MECHLORETHAMINE

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) 2,2'-Dichloro-n-methyldiethylamine
2) 2,2'-Dichlorodiethyl-methylamine
3) beta,beta'-Dichlorodiethyl-n-methylamine
4) bis(beta-Chloroethyl)methylamine
5) bis(2-Chloroethyl)methylamine
6) Caryolysin
7) Chlormethine
8) Cloramin
9) di(2-Chloroethyl)methylamine
10) Dichlor amine
11) Dichloren
12) Diethylamine, 2,2'-dichloro-n-methyl-
13) Embichin
14) HN2
15) HN-2
16) MBA
17) Mecloretamina
18) Methylbis(beta-chloroethyl)amine
19) Methyldi(2-chloroethyl)amine
20) Mustargen
21) Mustine
22) N-Methyl-bis(2-chloroethyl)amine
23) N-Methyl-lost
24) N-Methyl-2,2'-dichlorodiethylamine
25) n,n-bis(2-Chloroethyl)methylamine
26) T-1024
27) TL 146
28) ENT 25294
29) Molecular Formula: C5-H11-Cl2-N
30) NIOSH/RTECS IA 1750000
31) NSC 762
32) CAS 51-75-2
33) CAS 55-86-7 (Hydrochloride)
34) References: RTECS, 1988
35) CHLORAMIN
36) CHLORAMINE (CAS 51-75-2)

1.2.1) MOLECULAR FORMULA
1) C5-H11-Cl2-N
2) C5H11Cl2N HCl

Available Forms Sources

1) Mechlorethamine is available as powder vials containing 10 mg of mechlorethamine hydrochloride, provided in treatment sets of 4 vials (Prod Info Mustargen(R) intravenous injection, 2009).
2) Mechlorethamine is available as mechlorethamine 0.016% w/w gel (equivalent to 0.02% mechlorethamine hydrochloride) in 60 g tubes (Prod Info VALCHLOR(TM) topical gel, 2013).

1) Mechlorethamine is a nitrogen mustard prepared by the action of thionyl chloride on 2,2'-(methylimino)diethanol in trichloroethylene. It was developed as a gas warfare agent (Budavari, 2000; HSDB , 2002; Sittig, 1991).

1) Mechlorethamine gel is indicated for the topical treatment of stage IA and IB mycosis fungoides-type cutaneous T-cell lymphoma in patients who have received prior skin-directed therapy (Prod Info VALCHLOR(TM) topical gel, 2013).
2) Mechlorethamine is indicated intrapleurally, intraperitoneally, or intrapericardially for the palliative treatment of metastatic carcinoma resulting in effusion. Intravenous mechlorethamine is indicated for the palliative treatment of mycosis fungoides, stages III and IV Hodgkin disease, bronchogenic carcinoma, chronic lymphocytic leukemia (CLL), chronic myelocytic leukemia (CML), lymphosarcoma, and polycythemia vera (Prod Info Mustargen(R) intravenous injection, 2009).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Intravenous mechlorethamine is indicated for the palliative treatment of mycosis fungoides, stages III and IV Hodgkin disease, bronchogenic carcinoma, chronic lymphocytic leukemia (CLL), chronic myelocytic leukemia (CML), lymphosarcoma, and polycythemia vera. Mechlorethamine is also used intrapleurally, intraperitoneally, or intrapericardially for the palliative treatment of metastatic carcinoma resulting in effusion. Mechlorethamine gel is used for the topical treatment of stage IA and IB mycosis fungoides-type cutaneous T-cell lymphoma in patients who have received prior skin-directed therapy.
B) PHARMACOLOGY: Mechlorethamine hydrochloride, also known as HN2 hydrochloride, is an antineoplastic agent that is nitrogen analog of sulfur mustard. As a biologic alkylating agent, it exerts its cytotoxic effects by inhibiting the rapid proliferation of cancer cells.
C) TOXICOLOGY: Overdose effects are seen primarily in rapidly dividing cells (eg, bone marrow, gastrointestinal tract).
D) EPIDEMIOLOGY: Overdose is rare.
E) WITH THERAPEUTIC USE

1) INTRAVENOUS: Nausea and vomiting (onset: 1 to 3 hours; duration: 8 to 24 hours), anorexia, thrombosis, thrombophlebitis, maculopapular skin eruption, erythema multiforme, extravasation injury, jaundice, alopecia, vertigo, hearing loss, tinnitus, weakness, headache, drowsiness, vertigo, lightheadedness, seizures, progressive muscle paralysis, paresthesia, cerebral degeneration, coma, and hypersensitivity reactions, including anaphylaxis. HEMATOLOGIC EFFECTS: Severe myelosuppression has occasionally occurred and may be observed for up to 50 days or more after initiating mechlorethamine therapy. Lymphocytopenia (onset within 24 hours), granulocytopenia (onset within 6 to 8 days and lasts for 10 days to 3 weeks), thrombocytopenia (onset and duration, similar to granulocyte levels), persistent pancytopenia, and hemorrhagic complications have been reported. DERMAL: COMMON (5% or greater): Dermatitis, pruritus, bacterial skin infection, skin ulceration or blistering, and hyperpigmentation.

F) WITH POISONING/EXPOSURE

1) Overdose data are limited. Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses. Severe leukopenia, anemia, thrombocytopenia, and a hemorrhagic diathesis with subsequent delayed bleeding may develop following total doses higher than 0.4 mg/kg of body weight for a single course. Exposure of the eyes to mechlorethamine results in inflammation, pain, burning, photophobia, and blurred vision. Irreversible anterior eye injury and blindness may occur.

0.2.20)

A) Mechlorethamine is classified as FDA pregnancy category D. There are no adequate and well-controlled studies of mechlorethamine use in pregnancy women. However, at least 2 cases of congenital malformations have been reported among 6 women who received mechlorethamine during pregnancy. Mechlorethamine was teratogenic in animals after a single subQ dose. Women should avoid pregnancy during mechlorethamine therapy. Inform patients of these risks if mechlorethamine is used during pregnancy or if a patient becomes pregnant during treatment with this drug

0.2.21)

A) Mechlorethamine is a probable carcinogen in humans.

Laboratory Monitoring

Treatment Overview

0.4.3)

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)

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)

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).
2) Use of a 2% to 4% sodium thiosulfate solution has been recommended to decontaminate the SKIN ONLY (see main section for preparation).

0.4.6)

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.

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.

C) DECONTAMINATION

1) PREHOSPITAL: INGESTION: Exposure of the oral mucosa to mechlorethamine gel may result in pain, redness, and ulceration which may be severe. Patients may already have severe vomiting and gastrointestinal irritation. Administer activated charcoal if the ingestion is recent, the patient is not vomiting, and is able to maintain their airway. GI decontamination is not indicated after parenteral mechlorethamine exposure. DERMAL: Wash skin thoroughly with soap and water. OCULAR: Irrigate exposed eyes for at least 15 minutes.
2) HOSPITAL: INGESTION: Administer activated charcoal if the ingestion is recent, the patient is not vomiting, and is able to maintain their airway. GI decontamination is not indicated after parenteral mechlorethamine exposure. DERMAL: Wash skin thoroughly with soap and water; 2% sodium thiosulfate may be useful for decontaminating the skin. OCULAR: Irrigate exposed eyes for at least 15 minutes.

D) INTRATHECAL INJECTION

1) No clinical reports available, information 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). For large overdoses, 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). Albumin 5% or fresh frozen plasma (25 mL FFP/liter NS or LR) has also been used for perfusion. Give dexamethasone 4 mg IV every 6 hours to prevent arachnoiditis.

E) AIRWAY MANAGEMENT

1) Maintain open airway and perform orotracheal intubation if there are symptoms of airway or pulmonary injury.

F) ANTIDOTE

1) None.

G) 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. 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.

H) 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).

I) NAUSEA AND VOMITING

1) Treat severe nausea and vomiting with agents from several different classes. For example: 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).

J) STOMATITIS

K) EXTRAVASATION INJURY

1) If extravasation occurs, stop the infusion. Disconnect the IV tubing, but leave the cannula or needle in place. Attempt to aspirate the extravasated drug from the needle or cannula. If possible, withdraw 3 to 5 mL of blood and/or fluids through the needle/cannula. Administer sodium thiosulfate (see dosing below). Elevate the affected area. Ice packs can be applied for 15 to 20 minutes at least 4 times daily. Administer analgesia for severe pain. If pain persists, there is concern for compartment syndrome, or injury is apparent, an early surgical consult should be considered. Close observation of the extravasated area is suggested. If tissue sloughing, necrosis or blistering occurs, treat as a chemical burn (ie, antiseptic dressings, silver sulfadiazine, antibiotics when applicable). Surgical or enzymatic debridement may be required. Risk of infection is increased in chemotherapy patients with reduced neutrophil count following extravasation. Consider culturing any open wounds. Monitor the site for the development of cellulitis, which may require antibiotic therapy. SODIUM THIOSULFATE: Prepare a 0.17 moles/L (1/6 molar) solution by mixing 4 mL sodium thiosulfate 10% weight/volume with 6 mL sterile water for injection. Inject 2 mL subQ of sodium thiosulfate solution for each mg (mL) of mechlorethamine suspected to have extravasated into extravasation site using a 25-gauge or smaller needle (the needle is changed with each injection). Another source recommended the following dosing: inject 3 to 10 mL subQ into extravasation site.

L) HYPERSENSITIVITY REACTION

1) MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.

M) PATIENT DISPOSITION

1) HOME CRITERIA: There is no data to support home management.
2) ADMISSION CRITERIA: Patients with mechlorethamine overdose need to be admitted, as toxicity develops over several days. 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.
3) CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with mechlorethamine overdose. In addition, consultation with an infectious diseases physician with expertise in the management of neutropenic patients with infections is strongly recommended.
4) TRANSFER CRITERIA: Patients with large overdoses may benefit from early transfer to a cancer treatment or bone marrow transplant center.

N) 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 mechlorethamine may have severe comorbidities and may be receiving other drugs that may produce synergistic effects (ie, myelosuppression).

O) PHARMACOKINETICS

1) Mechlorethamine (injected as the hydrochloride) undergoes rapid chemical transformation. It combines with water or other reactive compound cells, which results in the drug no longer being present in the active form several minutes after drug administration.

P) DIFFERENTIAL DIAGNOSIS

1) Includes other agents that may cause myelosuppression.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Heent

3.4.3)

A) WITH POISONING/EXPOSURE

1) Exposure of the eyes to mechlorethamine results in inflammation, pain, burning, photophobia, and blurred vision. Irreversible anterior eye injury and blindness may occur (Prod Info VALCHLOR(TM) topical gel, 2013).
2) The nitrogen mustard gases, including mechlorethamine, when in contact with the eye are severely damaging, acting similar to the sulfur mustard gases, but more rapidly and with greater tendency to injure deeper ocular structures, particularly the iris and lens (Grant & Schuman, 1993).
3) CASE SERIES: Nine patients experienced eye pain, photophobia, excessive tearing, and blurred vision after exposure to hot chemical fluid (70 degree C) containing 2% to 3% nitrogen mustard. In one patient, physical examination showed bulbar conjunctival congestion (Wang & Xia, 2007).

B) ANIMAL STUDIES

1) In one animal study, the bilateral application of 1% nitrogen mustard to the eye of rabbits resulted in an intraocular pressure elevation within the first 6 hours followed by ocular hypotony, miosis, palpebral closure, conjunctival vasodilation, edema and an elevation of aqueous proteins. Topical application of diltiazem, before the administration of 1% nitrogen mustard, reduced chemical irritation of the eyes (Gonzalez et al, 1995).
2) This compound is a severe eye irritant in rabbits at a dose of 400 mcg (RTECS , 2002).

3.4.4)

A) WITH THERAPEUTIC USE

1) OTOTOXICITY: Mechlorethamine is ototoxic, producing hearing loss in cancer patients (Prod Info Mustargen(R) intravenous injection, 2009).
2) TINNITUS has been seen as a sign of delayed toxicity following therapy (epa, 1985; Prod Info Mustargen(R) intravenous injection, 2009).

B) ANIMAL STUDIES

1) Cats treated IV with 0.5 to 3 mg/kg showed severe hearing loss for frequencies below 500 Hz which was accompanied by loss of hair cells in the basal and middle turns of the cochlea (Cummings, 1968).

Cardiovascular

3.5.2)

A) THROMBOPHLEBITIS

1) WITH THERAPEUTIC USE

a) Thrombophlebitis may occur from the direct contact of mechlorethamine with the intima of the injected vein (Prod Info Mustargen(R) intravenous injection, 2009).

Respiratory

3.6.2)

A) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) Two of 9 patients exposed to hot chemical fluid (70 degree C) containing 2% to 3% nitrogen mustard developed lung injuries. One patient, a 48-year-old man experienced acute lung edema and inflammation with evidence of moist rales. On the fourth day, tracheotomy and mechanical ventilation were performed because of impaired oxygenation. Bronchoscopy revealed mucosal edema leading to the partial obstruction of respiratory tract airway. On the 12th day, he coughed out three pieces of tissue from the respiratory mucosa. Following supportive care, he recovered one month after injury without further airway sequelae (Wang & Xia, 2007).

Neurologic

3.7.2)

A) CENTRAL NERVOUS SYSTEM FINDING

1) WITH THERAPEUTIC USE

a) CNS effects following the intravenous administration include weakness, headache, drowsiness, vertigo, lightheadedness, convulsions, progressive muscle paralysis, paresthesia, cerebral degeneration, coma, and death (HSDB , 2002).

B) FEVER

1) WITH THERAPEUTIC USE

a) Hyperpyrexia was seen on two occasions in a patient with Hodgkin's disease who had received intravenous mechlorethamine; an acute rise in the cerebrospinal fluid pressure occurred (Bethlenfalvay & Bergin, 1972).

C) COMA

1) WITH THERAPEUTIC USE

a) Coma was seen on two occasions in a patient with Hodgkin's disease who had received intravenous mechlorethamine; an acute rise in the cerebrospinal fluid pressure occurred (Bethlenfalvay & Bergin, 1972).

D) NEUROPATHY

1) WITH THERAPEUTIC USE

a) Neurotoxicity appears to be a problem only when high doses and regional perfusion methods are used (HSDB , 2002; Weiss et al, 1974).

Gastrointestinal

3.8.2)

A) NAUSEA AND VOMITING

1) WITH THERAPEUTIC USE

a) Nausea and vomiting may occur because of destruction of the intestinal epithelium (Gilman et al, 1980) and usually develops 1 to 3 hours after infusion (Prod Info Mustargen(R) intravenous injection, 2009).

2) WITH POISONING/EXPOSURE

a) Nine patients experienced nausea and vomiting after exposure to hot chemical fluid (70 degree C) containing 2% to 3% nitrogen mustard (Wang & Xia, 2007).

B) LOSS OF APPETITE

1) WITH THERAPEUTIC USE

a) Anorexia has been reported following the intravenous administration of mechlorethamine (Prod Info Mustargen(R) intravenous injection, 2009).

C) STOMATITIS

1) WITH THERAPEUTIC USE

a) Exposure of the oral mucosa to mechlorethamine resulted in pain, redness, and ulceration which may be severe (Prod Info VALCHLOR(TM) topical gel, 2013).

3.8.3)

A) ANIMAL STUDIES

1) MALABSORPTION

a) GLUCOSE ABSORPTION: Mechlorethamine inhibited the absorption of glucose through the small intestine in rats. This loss was attributed to loss of intestinal tissue because the absorption was not affected on the basis of tissue weight (Leibowitz & Merker, 1971).

Hepatic

3.9.2)

A) ABNORMAL LIVER FUNCTION

1) WITH THERAPEUTIC USE

a) No significant changes occurred in levels of serum urea nitrogen, serum protein, serum bilirubin, alkaline phosphatase, and glutamine oxaloacetic and pyruvic transaminases among 23 male patients receiving mechlorethamine for bronchogenic carcinoma (Sensenbrenner & Owens, 1967).

2) WITH POISONING/EXPOSURE

a) Increased gamma-glutamultransferase (gamma-GT), a marker of oxidative stress, has been reported in patients with tissue injury following exposure to hot chemical fluid (70 degree C) containing 2% to 3% nitrogen mustard (Wang & Xia, 2007).

B) JAUNDICE

1) WITH THERAPEUTIC USE

a) Jaundice has infrequently been reported following the intravenous administration of mechlorethamine (Prod Info Mustargen(R) intravenous injection, 2009).

Genitourinary

3.10.2)

A) SEMEN EXAM: ABNORMAL

1) WITH THERAPEUTIC USE

a) Impaired spermatogenesis including germinal aplasia and swelling have been found as signs of delayed toxicity in cancer chemotherapy patients (epa, 1985).

3.10.3)

A) ANIMAL STUDIES

1) SEMEN ABNORMAL

a) Impaired spermatogenesis and abnormal sperm morphology have been induced in MICE (RTECS , 2002).

Hematologic

3.13.2)

A) HEMORRHAGE

1) WITH THERAPEUTIC USE

a) Hemorrhage may occur secondary to thrombocytopenia during chemotherapy (Gilman et al, 1980; Prod Info Mustargen(R) intravenous injection, 2009).
b) Hemorrhagic complications may be caused by hyperheparinemia. Erythrocyte and hemoglobin concentrations may rarely be decreased during the first 2 weeks of therapy (Prod Info Mustargen(R) intravenous injection, 2009).

2) WITH POISONING/EXPOSURE

B) LEUKOPENIA

1) WITH THERAPEUTIC USE

a) A rapid decline in the total white cell count occurred in 23 male patients who had received mechlorethamine for chemotherapy against bronchogenic carcinoma (Sensenbrenner & Owens, 1967).

2) WITH POISONING/EXPOSURE

a) Severe leukopenia, anemia, thrombocytopenia, and a hemorrhagic diathesis with subsequent delayed bleeding may develop following total doses higher than 0.4 mg/kg of body weight for a single course (Prod Info Mustargen(R) intravenous injection, 2009).
b) Decreased white blood cell counts developed in 3 patients two days after exposure to hot chemical fluid (70 degree C) containing 2% to 3% nitrogen mustard. All three patients were treated with granulocyte-macrophage colony stimulating factor (GM-CSF) on the second day, but it took approximately 7 to 10 days for white blood cells to increase. The decrease in white blood cells resulted from the loss of neutrophils, while the proportion of lymphocytes increased. One patient with severe burns had complicated hospital course with multiple organ dysfunction and Pseudomonas aeruginosa infection in the lung. He died on the 11th hospital day (Wang & Xia, 2007).

C) MYELOSUPPRESSION

1) WITH THERAPEUTIC USE

a) Severe myelosuppression has occasionally occurred, especially in patients with widespread disease and debility and in patients previously treated with other antineoplastic agents or x-ray. Depression of the hematopoietic system may be observed for up to 50 days or more after initiating mechlorethamine therapy (Prod Info Mustargen(R) intravenous injection, 2009).
b) Bone marrow depression occurred in cancer patients receiving mechlorethamine (Sensenbrenner & Owens, 1967). Persons with pre-existing bone marrow injury or primary hematological disturbance may be profoundly sensitive to the hematopoietic depressive effects of mechlorethamine (Karnofsky, 1958).

2) WITH POISONING/EXPOSURE

a) Severe leukopenia, anemia, thrombocytopenia, and a hemorrhagic diathesis with subsequent delayed bleeding may develop following total doses higher than 0.4 mg/kg of body weight for a single course (Prod Info Mustargen(R) intravenous injection, 2009).
b) Myelosuppression (decreased platelets and white blood cells) developed in 3 patients two days after exposure to hot chemical fluid (70 degree C) containing 2% to 3% nitrogen mustard. All three patients were treated with granulocyte-macrophage colony stimulating factor (GM-CSF) on the second day, but it took approximately 7 to 10 days for white blood cells and platelets to increase. One patient with severe burns had complicated hospital course with multiple organ dysfunction and Pseudomonas aeruginosa infection in the lung. He died on the 11th hospital day (Wang & Xia, 2007).

D) LYMPHOCYTOPENIA

1) WITH THERAPEUTIC USE

a) Lymphocytopenia generally develops within 24 hours following therapeutic drug administration, with significant granulocytopenia developing 6 to 8 days later and lasting for 10 to 21 days (Prod Info Mustargen(R) intravenous injection, 2009).

E) GRANULOCYTOPENIC DISORDER

1) WITH THERAPEUTIC USE

a) Severe granulocytopenia may infrequently develop within 6 to 8 days and lasts for 10 days to 3 weeks (Prod Info Mustargen(R) intravenous injection, 2009).

F) PANCYTOPENIA

1) WITH THERAPEUTIC USE

a) Persistent pancytopenia has been reported (Prod Info Mustargen(R) intravenous injection, 2009).

G) DECREASED PLATELET COUNT

1) WITH THERAPEUTIC USE

a) Thrombocytopenia may develop within 6 to 8 days and lasts for 10 days to 3 weeks. Severe thrombocytopenia have been reported. Patients have developed bleeding from the gums and GI tract, petechiae, and small subcutaneous hemorrhages. These effects were transient and disappeared in most cases (Prod Info Mustargen(R) intravenous injection, 2009).

2) WITH POISONING/EXPOSURE

a) Severe leukopenia, anemia, thrombocytopenia, and a hemorrhagic diathesis with subsequent delayed bleeding may develop following total doses higher than 0.4 mg/kg of body weight for a single course (Prod Info Mustargen(R) intravenous injection, 2009).
b) Low platelet counts developed in 3 patients 2 days after exposure to hot chemical fluid (70 degree C) containing 2% to 3% nitrogen mustard. It took approximately 7 to 10 days for platelets to increase. One patient with severe burns had complicated hospital course with multiple organ dysfunction and Pseudomonas aeruginosa infection in the lung. He died on the 11th hospital day (Wang & Xia, 2007).

H) DISORDER OF IRON METABOLISM

1) WITH THERAPEUTIC USE

a) Elevated serum iron binding capacity occurred in patients receiving mechlorethamine (Sensenbrenner & Owens, 1967).

I) THROMBOSIS

1) WITH THERAPEUTIC USE

a) Thrombosis may occur from the direct contact of mechlorethamine with the intima of the injected vein (Prod Info Mustargen(R) intravenous injection, 2009).

3.13.3)

A) ANIMAL STUDIES

1) MARROW DEPRESSION

a) MICE: Bone marrow depression occurred in mice receiving mechlorethamine (Trethewie, 1979).
b) MICE: Mechlorethamine did not produce residual injury to the bone marrow of mice when injected at 1.5 to 3 mg/kg weekly for 12 weeks (Trainor et al, 1979), or at a single IV dose of 4 mg/kg (Sharp et al, 1975).

2) ENDOCRINE DISORDER

a) MICE: THYMUS size was increased after a single IV injection of mechlorethamine in mice, and cyclical changes in thymic weight were seen during 100 days post-treatment, possibly because of induced synchronization in the thymic hematopoietic stem cells (Sharp et al, 1975).

Dermatologic

3.14.2)

A) DISCOLORATION OF SKIN

1) WITH THERAPEUTIC USE

a) Hyperpigmentation of the skin, of any grade, was reported in 5% of patients administered mechlorethamine 0.016% topical gel (n=128) compared with 7% of patients administered Aquaphor(R)-based mechlorethamine 0.016% ointment (n=127) in a randomized, observer-blinded trial of adults with mycosis fungoides-type cutaneous T-cell lymphoma (Prod Info VALCHLOR(TM) topical gel, 2013).
b) Hyperpigmentation was seen in the skin of patients treated with topical mechlorethamine for mycosis fungoides and psoriasis (Flaxman et al, 1973).
c) The mechanism of hyperpigmentation involved an increase in the number of melanosomes in dark- and light-skinned individuals, and an additional change in the arrangement and distribution in light-skinned individuals (Flaxman et al, 1973).

B) BULLOUS ERUPTION

1) WITH THERAPEUTIC USE

a) Mechlorethamine is a powerful vesicant (Dorr & Fritz, 1980). Contact of the skin, eyes or mucous membranes with the powder or a solution may result in severe blistering.
b) Skin ulceration or blistering, of any grade, was reported in 6% of patients administered mechlorethamine 0.016% topical gel (n=128) compared with 5% of patients administered Aquaphor(R)-based mechlorethamine 0.016% ointment (n=127) in a randomized, observer-blinded trial of adults with mycosis fungoides-type cutaneous T-cell lymphoma. Moderately-severe or severe skin ulceration or blistering occurred in 3% and 2% of patients, respectively (Prod Info VALCHLOR(TM) topical gel, 2013).

2) WITH POISONING/EXPOSURE

a) Mechlorethamine has the greatest blistering power of the nitrogen mustards in vapor form, but is intermediate as a liquid blistering agent (pp 3-10).

C) MACULOPAPULAR ERUPTION

1) WITH THERAPEUTIC USE

a) Maculopapular skin eruption and erythema multiforme have been reported following the intravenous administration of mechlorethamine (Prod Info Mustargen(R) intravenous injection, 2009).

D) CONTACT DERMATITIS

1) WITH THERAPEUTIC USE

a) Local bullous reaction (Goday et al, 1990), immediate anaphylactoid or urticarial reaction (Grunnet, 1976; Daughters et al, 1973), and delayed cell-mediated type reaction (Vonderheid, 1984; Avril, 1987) have been associated with topical application for mycosis fungoides.
b) Dermatitis, of any grade, was reported in 56% of patients administered mechlorethamine 0.016% topical gel (n=128) compared with 58% of patients administered Aquaphor(R)-based mechlorethamine 0.016% ointment (n=127) in a randomized, observer-blinded trial of adults with mycosis fungoides-type cutaneous T-cell lymphoma. Moderately-severe or severe dermatitis was reported in 23% and 17% of patients, respectively (Prod Info VALCHLOR(TM) topical gel, 2013)

E) INFECTION OF SKIN AND/OR SUBCUTANEOUS TISSUE

1) WITH THERAPEUTIC USE

a) Bacterial skin infection, of any grade, was reported in 11% of patients administered mechlorethamine 0.016% topical gel (n=128) compared with 9% of patients administered Aquaphor(R)-based mechlorethamine 0.016% ointment (n=127) in a randomized, observer-blinded trial of adults with mycosis fungoides-type cutaneous T-cell lymphoma. Moderately-severe or severe bacterial skin infection occurred in 2% of patients in both treatment groups (Prod Info VALCHLOR(TM) topical gel, 2013).

F) ALOPECIA

1) WITH THERAPEUTIC USE

a) Alopecia has been reported as a delayed effect of therapy (epa, 1985; HSDB , 2002).

G) ITCHING OF SKIN

1) WITH THERAPEUTIC USE

a) Pruritus, of any grade, was reported in 20% of patients administered mechlorethamine 0.016% topical gel (n=128) compared with 16% of patients administered Aquaphor(R)-based mechlorethamine 0.016% ointment (n=127) in a randomized, observer-blinded trial of adults with mycosis fungoides-type cutaneous T-cell lymphoma. Moderately-severe or severe pruritus occurred in 4% and 2% of patients, respectively (Prod Info VALCHLOR(TM) topical gel, 2013).

H) EXTRAVASATION INJURY

1) WITH THERAPEUTIC USE

a) Mechlorethamine is a DNA binding vesicant (Schulmeister, 2011). Extravasation injury may occur following mechlorethamine administration (Prod Info Mustargen(R) intravenous injection, 2009).

I) BURN

1) WITH POISONING/EXPOSURE

a) Nine patients experienced tissue damage after exposure to hot chemical fluid (70 degree C) containing 2% to 3% nitrogen mustard. Before presentation, all patients were washed with water for 20 minutes and were treated with povidone iodine. Four patients were transferred to the Burn Center with 15% to 50% (total body surface area) superficial partial-thickness burn of facial area, trunk and both upper and lower extremities. One patient, a 36-year-old man, presented with a 50% (total body surface area) superficial partial-thickness burn. On the third day, his skin injury worsened and the total burn surface area increased to 60% and the skin damage deepened to deep partial-thickness burns. His hospital course was complicated with multiple organ dysfunction and Pseudomonas aeruginosa infection in the lung. He died on the 11th hospital day (Wang & Xia, 2007).

Endocrine

3.16.2)

A) AMENORRHEA

1) WITH THERAPEUTIC USE

a) Amenorrhea has been reported as a delayed toxic effect in women (Prod Info Mustargen(R) intravenous injection, 2009).

Immunologic

3.19.2)

A) ACUTE ALLERGIC REACTION

1) WITH THERAPEUTIC USE

a) Hypersensitivity reactions, including anaphylaxis, have been reported following the intravenous administration of mechlorethamine (Prod Info Mustargen(R) intravenous injection, 2009).

Reproductive

3.20.1)

3.20.2)

A) CONGENITAL MALFORMATIONS

1) Both successful pregnancies and congenital malformations have been reported after use of combination chemotherapy that included mechlorethamine. Abnormalities reported include hydrocephalus, kidney malformation, oligodactyly, and atrial septal defect (Jones & Weinerman, 1979; Aviles et al, 1991; Zemlickis et al, 1992; Garrett, 1974; Mennuti et al, 1975; Thomas & Andes, 1976).
2) At least 2 cases of congenital malformations have been reported among 6 women who received mechlorethamine during pregnancy (Schardein, 1993).
3) A male child was born with digital defects (four toes on one foot and webbed toes on the other), one malformed ear, bowed tibia, and cerebral hemorrhage to a woman who had received mechlorethamine in combination with vinblastine and procarbazine at two months of pregnancy (Garrett, 1974a).
4) Renal defects occurred in a child after the mother had received combination chemotherapy including mechlorethamine during pregnancy (Mennuti et al, 1975a).
5) These malformations could not be ascribed to mechlorethamine alone because of the combined treatment.

B) ANIMAL STUDIES

1) FETAL MALFORMATION

a) RATS, FERRETS: Single injections of mechlorethamine subQ in rats and ferrets were linked to fetal malformations. In other animals, embryo death and growth retardation occurred following single injections of mechlorethamine subQ (Prod Info VALCHLOR(TM) topical gel, 2013; Prod Info Mustargen(R) intravenous injection, 2009).

2) SKELETAL MALFORMATION

a) RODENTS: Mechlorethamine was teratogenic in RATS and MICE; skeletal malformations were predominant (Muller, 1966).
b) Mechlorethamine was teratogenic in the mouse, rat, rabbit, and ferret (Schardein, 1993).
c) It caused malformations when injected directly into one uterine horn of pregnant RATS but did not appear to affect the fetuses in the other untreated horn; these results suggest that mechlorethamine may cause malformations by acting directly on the fetus (Muller, 1966).

3.20.3)

A) PREGNANCY CATEGORY

1) Mechlorethamine is classified as FDA pregnancy category D (Prod Info VALCHLOR(TM) topical gel, 2013; Prod Info Mustargen(R) intravenous injection, 2009).
2) Pregnancy should be avoided during mechlorethamine therapy. Case reports have described congenital malformations that occurred with prenatal exposure to systemically administered mechlorethamine. Inform patients of these risks if mechlorethamine is used during pregnancy or if a patient becomes pregnant during treatment with this drug (Prod Info VALCHLOR(TM) topical gel, 2013; Prod Info Mustargen(R) intravenous injection, 2009).
3) In general, alkylating agents when given during the first trimester are believed to cause slight increases in the risk of congenital malformations, but when given during the second or third trimesters are believed to only increase the risk of growth retardation (Glantz, 1994). Further investigation of these associations is needed. Depending upon the nature of the malignancy, the progression of the disease, and how advanced the gestation, chemotherapy can in some cases be deferred allowing fetal maturation to occur, and in some cases earlier-than-term delivery provides an acceptable compromise between maternal and fetal risk (Cunningham et al, 1993; Doll et al, 1988). Because apparently normal infants have been born despite exposure to virtually any antineoplastic agent or combination of agents, it should not be assumed that termination of pregnancy is necessary (unless it is in the best interest of the health of the mother), and the decision of the parents must take into account their desire to have children (Mitchell, 1995).

3.20.4)

A) BREAST MILK

1) It is not known whether mechlorethamine is excreted into human breast milk, and the potential for adverse effects in the nursing infant from exposure to the drug are unknown. Due to the lack of human safety information, it is recommended to discontinue nursing or to discontinue mechlorethamine in the nursing mother. The importance of therapy to the mother should be taken into consideration (Prod Info VALCHLOR(TM) topical gel, 2013; Prod Info Mustargen(R) intravenous injection, 2009).

3.20.5)

A) FERTILITY DECREASED FEMALE

1) Treatment with mechlorethamine IV has been linked with delayed menses, oligomenorrhea, and temporary or permanent amenorrhea (Prod Info VALCHLOR(TM) topical gel, 2013).

B) ANIMAL STUDIES

1) FERTILITY DECREASED FEMALE

a) Decreased fertility has developed in female rats (HSDB , 2000).

2) SEMEN ABNORMAL

a) In MOUSE studies the observed paternal toxic effect included changes in spermatogenesis and sperm morphology (HSDB , 2002).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS51-75-2 (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: Nitrogen mustard
b) Carcinogen Rating: 2A

1) The agent (mixture) is probably carcinogenic to humans. The exposure circumstance entails exposures that are probably carcinogenic to humans. This category is used when there is limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals. In some cases, an agent (mixture) may be classified in this category when there is inadequate evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals and strong evidence that the carcinogenesis is mediated by a mechanism that also operates in humans. Exceptionally, an agent, mixture or exposure circumstance may be classified in this category solely on the basis of limited evidence of carcinogenicity in humans.

3.21.2)

A) Mechlorethamine is a probable carcinogen in humans.

3.21.3)

A) SKIN CANCER

1) Non-melanoma skin cancers occurred, during the clinical trial or within the 1-year follow-up period, in 2% of patients administered the meclorethamine 0.016% topical gel (n=128) and in 6% of patients administered the Aquaphor(R)-based mechlorethamine 0.02% ointment (n=127) in the treatment of mycosis fungoides-type cutaneous T-cell lymphoma. Prior therapies known to cause non-melanomas skin cancers were reported in some patients (Prod Info VALCHLOR(TM) topical gel, 2013).

B) OTHER CANCERS

1) Mechlorethamine has been associated with an increased incidence of secondary malignancies, especially in patients treated with combination chemotherapy regimens (ASHP, 1986).

C) SKIN CARCINOMA

1) SUSPECT HUMAN CARCINOGEN: A high incidence of skin cancers was found in patients who had been treated with mechlorethamine for mycosis fungoides (Du Vivier et al, 1978; Kravitz & McDonald, 1978; RTECS , 1988; HSDB , 2000).

3.21.4)

A) SKIN CARCINOMA

1) In mice, squamous cell carcinomas were reported in 9 of 33 animals treated dermally (Zackheim & Smuckler, 1980).
2) Dermatitis, alopecia and scarring occurred at high incidence; inflammation may have facilitated penetration of the agent and establishment of tumors; a non-irritating dose was not established (Zackheim & Smuckler, 1980).
3) Mechlorethamine at subcarcinogenic doses on the skin enhanced the carcinogenicity of ultraviolet light in MICE (Epstein, 1984).
4) CHRONIC TOXICITY - In rats, carcinoma developed after intravenous administration for 1 year (RTECS , 1988; HSDB , 2000).
5) EQUIVOCAL TUMOR AGENT IN MICE when given on the skin for 14 or 23 weeks or IP for 39 weeks (RTECS , 1988; HSDB , 2000).

B) MALIGNANCY

1) Mechlorethamine has resulted in thymic lymphomas and pulmonary adenomas in mice injected with 4 IV doses of mechlorethamine 2.4 mg/kg 0.1% solution at 2-week intervals. Topical mechlorethamine resulted in squamous cell tumors in mice administered doses of 4 mg/kg for up to 33 weeks (Prod Info VALCHLOR(TM) topical gel, 2013).

C) NEOPLASM

1) NEOPLASTIC AGENT IN MICE when given IV for 42 days (RTECS , 1988).

Genotoxicity

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Mechlorethamine plasma concentrations are not clinically useful or readily available.
B) Monitor vital signs, serum electrolytes, renal function and liver enzymes in symptomatic patients.
C) Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery.
D) 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.
E) Clinically evaluate patients for the development of mucositis.
F) Monitor arterial blood gases and/or pulse oximetry, chest radiograph, and pulmonary function tests in patients with respiratory symptoms.

4.1.2)

A) HEMATOLOGIC

a) Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery.

4.1.4)

A) OTHER

1) MONITORING

a) Monitor audiograms if ototoxicity is suspected. In circumstances where ototoxicity is possible, obtain a baseline audiogram for comparison BEFORE beginning mechlorethamine therapy.

Methods

1) Colorimetric reaction with 4-(4'-nitrobenzyl)pyridine can be used to determine free mechlorethamine or its hydrochloride (IARC, 1975).
2) It can be measured in biological materials by a fluorometric method down to 0.02 mcg/mL (IARC, 1975).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients with mechlorethamine overdose need to be admitted, as toxicity develops over several days. 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.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with mechlorethamine overdose. In addition, consultation with an infectious diseases physician with expertise in the management of neutropenic patients with infections is strongly recommended.

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.

6.3.2)

6.3.2.1) ADMISSION CRITERIA/PARENTERAL

6.3.2.2) HOME CRITERIA/PARENTERAL

A) There is no data to support home management.

6.3.2.3) CONSULT CRITERIA/PARENTERAL

6.3.2.4) PATIENT TRANSFER/PARENTERAL

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

Monitoring

Oral Exposure

6.5.1)

A) SUMMARY

1) INGESTION: Exposure of the oral mucosa to mechlorethamine gel may result in pain, redness, and ulceration which may be severe. Patients may already have severe vomiting and gastrointestinal irritation. Administer activated charcoal if the ingestion is recent, the patient is not vomiting, and is able to maintain their airway. GI decontamination is not indicated after parenteral mechlorethamine exposure. DERMAL: Wash skin thoroughly with soap and water. OCULAR: Irrigate exposed eyes for at least 15 minutes.

B) DILUTION

1) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).

C) 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)

A) SUMMARY: Exposure of the oral mucosa to mechlorethamine gel may result in pain, redness, and ulceration which may be severe. Patients may already have severe vomiting and gastrointestinal irritation. Administer activated charcoal if the ingestion is recent, the patient is not vomiting, and is able to maintain their airway. GI decontamination is not indicated after parenteral mechlorethamine exposure.
B) 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.

C) CHARCOAL DOSE

1) 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).

a) 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).

2) ADVERSE EFFECTS/CONTRAINDICATIONS

a) 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.
b) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

D) DILUTION

6.5.3)

A) SUPPORT

1) MANAGEMENT OF MILD TO MODERATE TOXICITY: 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.
2) MANAGEMENT OF SEVERE TOXICITY: 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.

B) MONITORING OF PATIENT

1) Mechlorethamine plasma concentrations are not clinically useful or readily available.
2) Monitor vital signs, serum electrolytes, renal function and liver enzymes in symptomatic patients.
3) Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery.
4) 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.
5) Clinically evaluate patients for the development of mucositis.
6) Monitor arterial blood gases and/or pulse oximetry, chest radiograph, and pulmonary function tests in patients with respiratory symptoms.

C) MYELOSUPPRESSION

1) Severe myelosuppression has occasionally occurred and may be observed for up to 50 days or more after initiating mechlorethamine therapy. Lymphocytopenia (onset within 24 hours), granulocytopenia (onset within 6 to 8 days and lasts for 10 days to 3 weeks), thrombocytopenia (onset and duration, similar to granulocyte levels), persistent pancytopenia, and hemorrhagic complications have been reported (Prod Info Mustargen(R) intravenous injection, 2009).
2) 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 mechlorethamine overdose.
3) 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.

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 by continuous subQ or IV infusion (Prod Info NEUPOGEN(R) IV, subcutaneous injection, 2010). According to the American Society of Clinical Oncology (ASCO), treatment should be continued until the ANC is at least 2 to 3 x 10(9)/L (Smith et al, 2006).
2) SARGRAMOSTIM: The recommended dose is 250 mcg/m(2) day administered intravenously over a 4-hour period. Treatment should be continued until the ANC is at least 2 to 3 x 10(9)/L (Smith et al, 2006).

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 of 4 or 24 hours, or as a continuous 24 hour subQ infusion. The daily dose of filgrastim should be titrated based on neutrophil response (ie, absolute neutrophil count (ANC)) as follows (Prod Info NEUPOGEN(R) IV, subcutaneous injection, 2010):

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) IV, subcutaneous injection, 2010).
d) SARGRAMOSTIM: This agent has been indicated for the acceleration of myeloid recovery in patients after autologous or allogenic BMT. Usual dosing is 250 mcg/m(2)/day as a 2-hour IV infusion. Duration is based on neutrophil recovery (Prod Info LEUKINE(R) subcutaneous, IV injection, 2008).

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) 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); 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: Adults: 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; MAXIMUM: 10 mg/dose (Dupuis & Nathan, 2003).
c) PHENOTHIAZINES: Prochlorperazine: Adults: 25 mg suppository as needed every 12 hours or 10 mg orally or IV every 4 or 6 hours as needed; 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) tablets, injection, suppositories, syrup, 2004; Prod Info Compazine(R), 2002). Promethazine: Adults: 12.5 to 25 mg orally or IV every 4 hours; Children (2 yr and older) 12.5 to 25 mg OR 0.5 mg/pound orally every 4 to 6 hours as needed (Prod Info promethazine hcl rectal suppositories, 2007). 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: Dolasetron: Adults: 100 mg orally daily or 1.8 mg/kg IV or 100 mg IV. Granisetron: Adults: 1 to 2 mg orally daily or 1 mg orally twice daily or 0.01 mg/kg (maximum 1 mg) IV or transdermal patch containing 34.3 mg granisetron. Ondansetron: Adults: 16 mg orally or 8 mg IV daily (Kris et al, 2006; None Listed, 1999); Children (older than 3 years of age): 0.15 mg/kg IV 4 and 8 hours after chemotherapy (None Listed, 1999).
e) BENZODIAZEPINES: Lorazepam: Adults: 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: Adults: 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: Adults: 1 to 4 mg orally or IM/IV every 6 hours as needed (None Listed, 1999).

F) 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. 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). In patients with mechlorethamine overdose, administer 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.

G) 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).

Inhalation Exposure

6.7.1)

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.

6.7.2)

A) ACUTE LUNG INJURY

1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).

a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)

3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).

B) CORTICOSTEROID

1) Systemic administration of corticosteroids and antibiotics (when secondary infection develops) have been recommended for treatment of respiratory tract injury caused by other alkylating agents such as mustard gas (Requena et al, 1988).

C) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

6.8.1)

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)

A) CONSULTATION

1) Direct eye exposure to this agent may cause severe irritation. Prolonged initial flushing and early ophthalmologic consultation are advisable.

B) EXPERIMENTAL THERAPY

1) DILTIAZEM: In one animal (rabbits) study, topical application of diltiazem, before the administration of 1% nitrogen mustard, reduced chemical irritation of the eye caused by nitrogen mustard. Topical application of diltiazem 10 mM resulted in a transient, small intraocular pressure increase and reduced significantly the acute intraocular pressure elevation and conjunctival vasodilation caused by mustard gas. In addition, delayed conjunctival edema and palpebral closure were also attenuated. However, topical diltiazem 2.8 mM was effective only in reducing significantly conjunctival edema and vasodilation(Gonzalez et al, 1995).
2) ZINC OR GALLIUM-DESFERRIOXAMINE: One study reported that zinc or gallium-desferrioxamine may have beneficial effects on treating mustard injuries in eyes (Wang & Xia, 2007).

C) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Dermal Exposure

6.9.1)

A) 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) Use of a 2% sodium thiosulfate solution has been recommended to decontaminate the SKIN ONLY (Dorr & Fritz, 1980).

1) PREPARATION OF SOLUTION: Dilute 3 mL of 10% USP sodium thiosulfate for injection with 12 mL of sterile water, prepare fresh for each use (15 mL final volume). Larger volumes may be prepared using the same ratio.

6.9.2)

A) SKIN ABSORPTION

1) Systemic toxicity (myelosuppression) has developed after combined dermal and inhalation exposure (Wang & Xia, 2007).

a) Some chemicals can produce systemic poisoning by absorption through intact skin. Carefully observe patients with dermal exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Abstracts

Case Reports

1) DERMAL

a) Topical applications of mechlorethamine induced repigmentation in two patients afflicted with vitiligo (Van Scott & Yu, 1975).

2) ORAL

a) Seven volunteers were given mechlorethamine orally as single doses of 4 to 6 mg per day. Nausea, vomiting, headache and diarrhea which persisted for 24 hours were reported (Jager et al, 1943).
b) Leukopenia appeared when the dosage was increased to 1 mg 3 times daily for a total dose of 15 to 18 mg (Jager et al, 1943).

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) ROUTE OF ADMINISTRATION

1) TOPICAL: Apply thin film once daily to skin areas affected by mycosis fungoides (Prod Info VALCHLOR(TM) topical gel, 2013).
2) INTRAVENOUS: The total recommended IV dose for the palliative treatment of various indicated malignancies is 0.4 mg/kg/course using dry ideal body weight, as single dose or may divide into 0.1 to 0.2 mg/kg daily doses; may repeat after hematologic recovery (Prod Info Mustargen(R) intravenous injection, 2009).
3) INTRACAVITARY INJECTION: The recommended dose by intracavitary injection for palliative treatment of secondary to metastatic carcinoma is 0.4 mg/kg; 0.2 mg/kg (or 10 to 20 mg) by intrapericardial route (after injection, change the position of the patient every 5 to 10 minutes for an hour for a more uniform distribution of the drug). Doses reported in the literature vary widely and published articles regarding intracavitary use should be consulted (Prod Info Mustargen(R) intravenous injection, 2009).

7.2.2)

A) The safety and effectiveness of mechlorethamine have not been established in pediatric patients (Prod Info VALCHLOR(TM) topical gel, 2013; Prod Info Mustargen(R) intravenous injection, 2009).

Minimum Lethal Exposure

Maximum Tolerated Exposure

1) Eye Injury - 100 mg-min/m(3)
2) Skin absorption (masked personnel) - 2500 to 9000 mg-min/m(3)

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): 2A ; Listed as: Nitrogen mustard

a) 2A : The agent (mixture) is probably carcinogenic to humans. The exposure circumstance entails exposures that are probably carcinogenic to humans. This category is used when there is limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals. In some cases, an agent (mixture) may be classified in this category when there is inadequate evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals and strong evidence that the carcinogenesis is mediated by a mechanism that also operates in humans. Exceptionally, an agent, mixture or exposure circumstance may be classified in this category solely on the basis of limited evidence of carcinogenicity in humans.

4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
5) MAK (DFG, 2002): Category 1 ; Listed as: N-Methyl-bis(2-chloroethyl)amine (nitrogen mustard)

a) Category 1 : Substances that cause cancer in man and can be assumed to make a significant contribution to cancer risk. Epidemiological studies provide adequate evidence of a positive correlation between the exposure of humans and the occurence of cancer. Limited epidemiological data can be substantiated by evidence that the substance causes cancer by a mode of action that is relevant to man.

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) References: ITI, 1995 Lewis, 2000 RTECS, 2002 US Army, 1975

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 2400 mcg/kg

2) LD50- (ORAL)MOUSE:

a) 10 mg/kg

3) LD50- (SKIN)MOUSE:

a) 29 mg/kg

4) LD50- (SUBCUTANEOUS)MOUSE:

a) 2600 mcg/kg

5) LD50- (INTRAPERITONEAL)RAT:

a) 860 mcg/kg

6) LD50- (ORAL)RAT:

a) 10 mg/kg

7) LD50- (SKIN)RAT:

a) 12 mg/kg

8) LD50- (SUBCUTANEOUS)RAT:

a) 1200 mcg/kg

Pharmacology Toxicology

Toxicologic Mechanism

Physicochemical

Physical Characteristics

Ph

Molecular Weight

Animal Toxicology

Clinical Effects

11.1.6)

A) Cats treated with mechlorethamine 0.5 to 3 mg/kg IV showed hearing loss for frequencies below 500 Hz which was accompanied by loss of hair cells in the basal and middle turns of the cochlea (Cummings, 1988).

Range Of Toxicity

11.3.2)

A) LACK OF INFORMATION

1) No specific information on a minimal toxic dose was available at the time of this review.

11.3.4)

11.3.4.1) TOXICITY VALUES

A) GENERAL

1) PUBLISHED VALUES (RTECS , 1991)

1) LCLo (INHL) CAT: 290 mg/m(3)/10min (RTECS, 1988)
2) LDLo (ORAL) GOAT, SHEEP: 100 mg/kg (RTECS, 1988)
3) LDLo (SKIN) MONKEY: 50 mg/kg (RTECS, 1988)
4) LDLo (IV) PIGEON: 15 mg/kg (RTECS, 1988)
5) LDLo (IV) CHICKEN: 10 mg/kg (RTECS, 1988)

2) The maximum tolerated dose in Rhesus monkeys was 0.2 milligram/kilogram on a daily 1 to 5 day schedule (Freireich et al, 1966).
3) The maximum tolerated dose in dogs was 0.48 milligram/kilogram on a daily 1 to 5 day schedule (Freireich et al, 1966).

References

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MECHLORETHAMINE

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

Endocrine

Immunologic

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

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Eye Exposure

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Case Reports

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Workplace Standards

Toxicity Information

Toxicologic Mechanism

Physical Characteristics

Ph

Molecular Weight

Clinical Effects

Range Of Toxicity

General Bibliography