Mustargen Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Before using MUSTARGEN (mechlorethamine HCl USP) see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION.

MUSTARGEN, administered intravenously, is indicated for the palliative treatment of Hodgkin’s disease (Stages III and IV) as part of the MOPP chemotherapy combination (mechlorethamine, vincristine, procarbazine, and prednisone).

CONTRAINDICATIONS

The use of MUSTARGEN is contraindicated in the presence of known infectious diseases and in patients who have had previous anaphylactic reactions or who are hypersensitive to this drug or to any ingredient in the formulation or component of the container.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

MUSTARGEN (mechlorethamine HCl) should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents.

• Dose limiting toxicity is myelosuppression (see Systemic Toxicity,

  Hematologic);

• Hypersensitivity reactions, including anaphylaxis have occurred (see

  Systemic Toxicity, General);

• MUSTARGEN is a Carcinogen/Mutagen/Teratogen (see

  Carcinogenesis/Mutagenesis and Special Populations);

• MUSTARGEN is a powerful vesicant (see Adverse Reactions, Local

  Toxicity)

This drug is HIGHLY TOXIC and both powder and solution must be handled and administered with care (see Special Handling Instructions and Dosage and Administration). Avoid exposure during pregnancy.

General

The use of MUSTARGEN in patients with leucopenia, thrombocytopenia, and anemia, due to invasion of the bone marrow by tumor carries a greater risk. In such patients a good response to treatment with disappearance of the tumor from the bone marrow may be associated with improvement of bone marrow function. However, in the absence of a good response or in patients who have been previously treated with chemotherapeutic agents, hematopoiesis may be further compromised, and leucopenia, thrombocytopenia and anemia may become more severe and lead to the demise of the patient.

The hematologic status of the patient must first be determined. It is essential to understand the hazards and therapeutic effects to be expected. Careful clinical judgment must be exercised in selecting patients. If the indication for its use is not clear, the drug should not be used.

As nitrogen mustard therapy may contribute to extensive and rapid development of amyloidosis, it should be used only if foci of acute and chronic suppurative inflammation are absent.

Precautions must be observed with the use of MUSTARGEN and radiotherapy or other chemotherapy in alternating courses. Hematopoietic function is characteristically depressed by either form of therapy, and neither MUSTARGEN following radiotherapy nor radiotherapy subsequent to the drug should be given until bone marrow function has recovered. In particular, irradiation of such areas as sternum, ribs, and vertebrae shortly after a course of nitrogen mustard may lead to hematologic complications.

MUSTARGEN has been reported to have immunosuppressive activity. Therefore, it should be borne in mind that use of the drug may predispose the patient to bacterial, viral or fungal infections. This is more likely to occur when concomitant steroid therapy is employed.

Hyperuricemia may develop during therapy with MUSTARGEN. The problem of urate precipitation should be anticipated, particularly in the treatment of the lymphomas, and adequate methods for control of hyperuricemia should be instituted and careful attention directed toward adequate fluid intake before treatment.

Many abnormalities of renal, hepatic, and bone marrow function have been reported in patients with neoplastic disease and who are receiving MUSTARGEN. It is advisable to check renal, hepatic, and bone marrow functions frequently.

Carcinogenesis and Mutagenesis

Therapy with alkylating agents such as MUSTARGEN may be associated with an increased incidence of a second malignant tumor, especially when such therapy is combined with other antineoplastic agents or radiation therapy. The International Agency for Research on Cancer has judged that mechlorethamine is a probable carcinogen in humans. This is supported by limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in animals.

Young-adult female RF mice were injected intravenously with four doses of 2.4 mcg/kg of mechlorethamine (0.1% solution) at 2-week intervals with observations for up to 2 years. An increased incidence of thymic lymphomas and pulmonary adenomas was observed. Painting mechlorethamine on the skin of mice for period up to 33 weeks resulted in squamous cell tumors in 9 of 33 mice.

Mechlorethamine induced mutations in the Ames test, in E. coli, and Neurospora crassa. Mechlorethamine caused chromosome aberrations in a variety of plant and mammalian cells. Dominant lethal mutations were produced in ICR/Ha Swiss mice.

Mechlorethamine impaired fertility in the rat at a daily dose of 500 mg/kg intravenously for two weeks.

Special Populations

Pregnant Women: There is evidence that the nitrogen mustards have induced fetal abnormalities particularly when used early in pregnancy. MUSTARGEN has been shown to produce fetal malformations in the rat and ferret when given as single subcutaneous injections of 1 mg/kg (2-3 times the maximum recommended human dose). There are no adequate and well controlled studies in pregnant women.

The possible benefits of administration of MUSTARGEN in women of childbearing potential must be weighed against the considered risks; patients should be apprised of the risks involved. Women of childbearing potential should be advised to avoid becoming pregnant.

Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants for MUSTARGEN, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established by well-controlled studies. Use of MUSTARGEN in pediatric patients has been quite limited. MUSTARGEN has been used in Hodgkin’s disease, stages III and IV, in combination with other oncolytic agents (MOPP schedule).

Geriatric Use: Clinical studies of MUSTARGEN did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

ADVERSE REACTIONS

Clinical use of MUSTARGEN (mechlorethamine HCl USP) usually is accompanied by toxic manifestations.

Local Toxicity

MUSTARGEN (mechlorethamine HCl USP) is a powerful vesicant and is intended for intravenous use. Inhalation of dust or vapors and contact with skin or mucous membranes, especially that of the eyes, must be avoided. Should accidental eye contact occur, copious irrigation for at least 15 minutes with normal saline or a balanced salt ophthalmic irrigating solution should be instituted immediately, followed by prompt ophthalmologic consultation. Should accidental skin contact occur, the affected part must be irrigated immediately with copious amounts of water, for at least 15 minutes, followed by 2 percent sodium thiosulfate solution.

Thrombosis and thrombophlebitis may result from direct contact of the drug with the intima of the injected vein. Avoid high concentration and prolonged contact with the drug, especially in cases of elevated pressure in the antebrachial vein (e.g., in mediastinal tumor compression from severe superior vena cava syndrome).

Systemic Toxicity

General

Hypersensitivity reactions, including anaphylaxis, have been reported. Nausea, vomiting and depression of formed elements in the circulating blood are dose-limiting side effects and usually occur with the use of full doses of MUSTARGEN. Jaundice, alopecia, vertigo, tinnitus and diminished hearing may occur infrequently. Renal damage manifested by oliguria and azotemia has been reported.

Rarely, hemolytic anemia associated with lymphomas may be precipitated by treatment with alkylating agents including MUSTARGEN. Also, various chromosomal abnormalities have been reported in association with nitrogen mustard therapy.

MUSTARGEN is given preferably at night in case sedation for side effects is required. Nausea and vomiting usually occur 1 to 3 hours after use of the drug. Emesis may disappear in the first 8 hours, but nausea may persist for 24 hours. Nausea and vomiting may be so severe as to precipitate vascular accidents in patients with a hemorrhagic tendency. Premedication with antiemetics, in addition to sedatives, may help control severe nausea and vomiting. Anorexia, weakness and diarrhea may also occur.

Hematologic

The usual course of MUSTARGEN (total dose of 0.4 mg/kg/d either given as a single intravenous dose or divided into two or four daily doses of 0.2 or 0.1 mg/kg respectively) generally produces a lymphocytopenia within 24 hours after the first injection; significant granulocytopenia occurs within 6 to 8 days and lasts for 10 days to 3 weeks. Agranulocytosis appears to be relatively infrequent and recovery from leukopenia in most cases is complete within two weeks of the maximum reduction. Thrombocytopenia is variable but the time course of the appearance and recovery from reduced platelet counts generally parallels the sequence of granulocyte levels. In some cases severe thrombocytopenia may lead to bleeding from the gums and gastrointestinal tract, petechiae, and small subcutaneous hemorrhages; these symptoms appear to be transient and in most cases disappear with return to a normal platelet count. However, a severe and even uncontrollable depression of the hematopoietic system occasionally may follow the usual dose of MUSTARGEN, particularly in patients with widespread disease and debility and in patients previously treated with other antineoplastic agents or x-ray. Persistent pancytopenia has been reported. Erythrocyte and hemoglobin levels may decline during the first 2 weeks after therapy. Depression of the hematopoietic system may be found up to 50 days or more after starting therapy.

Skin

Occasionally, a maculopapular skin eruption occurs, but this may be idiosyncratic and does not necessarily recur with subsequent courses of the drug. In one patient erythema multiforme has been observed. Herpes zoster, a common complicating infection in patients with lymphomas, may first appear after therapy is instituted and on occasion may be precipitated by treatment. Further treatment should be discontinued during the acute phase of this illness to avoid progression to generalized herpes zoster.

Reproductive

Since the gonads are susceptible to MUSTARGEN, treatment may be followed by delayed menses, oligomenorrhea, or amenorrhea, temporary or permanent. Impaired spermatogenesis, azoospermia, and total germinal aplasia have been reported in male patients treated with alkylating agents, especially in combination with other drugs. In some instances spermatogenesis may return in patients in remission, but this may occur only several years after intensive chemotherapy has been discontinued. Patients should be warned of the potential risk to their reproductive capacity.

DRUG INTERACTIONS

No formal drug interaction studies have been carried out.

DOSAGE AND ADMINISTRATION

Intravenous Administration

The dosage of MUSTARGEN (mechlorethamine HCl USP) varies with the clinical situation, the therapeutic response and the magnitude of hematologic depression. A total dose of 0.4 mg/kg/d of body weight for each course usually is given either as a single dose or in divided doses of 0.1 to 0.2 mg/kg. Dosage should be based on ideal dry body weight. The presence of edema or ascites must be considered so that dosage will be based on actual weight unaugmented by these conditions.

Extravasation of the drug into surrounding tissues results in a painful inflammation. The area usually becomes indurated and sloughing may occur. If leakage of drug is obvious, prompt infiltration of the area with sterile isotonic sodium thiosulfate (1/6 molar) and application of an ice compress for 6 to 12 hours may minimize the local reaction. For a 1/6 molar solution of sodium thiosulfate, use 4.14 g of sodium thiosulfate per 100 mL of Sterile Water for Injection or 2.64 g of anhydrous sodium thiosulfate per 100 mL, or dilute 4 mL of Sodium Thiosulfate Injection USP (10%) with 6 mL of Sterile Water for Injection USP.

Within a few minutes after intravenous injection, MUSTARGEN undergoes chemical transformation, combines with reactive compounds, and is no longer present in its active form in the blood stream.

Subsequent courses should not be given until the patient has recovered hematologically from the previous course; this is best determined by repeated studies of the peripheral blood elements awaiting their return to normal levels. It is often possible to give repeated courses of MUSTARGEN as early as three weeks after treatment.

Preparation of Solution and Intravenous Administration

Each vial of MUSTARGEN contains 10 mg of mechlorethamine hydrochloride triturated with sodium chloride q.s. 100 mg. In neutral or alkaline aqueous solution it undergoes rapid chemical transformation and is highly unstable. Although solutions prepared according to instructions are acidic and do not decompose as rapidly, they should be prepared immediately before each injection since they will decompose on standing. When reconstituted, MUSTARGEN is a clear colorless solution. Do not use if the solution is discolored or if droplets of water are visible within the vial prior to reconstitution.

Using a sterile 10 mL syringe, inject 10 mL of Sterile Water for Injection or 10 mL Sodium Chloride for Injection into a vial of MUSTARGEN. With the needle still in the rubber stopper, shake the vial several times to dissolve the drug completely. The resultant solution contains 1 mg of mechlorethamine hydrochloride per mL.

Technique for Intravenous Administration

Withdraw into the syringe the calculated volume of solution required for a single injection. Dispose of any remaining solution after neutralization (see below). Although the drug may be injected directly into any suitable vein, it is injected preferably into the rubber or plastic tubing of a flowing intravenous infusion set. This reduces the possibility of severe local reactions due to extravasation or high concentration of the drug. Injecting the drug into the tubing rather than adding it to the entire volume of the infusion fluid minimizes a chemical reaction between the drug and the solution. The rate of injection apparently is not critical provided it is completed within a few minutes.

Neutralization of Equipment and Unused Solution

To clean rubber gloves, tubing, glassware, etc., after giving MUSTARGEN, soak them in an aqueous solution containing equal volumes of sodium thiosulfate (5%) and sodium bicarbonate (5%) for 45 minutes. Excess reagents and reaction products are washed away easily with water. Any unused injection solution should be neutralized by mixing with an equal volume of sodium thiosulfate/sodium bicarbonate solution. Allow the mixture to stand for 45 minutes. Vials that have contained MUSTARGEN should be treated in the same way with thiosulfate/bicarbonate solution before disposal.

OVERDOSAGE

The intravenous LD₅₀ of MUSTARGEN is 2 mg/kg and 1.6 mg/kg in the mouse and rat, respectively. The oral LD₅₀ for mechlorethamine hydrochloride is 20 mg/kg and 10 mg/kg in the mouse and rat, respectively.

The margin of safety in therapy with MUSTARGEN is narrow and considerable care must be exercised in the matter of dosage. Repeated examinations of blood are mandatory as a guide to subsequent therapy.

Manifestations

With total doses exceeding 0.4 mg/kg/d of body weight for a single course, severe leukopenia, anemia, thrombocytopenia and a hemorrhagic diathesis with subsequent delayed bleeding may develop. Death may follow.

Treatment of Overdosage

The only treatment in instances of excessive dosage appears to be repeated blood product transfusions, antibiotic treatment of complicating infections and general supportive measures.

PART II: SCIENTIFIC INFORMATION

ACTION AND CLINICAL PHARMACOLOGY

Mechlorethamine, a biologic alkylating agent, has a cytotoxic action which inhibits rapidly proliferating cells.

STORAGE AND STABILITY

Store at 15-30°C (59-86°F). Protect from light and humidity.

Solutions of mechlorethamine HCl decompose on standing; therefore, solutions of the drug should be prepared immediately before use.

SPECIAL HANDLING INSTRUCTIONS

Appropriate protective equipment should be worn when handling MUSTARGEN. Should accidental contact occur, contaminated clothing and shoes should be removed and destroyed immediately. Medical attention should be sought immediately.

Preparation of injectable antineoplastic drugs should be performed in a Class II laminar flow biological safety cabinet. Personnel preparing drugs of this class should wear chemical resistant, impervious gloves, safety goggles, other garments and shoe covers. Additional body garments should be used based upon the task being performed to avoid exposed skin surfaces and inhalation of vapors and dust. Appropriate techniques should be used to remove potentially contaminated clothing.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Sterile, light yellow brown crystalline powder for injection by the intravenous routes after dissolution. Each vial of MUSTARGEN contains 10 mg of mechlorethamine hydrochloride triturated with sodium chloride q.s. 100 mg. When dissolved with 10 mL Sterile Water for Injection or 0.9% Sodium Chloride for Injection, the resulting solution has a pH of 3-5 at a concentration of 1 mg mechlorethamine HCl per mL.

PHARMACEUTICAL INFORMATION

Proper name: Mechlorethamine HCl USP

Chemical name: 2-chloro-N-(2-chloroethyl)-N-methy-lethanamine hydrochloride.

Molecular formula and molecular mass: The empirical formula is C₅H₁₁Cl₂N•HCl, and the structural formula is: CH₃N(CH₂CH₂Cl)₂•HCl. The molecular weight is 192.52 and the melting point is 109-110ºC.

Physicochemical properties: Hygroscopic powder that is very soluble in water and also soluble in alcohol.

CLINICAL TRIALS

The approved indication is supported by referenced literature.

REFERENCES

1. 1. DeVita VT, Serpick AA, Carbon PP. Combination chemotherapy in the treatment of advanced Hodgkin’s disease. Ann Intern Med 1970;73:881-95.
2. 2.

   Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs,

   Washington, DC: Division of Safety, National Institutes of Health, US Department of Health and Human Services, Public Health Service publication, NIH 83-2621; 1983.

3 International Agency for Research on Cancer (IARC) Monograph Vol 9

“Aziridines, N-, S- and O-Mustards and Selenium1975; 268 pages; ISBN 92 832 1209 6”