VA Class:AN100
Mechlorethamine hydrochloride, a nitrogen mustard-derivative alkylating agent, is an antineoplastic agent.
Mechlorethamine hydrochloride is used in the treatment of Hodgkin's disease.100, 102 Various regimens have been used in combination therapy and comparative efficacy is continually being evaluated.103, 104, 105 Mechlorethamine is used with vincristine, procarbazine, and prednisone (known as the MOPP regimen) in an alternating schedule with the ABVD regimen (doxorubicin, bleomycin, vinblastine, and dacarbazine) for the treatment of Hodgkin's disease.102, 103, 104, 105 The use of mechlorethamine in other combination regimens for the treatment of advanced Hodgkin's disease is being investigated.105
Mechlorethamine is used as a component of combination chemotherapy regimens in the treatment of intermediate-grade non-Hodgkin's lymphoma.102
Mechlorethamine has been used and may produce brief remissions in the palliative treatment of some patients with lymphosarcoma. Mechlorethamine is also used occasionally in conjunction with radiation therapy in the treatment of compression of the spinal cord or major blood vessels due to lymphoma†.
Mechlorethamine has been used IV alone or with other antineoplastic agents (MOPP regimen) as an adjunct to other therapy (e.g., electron beam radiation therapy) or as palliative therapy alone in the treatment of mycosis fungoides. However, the best combination or sequential therapy has not been established and comparative efficacy is continually being evaluated.
For topical use of mechlorethamine in the treatment of mycosis fungoides-type cutaneous T-cell lymphoma, see Mechlorethamine Hydrochloride 84:92.
Mechlorethamine may be used by intracavitary injection to control pleural, peritoneal, or pericardial effusions caused by metastatic tumors, but it has largely been replaced for use in this manner by other agents such as tetracycline (parenteral dosage form no longer commercially available in the US) or bleomycin. Intracavitary injection of mechlorethamine is indicated only when malignant cells are present in the effusion and should not be used when the accumulated fluid is chylous in nature, since the results are likely to be poor.
Although mechlorethamine is labeled for use in bronchogenic carcinoma, chronic myelogenous leukemia, and chronic lymphocytic leukemia,100 other agents are preferred for the treatment of these neoplasms.102 Since patients with chronic lymphocytic leukemia appear to be especially sensitive to the hematopoietic toxicity of mechlorethamine, the manufacturer states that the drug should be used with extreme caution, if at all, for this condition. Mechlorethamine also is labeled for use in polycythemia vera,100 but other therapy is advised for this condition.
Reconstitution and Administration
Mechlorethamine hydrochloride is usually administered IV. The drug is extremely irritating to tissues and, therefore, should not be given IM or subcutaneously. Care should be taken to avoid extravasation of the drug. (See Cautions: Local Effects.) Mechlorethamine hydrochloride may also be given by intrapleural, intraperitoneal, or intrapericardial injection. Mechlorethamine hydrochloride should not be administered orally.100
Because of the toxic properties of mechlorethamine (e.g., corrosivity, carcinogenicity, mutagenicity, teratogenicity), special handling instructions should be reviewed prior to handling the drug and followed carefully. (See Precautions and Contraindications.)100 Exposure to mechlorethamine must be avoided during pregnancy.100 Appropriate protective equipment (e.g., chemical resistant, impervious gloves, safety goggles, outer garments and shoe covers) should be used during the preparation and administration of mechlorethamine solutions.100 Additional body garments (e.g., sleevelets, apron, gauntlets, disposable suits) should be worn as needed based on the task being performed to avoid exposure of skin surfaces and inhalation of vapors and dust.100 (For additional information on proper procedures for handling antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs 10:00.)
The powder for injection is reconstituted immediately before administration by adding 10 mL of sterile water for injection or 0.9% sodium chloride injection to the vial labeled as containing 10 mg of the drug and shaking the vial several times (with the needle still in the rubber stopper in order to minimize the risk of skin contact with the drug) to ensure complete dissolution of the drug. The resultant solution contains 1 mg of mechlorethamine hydrochloride per mL.
Mechlorethamine hydrochloride solutions should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
For IV administration, the desired dose of the reconstituted solution may then be injected over a few minutes directly into any suitable vein or preferably into the tubing or sidearm of a freely flowing IV infusion to reduce the risk of severe local reactions due to extravasation or high concentrations of the drug. The rate of injection apparently is not critical provided administration is completed within a few minutes. Because of the highly reactive nature of mechlorethamine, the drug should not be diluted in the entire volume of an IV infusion. Following injection of mechlorethamine, some clinicians recommend flushing the vein with the running IV infusion for 2-5 minutes and/or injecting 5-10 mL of IV solution into the sidearm to flush any remaining drug from the tubing. If mechlorethamine is administered by direct IV injection, the dose of the reconstituted solution should be withdrawn from the vial with one sterile needle and another sterile needle should be used for direct injection into the vein. In patients with elevated venous pressure because of mediastinal tumor compression of major blood vessels, some authorities recommend administration of mechlorethamine through an indwelling catheter inserted into the femoral vein.
For intracavitary administration, the reconstituted solution may be used or may be further diluted in up to 100 mL of 0.9% sodium chloride injection. Techniques for intracavitary administration of mechlorethamine vary, and the manufacturer recommends that specialized references be consulted. Before intrapleural or intraperitoneal instillation of mechlorethamine, paracentesis is performed, removing most of the fluid to facilitate contact of the drug with pleura or peritoneum. For intrapleural or intrapericardial injection, mechlorethamine is administered directly through the thoracentesis needle. For intraperitoneal injection, the drug is administered through a rubber catheter inserted into the trocar used for paracentesis or through an 18-gauge needle inserted at another site. The drug should be injected slowly, with frequent aspiration to ensure that a free flow of fluid is present; if fluid cannot be aspirated, injection of mechlorethamine solution outside the cavity may occur, resulting in pain and necrosis. Free flow of fluid is also necessary to prevent injection into a pocket and to ensure adequate dissemination of the drug. The position of the patient should be changed every 5-10 minutes for 1 hour following injection to uniformly distribute the drug throughout the body cavity. Remaining fluid may be removed from the pleural or peritoneal cavity by paracentesis 24-36 hours later. The patient should receive careful clinical and radiographic examinations to detect the reaccumulation of fluid.
Neutralization of Equipment and Unused Solution
Any equipment used in the administration of mechlorethamine (e.g., rubber gloves, tubing, glassware, etc.) should be neutralized by soaking for 45 minutes in an aqueous solution containing equal volumes of 5% sodium thiosulfate and 5% sodium bicarbonate; excess reagents and reaction products reportedly are easily washed away with water. Any unused solution should be neutralized by mixing with an equal volume of the sodium thiosulfate-sodium bicarbonate solution and allowed to stand for 45 minutes. Vials which have contained mechlorethamine should be treated in the same manner before disposal.
Dosage of mechlorethamine hydrochloride must be based on the clinical and hematologic response and tolerance of the patient in order to obtain optimum therapeutic results with minimum adverse effects. Dosage should be based on ideal body weight in patients with edema or ascites. Clinicians should consult published protocols for the dosage of mechlorethamine hydrochloride and other chemotherapeutic agents and the method and sequence of administration.
The usual IV dosage of mechlorethamine hydrochloride recommended by the manufacturer is a total of 0.4 mg/kg per course of therapy given as a single dose or in divided doses of 0.1-0.2 mg/kg daily. Many authorities prefer to administer mechlorethamine as single doses, since patients obtain the same clinical response but experience only 1 day of nausea, vomiting, and anorexia. Extreme caution must be used if the usual dosage is exceeded. (See Cautions: Hematologic Effects.) Subsequent courses of therapy should not be administered until hematologic recovery has occurred. The interval between courses of mechlorethamine therapy is usually 3-6 weeks.
In the treatment of advanced Hodgkin's disease, the usual dosage of mechlorethamine hydrochloride in the MOPP regimen is 6 mg/m2 given IV on days 1 and 8 of a 28-day cycle. In subsequent cycles of MOPP therapy, many clinicians generally recommend mechlorethamine hydrochloride dose reductions of 50% when leukocyte counts are 3000-3999/ mm3 and 75% when leukocyte counts are 1000-2999/ mm3 or platelet counts are 50,000-100,000/ mm3; mechlorethamine should not be administered when the leukocyte count is less than 1000/ mm3 or the platelet count is less than 50,000/ mm3.
Intracavitary doses of mechlorethamine vary, and the manufacturer recommends that specialized references be consulted. The usual intracavitary dose of the drug is 0.4 mg/kg, although 0.2 mg/kg (or 10-20 mg) has been used intrapericardially.
Extravasation of even small amounts of mechlorethamine results in painful inflammation and induration which may persist for 4-6 weeks. If the local reaction is severe, sloughing may occur. If extravasation occurs, as much infiltrated drug as possible should be aspirated. Although no specific treatments are of proven value in preventing or reducing tissue damage, the local reaction may be minimized by promptly infiltrating the area with sterile isotonic sodium thiosulfate injection (4.14% of the pentahydrate salt, 2.64% of the anhydrous salt, or a 4% solution prepared by diluting 4 mL of the 10% injection with 6 mL of sterile water for injection) and applying cold compresses for 6-12 hours.100
Thrombosis and thrombophlebitis may result from direct contact of the drug with the intima of the vein used for injection or as the result of insufficient dilution of mechlorethamine. Vein irritation can progress over several days to dark bluish-grey hyperpigmentation. High concentration and prolonged local contact with the drug should be avoided, especially in patients with elevated pressure in the antebrachial veins (e.g., in mediastinal tumor compression of major blood vessels). (See Dosage and Administration: Reconstitution and Administration.)
Hematologic toxicity is one of the major and dose-limiting adverse effects of mechlorethamine. The patient's hematologic status must be carefully monitored. (See Cautions: Precautions and Contraindications.) When total IV dosage exceeds 0.4 mg/kg for a single course, severe leukopenia, anemia, thrombocytopenia, and hemorrhagic diathesis with subsequent delayed bleeding may develop, leading to death from hemorrhage or sepsis. Severe and uncontrollable depression of the hematopoietic system has occasionally occurred following usual doses of mechlorethamine, especially in patients with widespread disease and debility and in patients previously treated with other antineoplastic agents or radiation therapy. Treatment of severe hematologic toxicity may consist of supportive therapy, antibiotics for complicating infections, and blood product transfusions.
At usual doses, lymphocytopenia generally occurs within 24 hours after administration of the first IV dose of mechlorethamine. Significant granulocytopenia occurs within 6-8 days and persists 10-21 days. In most cases, recovery from leukopenia is complete within 2 weeks after the nadir occurs, although agranulocytosis may occur occasionally. Thrombocytopenia is variable in degree, onset, and duration, but platelet levels generally parallel granulocyte levels. In some cases, severe thrombocytopenia may result in bleeding from the gums and GI tract, petechiae, and small subcutaneous hemorrhages; however, these symptoms appear to be transient, disappearing with the return of normal platelet counts in most cases. Persistent pancytopenia and, rarely, hemorrhagic complications resulting from hyperheparinemia have been reported. Erythrocyte and hemoglobin levels may decline during the first 2 weeks following mechlorethamine therapy, but decreases are rarely significant. Rarely, hemolytic anemia associated with lymphomas or chronic lymphocytic leukemia is precipitated.
Major and dose-limiting adverse effects of mechlorethamine are nausea and vomiting, which occur in up to 90% of patients who receive the drug and are presumably due to CNS stimulation. Vomiting, which may be severe enough to precipitate vascular accidents in patients with hemorrhagic tendencies, occurs within 0.5-8 hours (usually 1-3 hours) after administration of mechlorethamine. Emesis generally subsides within 8 hours, but nausea may persist 24 hours or longer. Premedication with antiemetics and sedatives may help to control nausea and vomiting. Other adverse GI effects of mechlorethamine include anorexia, diarrhea, severe hematemesis and dehydration secondary to vomiting, and, rarely, peptic ulcers.
Effects Following Intracavitary Administration
Intracavitary administration of mechlorethamine produces unpredictable systemic effects. In general, acute adverse effects such as nausea, vomiting, and bone marrow depression are milder than following IV administration; however, death has been reported following intracavitary administration of the drug. Intracavitary use of mechlorethamine should be avoided if the patient is receiving systemic therapy with an agent which might suppress bone marrow function. Pain occurs rarely after intrapleural administration. Following intraperitoneal injection, however, pain, nausea, vomiting, and diarrhea of 2-3 days duration are common; hypovolemia also has been reported. Following intrapericardial injection, transient cardiac irregularities and cardiac tamponade have occurred. Intrapericardial use of mechlorethamine reportedly causes a reactive effusion which can compromise cardiac output.
Adverse CNS effects which have occurred following IV administration of mechlorethamine include weakness, headache, drowsiness, vertigo, lightheadedness, convulsions, progressive muscle paralysis, paresthesia, cerebral degeneration, coma, and death. Serious neurotoxicity appears to be a problem only when high doses or intra-arterial† and regional perfusion† administration techniques are used. Immediate and delayed neurotoxicity, sometimes severe, has been reported in patients receiving higher than recommended doses of the drug in preparation for bone marrow transplantation†; neurotoxicity appeared to increase with age and dose administered and occurred more frequently in patients who also received procarbazine or cyclophosphamide.106
Dermatologic and Sensitivity Reactions
Adverse dermatologic effects of systemic mechlorethamine therapy occasionally include a maculopapular skin eruption which is apparently idiosyncratic. The maculopapular skin eruption does not necessarily recur with subsequent doses and is not a contraindication to future use of the drug. Erythema multiforme also has been reported. Hypersensitivity reactions, including anaphylaxis, have been reported in patients receiving IV mechlorethamine. A sensitivity reaction manifested as facial angioedema has been reported in at least one patient; the patient was not cross-sensitive to IV cyclophosphamide.101 Herpes zoster, which occurs commonly in patients with lymphoma, may be precipitated by treatment with mechlorethamine. The manufacturer recommends that mechlorethamine therapy be discontinued during the acute phase of herpes zoster infection to avoid dissemination.
As a result of extensive purine catabolism accompanying rapid cellular destruction, hyperuricemia may occur in some patients receiving IV mechlorethamine, especially those with lymphoma. In some patients, uric acid nephropathy progressing to acute renal failure may result. Uric acid nephropathy may be minimized or prevented by adequate hydration, alkalinization of the urine, and/or administration of allopurinol.
Rarely, alopecia, jaundice, tinnitus, diminished hearing, fever, and a metallic taste have been reported.
Precautions and Contraindications
Mechlorethamine hydrochloride is a highly toxic drug with a low therapeutic index, and a therapeutic response is not likely to occur without some evidence of toxicity. The drug must be used only under constant supervision by clinicians experienced in therapy with cytotoxic agents.100
Mechlorethamine is a powerful vesicant.100 Inhalation of dust or vapors and contact of the powder or solutions of the drug with skin and mucous membranes (especially the eyes) must be avoided.100 Exposure to mechlorethamine must be avoided during pregnancy.100 If eye contact occurs, copious irrigation for at least 15 minutes with water, 0.9% sodium chloride, or a balanced salt ophthalmic irrigating solution should be instituted immediately, followed by prompt ophthalmologic examination.100 If skin contact occurs, the affected part should be irrigated immediately with copious amounts of water for at least 15 minutes while removing contaminated clothing and shoes, followed by 2% sodium thiosulfate solution.100 Medical attention should be sought immediately, and contaminated clothing should be destroyed.100
Patients who receive myelosuppressive drugs experience an increased frequency of infections as well as hemorrhagic complications. Because these complications are potentially fatal, the patient should be instructed to notify the clinician if fever, sore throat, or unusual bleeding or bruising occurs. The patient's hematologic status must be carefully monitored and frequent blood counts performed. Depression of the hematopoietic system may continue 50 days or longer after starting therapy, but hematologic recovery is generally complete within 4-6 weeks after a dose of mechlorethamine. A rebound effect of blood components exceeding baseline levels may occur 5-7 weeks after initiation of therapy. If mechlorethamine therapy is preceded or followed by therapy with other antineoplastic agents or radiation, sufficient time should elapse between courses to allow for bone marrow recovery. Irradiation (in particular of areas such as the sternum, ribs, pelvis, and vertebrae) shortly following a course of mechlorethamine may lead to hematologic complications. Mechlorethamine must be used with extreme caution in patients with leukopenia, thrombocytopenia, or anemia caused by infiltration of bone marrow with malignant cells. In these patients, a good response to mechlorethamine therapy with the disappearance of tumor from the bone marrow may be associated with improved bone marrow function; however, in the absence of good response or in patients who have received previous treatment with antineoplastic agents, hematopoiesis may be further compromised, resulting in more severe leukopenia, thrombocytopenia, anemia, and possibly death. Patients with chronic lymphocytic leukemia appear to be especially sensitive to the hematopoietic effects of mechlorethamine and should receive the drug with extreme caution, if at all.
For additional information on precautions associated with the use of mechlorethamine, see the sections in Cautions on Local, Hematologic, and Other Adverse Effects, Effects Following Intracavitary Administration, and Dermatologic and Sensitivity Reactions.
The manufacturer states that mechlorethamine should not be used in patients with foci of acute or chronic suppurative inflammation as the use of the drug may contribute to the extensive and rapid development of amyloidosis. The manufacturer states that mechlorethamine is contraindicated in the presence of known infectious diseases; however, in some patients, treatment of the underlying malignancy in addition to other therapy (e.g., antibiotics) may be necessary before systemic infections can be controlled. In addition, mechlorethamine may also predispose patients to bacterial, viral, or fungal infections, especially patients receiving concomitant corticosteroid therapy. The drug also is contraindicated in individuals who have exhibited prior anaphylactic reactions to the drug.
The safety and efficacy of mechlorethamine in children have not been established.100 Mechlorethamine has been used in combination therapy (mechlorethamine with vincristine, procarbazine, and prednisone, known as the MOPP regimen) for the treatment of stage III and IV Hodgkin's disease in a limited number of pediatric patients.100
Safety and efficacy of mechlorethamine in geriatric patients have not been studied specifically to date.100 Drug dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range.100 The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.100
Mutagenicity and Carcinogenicity
Animal studies have shown mechlorethamine to be mutagenic and carcinogenic.100 Based on limited evidence in humans and sufficient evidence in animals, the International Agency for Research on Cancer has determined that mechlorethamine is a probable carcinogen in humans.100 IV or topical mechlorethamine may be associated with an increased incidence of a secondary malignancy, especially when therapy is combined with other antineoplastic agents or radiation therapy.100
Pregnancy, Fertility, and Lactation
Mechlorethamine hydrochloride can cause fetal toxicity when administered to pregnant women. Reproduction studies in rats and ferrets using single, subcutaneous 1-mg/kg doses (approximately 2-3 times the maximum recommended human dose) revealed fetal malformations. There are no adequate and controlled studies to date using mechlorethamine in pregnant women, and the drug should be used during pregnancy only in life-threatening situations or severe disease for which safer drugs cannot be used or are ineffective. Women of childbearing potential should be advised to avoid becoming pregnant while receiving the drug. When mechlorethamine is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.
Reproduction studies in rats receiving IV mechlorethamine hydrochloride dosages of 500 mg/kg for 2 weeks revealed evidence of impaired fertility. Delayed menstruation, oligomenorrhea, temporary or permanent amenorrhea, impaired spermatogenesis, azoospermia, and total germinal aplasia have occurred in patients receiving mechlorethamine, especially in combination with other agents. Patients should be informed of the potential risk to reproductive capacity.
It is not known whether mechlorethamine hydrochloride is distributed into milk. Because of the potential for serious adverse reactions to mechlorethamine in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.
Limited information is available on the acute toxicity of mechlorethamine.100 In animal studies, the acute lethal dose of mechlorethamine hydrochloride in mice and rats is 2 mg/kg and 1.6 mg/kg, respectively, for IV administration, and 20 mg/kg and 10 mg/kg, respectively, for oral administration.100
When total doses exceed 0.4 mg/kg of body weight for a single course of mechlorethamine, severe leukopenia, anemia, thrombocytopenia, and a hemorrhagic diathesis with subsequent delayed bleeding may develop and may result in death.100
Treatment of toxicity in cases of excessive dosage of mechlorethamine includes repeated transfusions with blood product, treatment of complicating infections with anti-infective agents, and general supportive measures.100
Mechlorethamine, as an alkylating agent, interferes with DNA replication and transcription of RNA and ultimately results in the disruption of nucleic acid function. Mechlorethamine also possesses weak immunosuppressive activity.
Following intracavitary administration, mechlorethamine produces a sclerosing effect, causing an inflammatory reaction on serous membranes and subsequent adherence of serosal surfaces.
Although mechlorethamine hydrochloride is absorbed after oral or parenteral administration, the drug is extremely irritating to tissues and, therefore, must be administered IV. Mechlorethamine hydrochloride is incompletely absorbed following intracavitary administration, probably due to rapid deactivation by body fluids. Following IV injection, the drug undergoes rapid chemical transformation and unchanged mechlorethamine is undetectable in the blood within a few minutes. Less than 0.01% of an IV dose is excreted unchanged in the urine.
Mechlorethamine hydrochloride, a nitrogen analog of sulfur mustard, is a bifunctional alkylating agent. The drug occurs as a hygroscopic, light yellow brown crystalline powder, is very soluble in water and soluble in alcohol, and has an approximate pKa of 6.1. The commercially available product also contains sodium chloride. Following reconstitution of the commercially available powder for injection with sterile water for injection or 0.9% sodium chloride injection, mechlorethamine hydrochloride solutions containing 1 mg of the drug per mL are clear and colorless and have a pH of 3-5.
Mechlorethamine hydrochloride powder for injection should be stored in light-resistant containers at 15-30°C; the powder for injection should be protected from humidity.100 In the dry form, mechlorethamine hydrochloride may be stable at temperatures up to 40°C. In neutral or alkaline aqueous solutions, the drug is highly unstable and undergoes rapid chemical transformation. Although more stable than neutral or alkaline solutions, acidic solutions of mechlorethamine hydrochloride decompose on standing; therefore, solutions of the drug should be prepared immediately before injection. Mechlorethamine hydrochloride should not be used if droplets of water are visible within the vial or if the reconstituted solution is not colorless.
Additional Information
For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection | 10 mg | Mustargen® | Ovation |
Only references cited for selected revisions after 1984 are available electronically.
100. Merck & Co. Trituration of Mustargen® (mechlorethamine HCl) for injection prescribing information. White Station, NJ; 2004 Feb.
101. Wilson KS, Alexander S. Hypersensitivity to mechlorethamine. Ann Intern Med . 1981; 94:823. [PubMed 7235433]
102. Anon. Drugs of choice for cancer. Treat Guidel Med Lett . 2003; 1:41-52. [PubMed 15529105]
103. Urba WJ, Longo DL. Hodgkin's disease. N Engl J Med . 1992; 326:678-687. [PubMed 1736106]
104. DeVita VT Jr, Hubbard SM. Hodgkin's disease. N Engl J Med . 1993; 328:560-5. [PubMed 8426624]
105. Adult Hodgkin's disease. From: CancerNet/PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Sep.
106. Sullivan KM, Storb R, Shulman HM et al. Immediate and delayed neurotoxicity after mechlorethamine preparation for bone marrow transplantation. Ann Intern Med . 1982; 97:182-9. [PubMed 7049028]