myelosuppression is the primary adverse event reported with these agents (Prod Info TREANDA(R) IV injection, 2010; Prod Info CeeNU(R) oral capsules, 2009; Prod Info BICNU(R) IV injection, 2007). However, hematologic toxicity with streptozocin is rare (Prod Info Zanosar(R), 2003).
    b) EARLY TOXICITY: Severe blood toxicity occurred following administration of high-dose lomustine (390 mg/m(2)), characterized by a nadir of polymorphonuclear cells between day 10 and 14 and a nadir of platelets between day 14 and 20 (Hildebrand et al, 1980).
    1) Bone marrow cellular elements (CFU-C) were reported low or absent on the third day following administration in those patients who later presented with early and severe blood toxicity.
    c) BENDAMUSTINE: Myelosuppression is likely to occur with therapy; in 2 NHL studies 98% of patients developed Grade 3 to 4 myelosuppression (Prod Info TREANDA(R) IV injection, 2010).
    d) CHLOROZOTOCIN: The structure of chlorozotocin was designed to reduce bone marrow toxicity and retain the antitumor activity. The relative bone marrow-sparing property of chlorozotocin holds true in comparison to the other nitrosoureas.
    1) Patients with normal marrow reserve tolerated a maximum dose of 120 mg/m(2) producing only mild depression of platelets (Hoth et al, 1978).
    2) WITH POISONING/EXPOSURE
    a) LOMUSTINE: Two patients with high-grade gliomas (one with a grade IV astrocytoma and the other with a glioblastoma multiforme) developed grade 4 neutropenia and thrombocytopenia approximately 2 weeks after taking lomustine at an oral dose of 800 mg over 4 to 5 days instead of their regular doses of 200 and 240 mg. Following supportive therapy, they recovered from the severe myelosuppression (Buyukcelik et al, 2004).
    D) ERYTHROCYTOSIS
    1) A case of polycythemia vera has been reported following treatment with ranimustine. Seven months after initial therapy with ranimustine, a patient developed polycythemia (RBC 7.39 x 10(6)/microliter; Hb 19.1 g/dL; Hct 65.9%) (Harashima et al, 1996).
    E) LACK OF EFFECT
    1) WITH THERAPEUTIC USE
    a) Hemoglobin remains fairly constant (Hornsten et al, 1983).

Dermatologic

    3.14.1) SUMMARY
    A) Skin irritation may occur.
    3.14.2) CLINICAL EFFECTS
    A) DISCOLORATION OF SKIN
    1) WITH THERAPEUTIC USE
    a) Topical reactions characterized by pain and/or brown-staining of the skin may occur from carmustine (Prod Info BICNU(R) IV injection, 2007).
    B) INJECTION SITE PAIN
    1) WITH THERAPEUTIC USE
    a) Carmustine can cause pain at injection sites even when it is administered appropriately into the vein (Prod Info BICNU(R) IV injection, 2007).
    C) FLUSHING
    1) WITH THERAPEUTIC USE
    a) Flushing can occur with rapid IV administration of carmustine (Prod Info BICNU(R) IV injection, 2007).
    b) CASE REPORT: Intense flushing of the skin of the upper chest and face was reported during an infusion of high dose carmustine (600 mg/m(2)) over about 1.5 hours (Henner et al, 1986).
    1) This reaction may be secondary to the ethanol used to dissolve the dose of BCNU (Higby, 1987).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) WITH THERAPEUTIC USE
    a) BENDAMUSTINE: Hypersensitivity including fever, chills, pruritus and rash have occurred commonly with therapy. Severe anaphylactoid reactions have been reported rarely with therapeutic use of bendamustine, but have typically occurred following the second or subsequent cycles of therapy (Prod Info TREANDA(R) IV injection, 2010).

Reproductive

    3.20.1) SUMMARY
    A) Use of these agents during pregnancy or while breast feeding is not recommended. Bendamustine and carmustine are classified as FDA pregnancy category D. These agents are reported to be teratogenic and embryotoxic in animals. Studies of bendamustine in pregnant women have not been conducted; however, fetal malformations as well as embryofetal lethality have been observed in animals administered bendamustine intraperitoneally. Studies of carmustine or lomustine in pregnant women have not been conducted; however, fetal malformations including anophthalmia, micrognathia, and omphalocele were observed in rats administered intraperitoneal carmustine. Increased embryofetal deaths, reduced numbers of litters, and reduced litter size were observed in rabbits administered intravenous carmustine. Embryonic resorption, post-implantation loss, and a number of malformations were noted after the administration of lomustine in rats.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) BENDAMUSTINE
    a) In studies in pregnant mice, a decrease in fetal body weights and an increase in resorptions, skeletal and visceral malformations (exencephaly, cleft palates, accessory rib, and spinal deformities) occurred with a single 210 mg/m(2) (70 mg/kg) intraperitoneal injection administered during organogenesis. This dose did not cause maternal toxicity. When bendamustine was repeated on gestation days 7 to 11, increased resorptions with and abnormalities similar to those resulting from single injections were detected with 75 mg/m(2) (25 mg/kg) and 112.5 mg/m(2) (37.5 mg/kg) doses, respectively. A significant increase in external (effect on head, tail, and herniation of external organs) and internal (hydrocephalus and hydronephrosis) malformations were observed in pregnant rats given single intraperitoneal injections of bendamustine from 120 mg/m(2) (20 mg/kg) on gestation days 4, 7, 9, 11, or 13 (Prod Info TREANDA(R) intravenous injection, 2013).
    2) CARMUSTINE
    a) RATS: In animal studies, carmustine was embryotoxic and teratogenic at exposures less than or similar to the exposure at the recommended human dose on a mg/m(2) basis. Intraperitoneal doses of 1 mg/kg/day (approximately 0.12 the recommended human dose of 8 wafters of 7.7 mg/wafer on a mg/m(2) basis) given to rats on gestation days 6 through 15 resulted in fetal malformations, including anophthalmia, micrognathia, and omphalocele (Prod Info GLIADEL(R) WAFER wafer implant, 2013).
    3) LOMUSTINE
    a) Teratogenic effects in association with lomustine use have been reported in animals. Alkylating agents given during the first trimester are generally believed to slightly increase the risk of congenital malformations, whereas those given during the second or third trimesters are believed only to increase the risk of growth retardation (Glantz, 1994).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) BENDAMUSTINE
    a) While there are no adequate and well-controlled studies of bendamustine in pregnant women, this drug can cause fetal harm when administered to a pregnant woman. Women should be advised to avoid pregnancy during and for 3 months after therapy has stopped. If bendamustine is used during pregnancy, or if the patient becomes pregnant while on bendamustine, inform the patient of the potential harm to the fetus. Advise men taking bendamustine to use reliable contraception during the same time period (Prod Info TREANDA(R) intravenous injection, 2013).
    2) CARMUSTINE
    a) There are no adequate and well-controlled studies of carmustine in pregnant women; however, carmustine may cause fetal harm when given to a pregnant woman. Women of childbearing potential are cautioned against becoming pregnant while receiving IV carmustine (Prod Info BiCNU(R) IV injection, 2011) or following implantation of carmustine wafers. If a patient does become pregnant under these circumstances, she should be advised of the potential consequences to the fetus (Prod Info GLIADEL(R) WAFER wafer implant, 2013).
    3) LOMUSTINE
    a) There are no available data on the use of lomustine in pregnant women. However, it was teratogenic and embryotoxic in animal studies at approximately 2 to 4 times the total human dose of 130 mg/m(2) (based on body surface area) over 6 weeks (Prod Info GLEOSTINE(R) oral capsules, 2016).
    B) PREGNANCY CATEGORY
    1) Bendamustine and carmustine are classified as FDA category D (Prod Info BiCNU(R) IV injection, 2011; Prod Info GLIADEL(R) WAFER wafer implant, 2013; Prod Info TREANDA(R) intravenous injection, 2013).
    C) LOMUSTINE
    1) Lomustine can cause fetal harm based on its mechanism of action and animal studies. Women of reproductive potential should be advised to use effective contraception during therapy and for 2 weeks after the last dose of lomustine. Men with female partners of reproductive potential should use effective contraception during therapy and for 3.5 months after the completion of therapy (Prod Info GLEOSTINE(R) oral capsules, 2016).
    D) ANIMAL STUDIES
    1) BENDAMUSTINE
    a) Embryo and fetal lethality was observed in pregnant rats given single intraperitoneal injections of 120 mg/m(2) (20 mg/kg) bendamustine on gestation days 4, 7, 9, 11, or 13 (Prod Info TREANDA(R) intravenous injection, 2013).
    2) CARMUSTINE
    a) Carmustine has been reported to be embryotoxic in rats and rabbits (Prod Info BiCNU(R) IV injection, 2011). Intravenous doses of carmustine at 4 mg/kg/day (about 1.2 times the recommended human dose on a mg/m(2) basis) given to rabbits resulted in embryotoxicity characterized by increased embryofetal deaths, reduced numbers of litters, and reduced litter sizes (Prod Info GLIADEL(R) WAFER wafer implant, 2013).
    3) LOMUSTINE
    a) Embryonic resorption and post-implantation loss occurred at 0.18 times the clinical human dose based on body surface area (BSA) over 6 weeks of administration. Malformations including omphalocele, ectepia cordis, scoliosis, syndactyly, and hydrocephalus (among others) occurred at all tested dose levels. In another study, at doses approximately 0.27 times the clinical dose based on BSA administered during organogenesis, increased abortion rates and decreased weights of surviving pups persisted postnatally (Prod Info GLEOSTINE(R) oral capsules, 2016).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) BREAST MILK
    a) SUMMARY: Due to the toxic nature of this group of compounds and potential risk to the infant, breastfeeding is not recommended.
    b) Although there is no data available regarding the excretion of bendamustine or carmustine in human breast milk, due to the potential for serious adverse events in the nursing infant, a decision should be made to either discontinue nursing or discontinue the drug, giving consideration to the importance of the drug to the mother (Prod Info GLIADEL(R) WAFER wafer implant, 2013; Prod Info TREANDA(R) intravenous injection, 2013).
    c) Chlorozotocin is a water soluble analog of streptozocin and probably does not pass into the milk easily.
    d) Lomustine and semustine are lipid soluble; therefore, one would expect some penetration into milk. However, there are no reports available to determine the presence of lomustine or its metabolites in human milk or its effects on breastfed infants. Due to the potential risk for serious adverse reactions in breastfed infants, women should be advised to not breastfeed during therapy with lomustine and for 2 weeks after the last dose (Prod Info GLEOSTINE(R) oral capsules, 2016).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) CARMUSTINE
    a) Intraperitoneal administration of 8 mg/kg/week for 8 weeks of carmustine (equivalent to approximately 1.3 times the recommended human dose on a mg/m(2) basis) caused testicular degeneration in male rats (Prod Info GLIADEL(R) WAFER wafer implant, 2013).
    2) LOMUSTINE
    a) According to its mechanism of action and animal data, lomustine may reduce fertility in males and females and can cause fetal harm (Prod Info GLEOSTINE(R) oral capsules, 2016).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) Carcinogenic potential has been reported in humans following the use of nitrosourea therapy.
    3.21.3) HUMAN STUDIES
    A) CARCINOGENIC POTENTIAL
    1) Carcinogenic potential has been reported in humans following the use of nitrosourea therapy (Prod Info BiCNU(R) IV injection, 2010).
    B) SECONDARY MALIGNANCIES
    1) Secondary malignancies including myelodysplasia and acute leukemia occur after long-term lomustine use (Prod Info GLEOSTINE(R) oral capsules, 2016).
    C) LEUKEMIA
    1) CASE REPORTS: Two cases of acute myeloid leukemia following treatment with high doses of procarbazine, lomustine, and vincristine (Perry et al, 1998)
    2) CASE REPORT: A 55-year-old man developed therapy-related acute nonlymphocytic leukemia 9 months after the initiation of PCNU 75 mg/m(2) IV every 6 weeks for 3 cycles for advanced adenocarcinoma of the rectum. Complete remission of the leukemia was achieved with high-dose ara-C treatment. Treatment of the primary tumor included 54 Gy of combined photon and electron beam radiation therapy to the lower lumbar spine and pelvic region and 4 cycles of 5-FU 12 mg/kg IV daily for 5 days every month in addition to the PCNU therapy (Shepard et al, 1988).
    3.21.4) ANIMAL STUDIES
    A) CARMUSTINE
    1) A marked increase in tumor incidence has been reported in rats and mice following doses of carmustine that were equivalent to human dosing (Prod Info BiCNU(R) IV injection, 2010).
    B) LOMUSTINE
    1) A marked increase in tumor incidence has been reported in rats and mice after administration of lomustine doses lower than those employed clinically (Prod Info GLEOSTINE(R) oral capsules, 2016).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor hematocrit, platelet count, total leukocyte count with a differential, and renal function and hepatic enzymes.
    4.1.2) SERUM/BLOOD
    A) HEMATOLOGIC
    1) Hematocrit, platelet count, and total leukocyte count with differential should be monitored.
    B) BLOOD/SERUM CHEMISTRY
    1) Renal function and hepatic enzymes may be useful.
    4.1.4) OTHER
    A) OTHER
    1) PULMONARY FUNCTION TESTS
    a) Pulmonary function tests should be considered if the patient was taking carmustine chronically or received high dose therapy.

Methods

    A) OTHER
    1) Plasma concentrations of lomustine have been determined by a colorimetric method (Loo & Dion, 1965).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) After acute overdose, admit patient for observation and gastrointestinal decontamination due to lack of clinical experience in treating nitrosourea poisonings.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Schedule follow-up of laboratory parameters weekly for a minimum of 4 to 6 weeks.

Monitoring

    A) Monitor hematocrit, platelet count, total leukocyte count with a differential, and renal function and hepatic enzymes.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    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) TREATMENT
    A) SUPPORT
    1) Observe patient and treat symptomatically.
    B) MONITORING OF PATIENT
    1) Follow renal function, liver enzymes, and bone marrow depression for a minimum of 4 weeks or until bone marrow counts normalize.
    2) Monitor patient for signs of hemorrhage during thrombocytopenic phase. Platelet transfusions may be necessary.
    3) Monitor patient for signs of infection during granulocytopenic phase. Antibiotics may be necessary for documented infection.
    4) Monitor pulmonary function for pulmonary toxicity from chronic or high dose exposure to carmustine. It appears to be a cumulative dose effect.
    C) FLUID/ELECTROLYTE BALANCE REGULATION
    1) Fluid hydration orally may be of value to prevent gastrointestinal pain from lomustine. Fluid hydration has been recommended to prevent nephrotoxicity from semustine (Hildebrand et al, 1980).
    D) COLONY STIMULATING FACTOR
    1) GM-CSF has been used to treat granulocytopenia caused by a severe lomustine overdose (Trent et al, 1995).
    2) In this case, a dose of 5 mcg/kg/day was administered subcutaneously. The absolute granulocyte count rose 40 days after her first dose of lomustine. She also received transfusion of leukophoresed cells.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).
    6.8.2) TREATMENT
    A) IRRITATION SYMPTOM
    1) These agents may be irritating and are lipid soluble. Irrigate with lots of fluid as soon as possible to prevent potential injury.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) INITIAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    B) DISPOSAL GUIDELINES
    1) LABELING: Cytotoxic waste should be regarded as HAZARDOUS or TOXIC waste. It must be handled differently from other trash and should be clearly labeled "HAZARDOUS CHEMICAL WASTE - DISPOSE OF PROPERLY" (Anon, 1990).
    2) CONTAINER: Cytotoxic waste may be placed in a leakproof, puncture resistant container which is then placed in disposable wire-tie or sealable 4-mil-thick polyethylene or 2-mil-thick propylethylene bags. These bags should be colored so as to be easily distinguishable from other trash bags, and labeled with a "Cytotoxic Hazard" label (Jeffrey LP, Anderson RW & Fortner CL et al, 1984; Anon, 1986).
    3) SPILL PROCEDURE: Spills should be cleaned up immediately by a person trained in such procedures and wearing appropriate protective clothing (commercial spill kits are available) (Anon, 1990). The area of the spill should be marked so that while cleanup is occurring someone in the area is not accidentally contaminated. Broken glass should be carefully removed possibly by using a scoop. A broom or mop is not advised due to the risk of further contamination of the environment.
    4) DISPOSAL: Cytotoxic waste may be disposed of at an EPA permitted hazardous waste incinerator, an EPA permitted hazardous waste burial site, or by a licensed hazardous waste disposal company and in accordance with all applicable state, federal, and local regulations (Anon, 1990; Jeffrey LP, Anderson RW & Fortner CL et al, 1984).
    C) SMALL SPILL CLEANUP
    1) SUMMARY: Small spills (less than 5 milliliters or 5 grams) should be cleaned immediately by personnel wearing double surgical latex gloves, disposable gown, a face shield or splash goggles and a dust/mist respirator mask (Anon, 1986; Chasse & Gaudet, 1992; Peters, 1995).
    a) CLEAN UP PROCEDURE: Liquids should be adsorbed with gauze pads; solids should be wiped up with wet absorbent gauze (Anon, 1986).
    b) DECONTAMINATION: The spill area should be further decontaminated by THREE washings using a detergent solution (germicidal solutions are not recommended) followed by a rinse of clear water (Anon, 1986).
    c) DISPOSAL: All materials used in the cleanup procedure should be disposed of in the cytotoxic waste bag (Anon, 1986).
    D) LARGE SPILL CLEANUP
    1) SUMMARY: Large spills (greater than 5 milliliters or 5 grams) should be covered immediately with absorbent sheets or spill control pads to reduce the spread. If a powder was spilled use a damp cloth or towel (Anon, 1986).
    a) SECURE AREA: Restrict access to the spill area and take precautions to minimize the generation of aerosols (Anon, 1986).
    b) PERSONNEL PROTECTION: Protective clothing should be worn as with the small spill with the addition of a respirator or breathing apparatus when there is an airborne contamination danger (Anon, 1986).
    c) DECONTAMINATION: The area should be further decontaminated by THREE washings using a detergent solution (germicidal solutions are not recommended) followed by a rinse of clear water (Anon, 1986).
    d) DISPOSAL: All materials used in the cleanup procedure should be disposed of in the cytotoxic waste bag (Anon, 1986).
    E) PERSONNEL PROTECTION
    1) PROTECTIVE CLOTHING: A double layer of disposable surgical latex gloves, protective disposable gowns (non-permeable, made of lint-free, low-permeability fabric with a solid front, long sleeves, and tight-fitting elastic or knit cuffs) with cuff tucked into glove, eye protection (splash goggles), breathing apparatus, in ventilated cabinets when there is airborne contamination danger (Centers for Disease Control and Prevention (CDC), 2012; Anon, 1990a; Anon, 1986).
    2) DECONTAMINATION/CLOTHING: Laundering of non-disposable materials has not been demonstrated to remove cytotoxic contaminants. DISPOSAL: The appropriate procedure for the disposal of these materials should be determined by the institution (or as required by state or local regulation or disposal contractor) (Centers for Disease Control and Prevention (CDC), 2012; Anon, 1990a).
    6.9.2) TREATMENT
    A) CARCINOGEN
    1) These agents may be carcinogenic. Decontaminate skin thoroughly.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

    A) SUMMARY
    1) There is no data on enhanced elimination of nitrosoureas. Hemodialysis would probably be ineffective because of the large volume of distribution, lipid solubility, and low plasma concentration.
    2) The metabolites have a longer half-life and some of them may be active compounds. Extracorporeal methods of removal of the metabolites have not been reported.

Abstracts

Case Reports

    A) ADULT
    1) Hornsten et al (1983) reported a 62-year-old man taking lomustine (CCNU) for Hodgkin's disease (Hornsten et al, 1983).
    a) Each course of treatment consisted of CCNU 120 mg orally on day 1, vinblastine 10 mg intravenously on days 1 and 7, procarbazine 150 mg for 14 days, and prednisone 45 mg for 14 days, to be repeated in a cycle every 6 weeks.
    b) The patient misunderstood the dose of CCNU on the fourth course of treatment and took 40 mg lomustine orally for 15 days. When the error was discovered, all medications were discontinued except prednisone 15 mg/day.
    c) Seven days after the medications were stopped, lymph node and liver enlargement were reported. Thrombocytopenia occurred 4 weeks after the start of the fourth course of treatment, reached a minimum count of about 10 x 10(9)/liter, stayed at that level for about 1 week, and then began to normalize.
    d) Platelet transfusions were given twice. Epistaxis was reported, but there were no other signs of hemorrhage. The leukocytes reached their nadir about 1 week after the thrombocytes and remained low (0.5 x 10(9)/liter) for nearly 2 weeks.
    e) It took about 2 more weeks for the leukocyte count to normalize. A mild fever (38 degrees C) of a few days duration was reported following the granulocytopenic phase. There were no other signs of infection and cultures were negative.
    f) The hemoglobin remained steady at 90 to 100 grams/liter. No sequelae were reported and the patient was in complete remission without further cytotoxic treatment.
    2) ACUTE EFFECTS: Henner et al (1986) described acute effects of tachycardia, hypotension, flushing, confusion, nausea, and vomiting secondary to IV infusion of high-dose BCNU (Henner et al, 1986). Higby (1987) attributed these reactions to the effect of acute ethanol infusion, secondary to preparing the IV infusion according to labeled instructions (Higby, 1987).

Range Of Toxicity

Summary

    A) The range of toxicity is not well defined for these agents.
    B) A patient survived an overdose of 600 mg lomustine ingested over 15 days. Delayed bone marrow toxicity was reported. Two patients survived after taking 800 mg of lomustine over 5 days. Both patients experienced severe myelosuppression. An adult died of multiorgan system failure after ingesting 1400 milligrams of lomustine.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) BENDAMUSTINE
    a) CHRONIC LYMPHOCYTIC LEUKEMIA
    1) BENDEKA(TM): The recommended dose is 100 mg/m(2) given IV (infused over 10 minutes) on Days 1 and 2 of a 28-day cycle for up to 6 cycles. Dose modification is indicated for clinically significant grade 3 or more toxicity (Prod Info BENDEKA(TM) intravenous injection, 2015).
    2) TREANDA(R): The recommended dose is 100 mg/m(2) given IV (infused over 30 minutes) on Days 1 and 2 of a 28-day cycle for up to 6 cycles. Dose modification is indicated for clinically significant grade 3 or more hematologic toxicity (Prod Info TREANDA(R) intravenous injection, 2012).
    b) NON-HODGKIN'S LYMPHOMA
    1) BENDEKA(TM): The recommended dose is 120 mg/m(2) given IV (infused over 10 minutes) on Days 1 and 2 of a 28-day cycle for up to 6 cycles. Dose modification is indicated for clinically significant grade 4 hematologic toxicity or grade 3 or greater non-hematologic toxicity (Prod Info BENDEKA(TM) intravenous injection, 2015).
    2) TREANDA(R): The recommended dose is 120 mg/m(2) given IV over 60 minutes on Days 1 and 2 of a 21-day cycle; up to 8 cycles. Dose modification is indicated for clinically significant grade 4 or more hematologic toxicity (Prod Info TREANDA(R) intravenous injection, 2012).
    2) CARMUSTINE: When used as a single agent in previously untreated patients, the dose is 150 to 200 mg/m(2) IV every 6 weeks. Dose is adjusted when used with other myelosuppressive drugs or in patients with depleted bone marrow reserve (Prod Info BICNU(R) IV injection, 2007).
    3) LOMUSTINE: The recommended dose is a single dose of 130 mg/m(2) orally every 6 weeks. Reduce dose to 100 mg/m(2) every 6 weeks in patients with compromised bone marrow function; reduce further based on hematologic response from prior dose (Prod Info GLEOSTINE(R) oral capsules, 2016).
    4) STREPTOZOCIN: Recommended dose: Given IV at a dose of 500 mg/m(2) daily for 5 days every 6 weeks; alternatively, given IV at a dose of 1000 mg/m(2) per week. MAXIMUM DOSE: A single dose of 1500 mg/m(2) should not be exceeded; may cause azotemia (Prod Info ZANOSAR(R) powder for IV solution, 2003).
    7.2.2) PEDIATRIC
    A) SPECIFIC SUBSTANCE
    1) BENDAMUSTINE: The effectiveness in pediatric patients has not been established (Prod Info BENDEKA(TM) intravenous injection, 2015; Prod Info TREANDA(R) intravenous injection, 2012).
    a) Acute Lymphocytic Leukemia/Acute Myeloid Leukemia: 90 mg/m(2) or 120 mg/m(2) IV over 60 minutes on Days 1 and 2 of a 21-day cycle; safety profile consistent with that of adults (Prod Info BENDEKA(TM) intravenous injection, 2015; Prod Info TREANDA(R) intravenous injection, 2012).
    2) CARMUSTINE: The safety and effectiveness in pediatric patients have not been determined. Based on long-term studies in children that had received carmustine, delayed onset of severe pulmonary fibrosis was observed; therefore, the benefits of treatment must be carefully considered due to the high risk of pulmonary toxicity (Prod Info BICNU(R) IV injection, 2007).
    3) LOMUSTINE: The recommended dose is a single dose of 130 mg/m(2) orally every 6 weeks. Reduce dose to 100 mg/m(2) every 6 weeks in patients with compromised bone marrow function; reduce further based on hematologic response from prior dose (Prod Info GLEOSTINE(R) oral capsules, 2016).
    4) STREPTOZOCIN: The safety and effectiveness in pediatric patients has not been established (Prod Info ZANOSAR(R) powder for IV solution, 2003).

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) The minimum lethal dose for these agents is not known.
    2) SPECIFIC SUBSTANCE
    a) LOMUSTINE - A 28-year-old woman died of multiorgan failure 59 days after taking 1400 milligrams of lomustine over one week (200 milligrams daily) (Trent et al, 1995).

Maximum Tolerated Exposure

    A) SPECIFIC SUBSTANCE
    1) BENDAMUSTINE: The reported maximum single dose was 280 mg/m(2). Of the 4 patients treated at this dose, 3 developed ECG changes including QT prolongation (n=1), sinus tachycardia (n=1), ST and T wave deviations (n=2), and left anterior fascicular block (n=1). Ejection fraction and cardiac enzymes remained normal in all patients (Prod Info TREANDA(R) IV injection, 2010).
    2) LOMUSTINE: A patient survived an overdose of 600 milligrams lomustine ingested over 15 days. Delayed bone marrow toxicity was reported.
    a) Two patients with high-grade gliomas (one with a grade IV astrocytoma and the other with a glioblastoma multiforme) developed grade 4 neutropenia and thrombocytopenia approximately 2 weeks after taking lomustine at an oral dose of 800 mg over 4 to 5 days instead of their regular doses of 200 and 240 mg. Following supportive therapy, they recovered from the severe myelosuppression (Buyukcelik et al, 2004).
    3) SEMUSTINE: Total doses exceeding 1200 milligrams/square meter have been associated with nephrotoxicity.

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) GENERAL
    a) Toxic serum levels are not known.

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) BENDAMUSTINE
    B) CARMUSTINE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 26 mg/kg (Budavari, 1996)
    2) LD50- (ORAL)MOUSE:
    a) 19-25 mg/kg (Budavari, 1996)
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) 24 mg/kg (Budavari, 1996)
    4) LD50- (ORAL)RAT:
    a) 30 to 34 mg/kg (Budavari, 1996)
    C) TAUROMUSTINE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) Male, 42 mg/kg (Hartley-Asp et al, 1988)
    b) Female, 45 mg/kg (Hartley-Asp et al, 1988)
    2) LD50- (ORAL)MOUSE:
    a) Male, 36 mg/kg (Hartley-Asp et al, 1988)
    b) Female, 51 mg/kg (Hartley-Asp et al, 1988)
    3) LD50- (INTRAPERITONEAL)RAT:
    a) Male, 32 mg/kg (Hartley-Asp et al, 1988)
    b) Female, 35 mg/kg (Hartley-Asp et al, 1988)
    4) LD50- (ORAL)RAT:
    a) 39 mg/kg (Hartley-Asp et al, 1988)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Nitrosoureas are classified as alkylating agents. DNA cross-linking is possible, interfering with DNA synthesis as well as synthesis of RNA proteins. They may also inhibit several key enzymes leading to the formation of DNA.
    1) The nitrosoureas react as alkylating agents at nucleophilic sites in purine and pyrimidine moieties of DNA. The predominant site of this alkylation is N7 of guanine, which is followed by the site N3 of adenine and O6 of guanine. The formation and persistence of O(6)-alkylguanine (O(6)-AG) may be of primary importance in cytotoxicity of the nitrosoureas (Syrkin & Gorbacheva, 1996).
    B) Bendamustine is considered active against quiescent and dividing cells; however, the exact mechanism of action remains unknown (Prod Info TREANDA(R) IV injection, 2010).
    C) CARMUSTINE: It is suggested that the antineoplastic and toxic activities are due to its metabolites (Prod Info BICNU(R) IV injection, 2007).

Toxicologic Mechanism

    A) Most antitumor agents are not specific for tumor cells. Rapidly proliferating cells are more sensitive to antitumor agents. Toxicity in normal cells is more evident in rapidly proliferating cells such as those lining the gut and the hemopoietic system (bone marrow).
    1) Bone marrow depression and gastrointestinal symptoms are anticipated events following exposure with these agents.

Physicochemical

Physical Characteristics

    A) BENDAMUSTINE HYDROCHLORIDE is a white to off-white lyophilized powder that is nonpyrogenic (Prod Info TREANDA(R) intravenous injection, 2013).
    B) CARMUSTINE is a congealed mass or pale yellow flakes that are poorly soluble in water, highly soluble in alcohol and lipids, and have a melting point between 30.5 and 32 degrees C (86.9 and 89.6 degrees F) (Prod Info BiCNU(R) IV injection, 2011).
    C) CHLOROZOTOCIN is an ivory crystal (Budavari, 1996)
    D) LOMUSTINE is a yellow powder which is soluble in 10% ethanol (0.05 mg/mL) and in absolute alcohol (70 mg/mL) and is relatively insoluble in water (less than 0.05 mg/mL) (Prod Info CeeNU(R) oral capsules, 2010).

Ph

    A) BENDAMUSTINE HYDROCHLORIDE: 2.5 to 3.5 (when reconstituted with sterile water for injection) (Prod Info TREANDA(R) intravenous injection, 2013)
    B) CARMUSTINE: 5.6 to 6 (solution for injection prepared as directed by manufacturer) (Prod Info BiCNU(R), 1999)

Molecular Weight

    A) BENDAMUSTINE HYDROCHLORIDE: 394.7 (Prod Info TREANDA(R) intravenous injection, 2013)
    B) CARMUSTINE: 214.06 (Prod Info BiCNU(R) IV injection, 2011)
    C) CHLOROZOTOCIN: 313.69 (Budavari, 1996)
    D) LOMUSTINE: 233.71 (Prod Info CeeNU(R) oral capsules, 2010)
    E) SEMUSTINE: 247.7

References

General Bibliography

    1) Addiego JE, Ridgway D, & Bleyer WA: The acute management of intrathecal methotrexate overdose: pharmacologic rationale and guidelines. J Pediatr 1981; 98(5):825-828.
    2) Adolphe AB, Glasofer ED, Troetel WM, et al: Fat of streptozotocin (NSC-85998) in patients with advanced cancer. Cancer Chemother Rep 1975; 59:547-556.
    3) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    4) Anon: ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm 1990; 47:1033-1048.
    5) Anon: ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm 1990a; 47:1033-1049.
    6) Anon: OSHA work-practice guidelines for personnel dealing with cytotoxic (antineoplastic) drugs. Am J Hosp Pharm 1986; 43:1193-1204.
    7) Bhuyan BK, Kuentzel SL, Gray LG, et al: Tissue distribution of streptozotocin (NSC-85998). Cancer Chemother Rep 1974; 58:157-165.
    8) Blaney SM, Poplack DG, Godwin K, et al: Effect of body position on ventricular CSF methotrexate concentration following intralumbar administration. J Clin Oncol 1995; 13(1):177-179.
    9) Budavari S: The Merck Index, 12th ed, Merck & Company, Inc, Whitehouse Station, NJ, 1996.
    10) Burgess JL, Kirk M, Borron SW, et al: Emergency department hazardous materials protocol for contaminated patients. Ann Emerg Med 1999; 34(2):205-212.
    11) Buyukcelik A, Akbulut H, Yalcin B, et al: Overdose of lomustine: report of two cases. Tumori 2004; 90:628-629.
    12) Centers for Disease Control and Prevention (CDC): NIOSH list of antineoplastic and other hazardous drugs in healthcare settings 2012. Centers for Disease Control and Prevention (CDC). Atlanta, GA. 2012. Available from URL: http://www.cdc.gov/niosh/docs/2012-150/pdfs/2012-150.pdf. As accessed 2013-05-14.
    13) Chasse MA & Gaudet S: Safe handling of cytotoxic agents. AARN News Letter 1992; 48:14-15.
    14) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    15) Connor TH, Laidlaw JL, & Theiss JC: Permeability of latex and polyvinyl chloride gloves to carmustine. Am J Hosp Pharm 1984; 41:676-679.
    16) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    17) Dorr RT & Fritz WL: Cancer Chemotherapy Handbook, Elsevier, New York, NY, 1980.
    18) Dorr RT & Von Hoff DD: Cancer Chemotherapy Handbook, 2nd ed, Appleton & Lange, Norwalk, CT, 1994.
    19) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    20) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    21) Gaetani P, Silbani V, & Butti G: Nitrosourea derivatives-induced pulmonary toxicity in patients treated for malignant brain tumors. Early subclinical detection and its prevention. Eur J Cancer Clin Oncol 1987; 23:267-271.
    22) Glantz JC: Reproductive toxicology of alkylating agents. Obstet Gynecol Surv 1994; 49:709-715.
    23) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    24) Gosselin S & Isbister GK: Re: Treatment of accidental intrathecal methotrexate overdose. J Natl Cancer Inst 2005; 97(8):609-610.
    25) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    26) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    27) Harashima S, Okamura T, & Umeno M: A case of myelofibrosis that developed polycythemia vera following treatment with ranimustine and then acute myelogenous leukemia. Rinsho Ketsueki 1996; 37:713-718.
    28) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    29) Henner WD, Peters WP, & Eder JP: Pharmacokinetics and immediate effects of high-dose carmustine in man. Cancer Treat Rep 1986; 70:877-880.
    30) Higby DJ: "Pharmacokinetics and immediate effects of high-dose carmustine in man" (letter). Cancer Treat Rep 1987; 71:433.
    31) Hildebrand J, Badjou R, & Collard-Ronge E: Treatment of brain gliomas with high dose of CCNU and autologous bone marrow transplantation. Biomed 1980; 32:71-75.
    32) Hornsten P, Sundman-Engberg B, & Gahrton G: CCNU toxicity after an overdose in a patient with Hodgkin's disease. Scand J Haematol 1983; 31:9-14.
    33) Hoth D, Wooley P, & Green D: Phase I studies on chlorozotocin. Clin Pharmacol Therap 1978; 23:712-722.
    34) Ignoffo RJ & Friedman MA: Therapy of local toxicities caused by extravasation of cancer chemotherapeutic drugs. Cancer Treat Rev 1980; 7(1):17-27.
    35) Iliadis A, Launay-Iliadis MC, & Lucas C: Pharmacokinetics and pharmacodynamics of nitrosurea fotemustine: a french cancer center multicentric study. Eur J Cancer 1996; 32A:455-460. .SK 1 Kanj SS, Sharara A, Shpall EJ et al: Myocardial ischemia associated with high-dose carmustine infusion. Cancer 1991; 68:1910-1912.
    36) Jeffrey LP, Anderson RW & Fortner CL et al: Recommendations for handling cytotoxic agents. National Study Commission on Cytotoxic Exposure (Sept), 1984.
    37) Karunanayake EH, Hearse DJ, & Mellows G: The metabolic fat and elimination of streptozotocin. Biochem Soc Trans 1975; 3:410-414.
    38) Khalil Z, Pageot N, Carlander B, et al: Neurological toxicity during metastatic melanoma treatment with fotemustine. Melanoma Res 2005; 15(6):563-564.
    39) Lee FYR, Workman P, Roberts JT, et al: Clinical pharmacokinetics or oral CCNU (Lomustine). Cancer Chemother Pharmacol 1985; 14:125-131.
    40) Levin VA, Hoffman W, & Weinkam RJ: Pharmacokinetics of BCNU in man: a preliminary study of 20 patients. Cancer Treat Rep 1978; 62:1305-1312.
    41) Loo TL & Dion RL: Colorimetric methods for the determination of 1,3-bis(2-chloroethyl)-1- nitrosourea. J Pharm Sci 1965; 54:809.
    42) Mahaley MS Jr: Commentary on ocular toxicity following intracarotid chemotherapy (editorial). J Clin Neuro Ophthalmol 1987; 7:92.
    43) McLellan R & Taylor HR: Optic neuroretinitis in association with BCNU and procarbazine therapy. Med Pediatr Oncol 1978; 4:43-48.
    44) Meggs WJ & Hoffman RS: Fatality resulting from intraventricular vincristine administration. J Toxicol Clin Toxicol 1998; 36(3):243-246.
    45) Michelagnoli MP, Bailey CC, Wilson I, et al: Potential salvage therapy for inadvertent intrathecal administration of vincristine. Br J Haematol 1997; 99:364-367.
    46) Mitchell EP, Killen JY, & Smith FP: Phase II study of PCNU in colorectal carcinoma. Cancer Treat Rep 1981; 65:1129-1130.
    47) Naradzay J & Barish RA: Approach to ophthalmologic emergencies. Med Clin North Am 2006; 90(2):305-328.
    48) National Heart,Lung,and Blood Institute: Expert panel report 3: guidelines for the diagnosis and management of asthma. National Heart,Lung,and Blood Institute. Bethesda, MD. 2007. Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.
    49) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    50) O'Driscoll BR, Hasleton PS, & Taylor PM: Active lung fibrosis up to 17 years after chemotherapy with carmustine (BCNU) in childhood. N Engl J Med 1990; 323:378-382.
    51) O'Marcaigh AS, Johnson CM, & Smithson WA: Successful treatment of intrathecal methotrexate overdose by using ventriculolumbar perfusion and trathecal instillation of carboxypeptidase G2. Mayo Clin Proc 1996; 71:161-165.
    52) Oliverio VT: Pharmacology of the nitrosoureas: An overview. Cancer Treat Rep 1976; 60:703.
    53) Peate WF: Work-related eye injuries and illnesses. Am Fam Physician 2007; 75(7):1017-1022.
    54) Perry JR, Brown MT, & Gockerman JP: Acute leukemia following treatment of malignant glioma. J Neurooncol 1998; 40:39-46.
    55) Peters BG: Technical considerations in the preparation and dispensing of chemotherapy. Top Hosp Pharm Manage 1995; 14:78-88.
    56) Pickrell L & Purvin V: Ischemic optic neuropathy secondary to intracarotid infusion of BCNU. J Clin Neuro Ophthalmol 1987; 7:87-91.
    57) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    58) Product Information: BENDEKA(TM) intravenous injection, bendamustine HCl intravenous injection. Teva Pharmaceuticals (per manufacturer), North Wales , PA, 2015.
    59) Product Information: BICNU(R) IV injection, carmustine IV injection. Ben Venue Laboratories Inc, Bedford, OH, 2007.
    60) Product Information: BiCNU(R) IV injection, carmustine IV injection. Ben Venue Laboratories, Inc., Bedford, OH, 2010.
    61) Product Information: BiCNU(R) IV injection, carmustine IV injection. Bristol-Myers Squibb Company (per FDA), Princeton, NJ, 2011.
    62) Product Information: BiCNU(R) IV injection, carmustine IV injection. Bristol-Myers Squibb Company, Princeton, NJ, 2011a.
    63) Product Information: BiCNU(R), carmustine. Bristol-Myers Squibb Oncology Division, Princeton, NJ, USA, 1999.
    64) Product Information: CeeNU(R) oral capsules, lomustine oral capsules. Bristol-Myers Squibb Company (per DailyMed), Princeton, NJ, 2010.
    65) Product Information: CeeNU(R) oral capsules, lomustine oral capsules. Bristol-Myers Squibb Company, Princeton, NJ, 2009.
    66) Product Information: GLEOSTINE(R) oral capsules, lomustine oral capsules. NextSource Biotechnology, LLC (per FDA), Miami, FL, 2016.
    67) Product Information: GLIADEL(R) WAFER wafer implant, carmustine wafer implant. Arbor Pharmaceuticals, LLC (per FDA), Atlanta, GA, 2013.
    68) Product Information: TREANDA(R) IV injection, bendamustine hcl IV injection. Cephalon,Inc, Frazer, PA, 2008.
    69) Product Information: TREANDA(R) IV injection, bendamustine hydrochloride IV injection. Cephalon Inc, Frazer, PA, 2010.
    70) Product Information: TREANDA(R) intravenous injection, bendamustine HCl intravenous injection. Cephalon, Inc. (per FDA), Frazer, PA, 2012.
    71) Product Information: TREANDA(R) intravenous injection, bendamustine HCl intravenous injection. Teva Pharmaceuticals USA, Inc. (per FDA), North Wales, PA, 2013.
    72) Product Information: ZANOSAR(R) powder for IV solution, streptozocin powder for IV solution. Sicor Pharmaceuticals Inc., Irvine, CA, 2003.
    73) Product Information: Zanosar(R), streptozocin. Pharmacia & Upjohn, Inc, Kalamazoo, MI, 1997.
    74) Product Information: Zanosar(R), streptozocin. Pharmacia and Upjohn Co., Kalamazoo, MI, 2003.
    75) RTECS : Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires 1989; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    76) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    77) Schmitz N & Diehl V: Carmustine and the lungs. Lancet 1997; 349:1712-1713.
    78) Shepard KV, Larson R, & Le Beau MM: Acute leukemia occurring after radiotherapy and chemotherapy with a nitrosourea, PCNU. Invest New Drugs 1988; 6:121-124.
    79) Shingleton BJ, Bienfang DC, & Albert DM: Ocular toxicity associated with high-dose carmustine. Arch Ophthalmol 1983; 100:1766-1772.
    80) Smith AC: The pulmonary toxicity of nitrosoureas. Pharmacol Ther 1989; 41:443-460.
    81) Smith DC, Gerson SL, & Liu L: Carmustine and streptozocin in refractory melanoma: an attempt at modulation of O(6)-alkylguanine-DNA-alkyltransferase. Clin Cancer Res 1996; 2:1129-1134.
    82) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    83) Stone MD & Richardson MG: Pulmonary toxicity of lomustine. Cancer Treat Rep 1987; 71:786-787.
    84) Syrkin AB & Gorbacheva LB: The biochemical mechanisms of the action of N-alkyl-N-nitrosoureas. The possible reasons for drug resistance to these compounds. Eksp Klin Farmakol 1996; 59:69-75.
    85) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.
    86) Trent KC, Myers L, & Moreb J: Multiorgan failure associated with lomustine overdose. Ann Pharmacother 1995; 29:384-386.
    87) Weinstein AS, Diener-West M, & Nelson DF: Pulmonary toxicity of carmustine in patients treated for malignant glioma. Cancer Treat Rep 1986; 70:943-946.
    88) Weiss RB, Poster DS, & Penta JS: The nitrosoureas and pulmonary toxicity. Cancer Treat Rev 1981; 8:111-125.
    89) Widemann BC, Balis FM, Shalabi A, et al: Treatment of accidental intrathecal methotrexate overdose with intrathecal carboxypeptidase G2. J Nat Cancer Inst 2004; 96(20):1557-1559.
    90) Wilson WB, Perez GM, & Kleinschmidt-Demasters BK: Sudden onset of blindness in patients treated with oral CCNU and low-dose cranial irradiation. Cancer 1987; 59:901-907.