Mustargen (Mechlorethamine HCl)



Mechlorethamine HCl

Alkylating Agent

Action And Clinical Pharmacology: Mechlorethamine, a biologic alkylating agent, has a cytotoxic action which inhibits rapidly proliferating cells. tag_IndicationsIndications

Indications And Clinical Uses: Before using mechlorethamine see Contraindications, Warnings, Precautions, Adverse Effects and Dosage.

Administered i.v., mechlorethamine is indicated for the palliative treatment of Hodgkin’s disease (Stages III and IV), lymphosarcoma, chronic myelocytic or chronic lymphocytic leukemia, polycythemia vera, mycosis fungoides and bronchogenic carcinoma.

Mechlorethamine, administered intrapleurally, intraperitoneally or intrapericardially, is indicated for the palliative treatment of metastatic carcinoma resulting in effusion.

Contra-Indications: Because of the toxicity of mechlorethamine, and the unpleasant side effects following its use, the potential risk and discomfort from the use of mechlorethamine 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. Routine use in all cases of widely disseminated neoplasms is to be discouraged.

The use of mechlorethamine 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. Its use is contraindicated in the presence of known infectious diseases. Results are unpredictable in disseminated and malignant tumors of different types.

Manufacturers’ Warnings In Clinical States: Extravasation of the drug into s.c. 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/100 mL of Sterile Water for Injection or 2.64 g of anhydrous sodium thiosulfate/100 mL or dilute 4 mL of Sodium Thiosulfate Injection USP (10%) with 6 mL of Sterile Water for Injection USP.

Before using mechlorethamine, 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.

Precautions: Mechlorethamine is highly toxic and both powder and solution must be handled and administered with care. Since this product is a powerful vesicant, it is intended primarily for i.v. use, and in most instances is given by this route. 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 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% sodium thiosulfate solution (see Warnings).

Do not use if the solution is discolored or if droplets of water are visible within the vial. Prepare fresh solution for injection and dispose of the unused portion after neutralization (see Dosage).

Precautions must be observed with the use of mechlorethamine and x-ray therapy or other chemotherapy in alternating courses. Hematopoietic function is characteristically depressed by either form of therapy, and neither mechlorethamine 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.

Therapy with alkylating agents such as mechlorethamine may be associated with an increased incidence of a second malignant tumor, especially when such therapy is combined with other antineoplastic agent or radiation therapy.

Hyperuricemia may develop during therapy. 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, mechlorethamine should be given in this condition with great caution, if at all.

Pregnancy: There is evidence that the nitrogen mustards have induced fetal abnormalities particularly when used early in pregnancy. The possible benefits of administration in women of childbearing potential must be weighed against the considered risks; patients should be apprised of the risks involved. In pregnant patients requiring treatment for a life-threatening progressive tumor, use of mechlorethamine should be avoided at least until the third trimester.

Adverse Reactions: Clinical use usually is accompanied by toxic manifestations.

Local: 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: 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 mechlorethamine. 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 mechlorethamine. Also, various chromosomal abnormalities have been reported in association with nitrogen mustard therapy.

Mechlorethamine is given preferably at night in case sedation for adverse 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.

The usual course of mechlorethamine (total dose of 0.4 mg/kg either given as a single i.v. dose or divided into 2 or 4 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 2 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 s.c. 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 mechlorethamine, 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. Renal damage manifested by azotemia and oliguria has been reported.

Mechlorethamine 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. This is more likely to occur when concomitant steroid therapy is employed.

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.

Since the gonads are susceptible to mechlorethamine, 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.

With total doses exceeding 0.4 mg/kg body weight for a single course, severe leukopenia, anemia, thrombocytopenia and a hemorrhagic diathesis with subsequent delayed bleeding may develop. Death may follow. The only treatment in instances of excessive dosage appears to be repeated blood product transfusions, antibiotic treatment of complicating infections and general supportive measures. Extreme caution must be used in exceeding the average recommended dose.

Dosage And Administration: I.V. Administration: The dosage varies with the clinical situation, the therapeutic response and the magnitude of hematologic depression. A total dose of 0.4 mg/kg 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/day. 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.

Within a few minutes after i.v. injection, mechlorethamine 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 mechlorethamine as early as 3 weeks after treatment.

The margin of safety in therapy with mechlorethamine 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.

Preparation of Solution and I.V. Administration: Each vial contains 10 mg of mechlorethamine HCl 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.

Using a sterile 10 mL syringe, inject 10 mL of Sterile Water for Injection or 10 mL Sodium Chloride Injection into a vial of mechlorethamine. 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 HCl/mL.

Withdraw into the syringe the calculated volume of solution required for a single injection. Dispose of any remaining solution after neutralization. Although the drug may be injected directly into any suitable vein, it is injected preferably into the rubber or plastic tubing of a flowing i.v. 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.

Intracavitary Administration: Nitrogen mustard has been used by intracavitary administration with varying success in certain malignant conditions for control of pleural, peritoneal, and pericardial effusions caused by malignant cells.

The technic and the dose used by any of these routes varies. Therefore, if mechlorethamine is given by the intracavitary route, the published articles concerning such use should be consulted. Because of the inherent risks involved, the physician should be experienced in the appropriate injection technics, and be thoroughly aware of the indications, dosages, hazards and precautions as set forth in the published literature. When using mechlorethamine by the intracavitary route, the general precautions concerning this agent should be borne in mind.

As a general guide, reference is made especially to the technics of Weisberger et al. Intracavitary use is indicated in the presence of pleural, peritoneal, or pericardial effusion due to metastatic tumors. Local therapy with nitrogen mustard is used only when malignant cells are demonstrated in the effusion. Intracavitary injection is not recommended when the accumulated fluid is chylous in nature, since results are likely to be poor.

Paracentesis is first performed with most of the fluid being removed from the pleural or peritoneal cavity. The intracavitary use may exert at least some of its effect through production of a chemical poudrage. Therefore, the removal of excess fluid allows the drug to more easily contact the peritoneal and pleural linings. For intrapleural or intrapericardial injection nitrogen mustard is introduced directly through the thoracentesis needle. For intraperitoneal injection it is given through a rubber catheter inserted into the trocar used for paracentesis or through a No. 18 gauge needle inserted at another site. This drug should be injected slowly, with frequent aspiration to ensure that a free flow of fluid is present. If fluid cannot be aspirated, pain and necrosis due to injection of solution outside the cavity may occur. Free flow of fluid also is necessary to prevent injection into a loculated pocket and to ensure adequate dissemination of nitrogen mustard.

The usual dose of nitrogen mustard for intracavitary injection is 0.4 mg/kg of body weight, though 0.2 mg/kg (or 10 to 20 mg) has been used by the intrapericardial route. The solution is prepared, as previously described for i.v. injection, by adding 10 mL of Sterile Water for Injection or 10 mL of Sodium Chloride Injection to the vial containing 10 mg of mechlorethamine (Amounts of diluent of 50 to 100 mL of normal saline have also been used). The position of the patient should be changed every 5 to 10 minutes for an hour after injection to obtain more uniform distribution of the drug throughout the serous cavity. The remaining fluid may be removed from the pleural or peritoneal cavity by paracentesis 24 to 36 hours later. The patient should be followed carefully by a clinical and x-ray examination to detect reaccumulation of fluid.

Pain occurs rarely with intrapleural use; it is common with intraperitoneal injection and is often associated with nausea, vomiting and diarrhea of 2 to 3 days duration. Transient cardiac irregularities may occur with intrapericardial injection. Death, possibly accelerated by mechlorethamine, has been reported following the use of this agent by the intracavitary route. Although absorption of mechlorethamine when given by the intracavitary route is probably not complete because of its rapid deactivation by body fluids, the systemic effect is unpredictable. The acute side effects such as nausea and vomiting are usually mild. Bone marrow depression is generally milder than when the drug is given i.v. Care should be taken to avoid use by the intracavitary route when other agents which may suppress bone marrow function are being used systemically.

To clean rubber gloves, tubing, glassware, etc., after giving mechlorethamine, 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 mechlorethamine should be treated in the same way with thiosulfate/bicarbonate solution before disposal.

Availability And Storage: Each vial of light yellow/brown powder contains: mechlorethamine HCl 10 mg triturated with sodium chloride q.s. 100 mg.

MUSTARGEN® MSD Mechlorethamine HCl Alkylating Agent

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