FDA label 7b929598-948e-05d1-e053-2991aa0a9e4f

WARNINGS MUSTARGEN ® (mechlorethamine HCl) should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents. This drug is HIGHLY TOXIC and both powder and solution must be handled and administered with care. Inhalation of dust or vapors and contact with skin or mucous membranes, especially those of the eyes, must be avoided. Avoid exposure during pregnancy. Due to the toxic properties of mechlorethamine (e.g., corrosivity, carcinogenicity, mutagenicity, teratogenicity), special handling procedures should be reviewed prior to handling and followed diligently. Extravasation of the drug into subcutaneous 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 (10%) with 6 mL of Sterile Water for Injection.

WARNINGS Before using MUSTARGEN, an accurate histologic diagnosis of the disease, a knowledge of its natural course, and an adequate clinical history are important. 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. Usage in Pregnancy: Mechlorethamine hydrochloride can cause fetal harm when administered to a pregnant woman. 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. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

PRECAUTIONS General: This drug is HIGHLY TOXIC and both powder and solution must be handled and administered with care. (See boxed warning and DOSAGE AND ADMINISTRATION, Special Handling .) Since MUSTARGEN is a powerful vesicant, it is intended primarily for intravenous use, and in most cases is given by this route. Inhalation of dust or vapors and contact with skin or mucous membranes, especially those of the eyes, must be avoided. Appropriate protective equipment should be worn when handling MUSTARGEN. Should accidental eye contact occur, copious irrigation for at least 15 minutes with water, 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 while removing contaminated clothing and shoes, followed by 2% sodium thiosulfate solution. Medical attention should be sought immediately. Contaminated clothing should be destroyed. (See DOSAGE AND ADMINISTRATION, Special Handling .) Because of the toxicity of MUSTARGEN, and the unpleasant side effects following its use, the potential risk and discomfort from the use of this drug in patients with inoperable neoplasms or in the terminal stage of the disease must be balanced against the limited gain obtainable. These gains will vary with the nature and the status of the disease under treatment. The routine use of MUSTARGEN in all cases of widely disseminated neoplasms is to be discouraged. The use of MUSTARGEN in patients with leukopenia, 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 leukopenia, thrombocytopenia and anemia may become more severe and lead to the demise of the patient. Tumors of bone and nervous tissue have responded poorly to therapy. Results are unpredictable in disseminated and malignant tumors of different types. Precautions must be observed with the use of MUSTARGEN and x-ray therapy or other chemotherapy in alternating courses. Hematopoietic function is characteristically depressed by either form of therapy, and neither MUSTARGEN following x-ray therapy nor x-ray therapy 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 infection. 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. Since drug toxicity, especially sensitivity to bone marrow failure, seems to be more common in chronic lymphatic leukemia than in other conditions, the drug should be given in this condition with great caution, if at all. Extreme caution must be used in exceeding the average recommended dose. (See OVERDOSAGE .) Laboratory Tests: Many abnormalities of renal, hepatic, and bone marrow function have been reported in patients with neoplastic disease and receiving mechlorethamine. It is advisable to check renal, hepatic, and bone marrow functions frequently. Carcinogenesis, Mutagenesis, Impairment of Fertility: 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 mg/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 periods 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. Pregnancy: See WARNINGS . 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 from 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). The MOPP chemotherapy combination includes mechlorethamine, vincristine, procarbazine, and prednisone or prednisolone. [2] , [3] 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 usually is accompanied by toxic manifestations . Local Toxicity: 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 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. Rarely, hemolytic anemia associated with such diseases as the lymphomas and chronic lymphocytic leukemia 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 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. In rare instances, hemorrhagic complications may be due to hyperheparinemia. Erythrocyte and hemoglobin levels may decline during the first 2 weeks after therapy but rarely significantly. Depression of the hematopoietic system may be found up to 50 days or more after starting therapy. Integumentary: Occasionally, a maculopapular skin eruption occurs, but this may be idiosyncratic and does not necessarily recur with subsequent courses of the drug. 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 catamenia, oligomenorrhea, or temporary or permanent amenorrhea. 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. To report suspected adverse reactions, contact Recordati Rare Diseases Inc. at 1-888-575-8344 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.