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    Nitrogen Mustard Analogs
    Other Topical Antineoplastics

    BOXED WARNING

    Anemia, bleeding, bone marrow suppression, herpes infection, immunosuppression, infection, leukopenia, neutropenia, radiation therapy, requires an experienced clinician, thrombocytopenia, varicella, viral infection

    Hematologic toxicity (e.g., anemia, neutropenia, leukopenia, and thrombocytopenia) has been reported with mechlorethamine therapy. This drug requires an experienced clinician knowledgeable in the use of cancer chemotherapy. Infection and bleeding may occur as a result of bone marrow suppression. Intravenous (IV) mechlorethamine should be used cautiously in patients receiving other myelosuppressive therapy (e.g., radiation therapy). Monitor hematologic parameters (e.g., complete blood count panel) frequently during therapy. Bone morrow function should be recovered prior to administering IV mechlorethamine and/or radiation therapy. Use of IV mechlorethamine is contraindicated in patients who have an infectious disease. Immunosuppression has been reported with IV mechlorethamine therapy and bacterial, fungal, or viral infection (e.g., varicella, herpes infection) may occur. Herpes zoster infection may occur during or be precipitated by mechlorethamine treatment. Discontinue therapy in patients with herpes zoster infection.

    Extravasation

    Extravasation resulting in severe tissue damage (e.g., inflammation, induration, or sloughing of tissue) has been reported with mechlorethamine therapy. If extravasation or signs of drug leakage occur, promptly treat with sterile isotonic sodium thiosulfate (1/6 molar) and apply an ice compress for 6 to 12 hours. 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. Alternatively, dilute 4 mL of 10% sodium thiosulfate injection with 6 mL of Sterile Water for Injection.

    Accidental exposure, ocular exposure

    Mechlorethamine is highly toxic and the powder, solution must be handled and administered with care; all injectable forms contain a boxed warning against accidental exposure. Review and diligently follow special handling procedures before and during mechlorethamine handling because of the toxic properties of the drug such as corrosivity, carcinogenicity, mutagenicity, and teratogenicity. Appropriate protective equipment should be worn to avoid accidental exposure to mechlorethamine during preparation, handling, and administration. Avoid exposure to the eyes, avoid inhalation of dust or vapors, and avoid accidental contact with the skin or mucous membranes. Contaminated clothing should be destroyed. To clean gloves, tubing, surfaces, etc., after contact with mechlorethamine, soak in aqueous solution containing equal parts sodium thiosulfate 5% and sodium bicarbonate 5% for 45 minutes. Any unused solution and vials should be neutralized by mixing with an equal volume of sodium thiosulfate/sodium bicarbonate solution prior to disposal. Accidental skin contact with parenteral mechlorethamine should be treated with thorough rinsing of the area with water for at least 15 minutes, while removing contaminated clothing and shoes, followed by rinsing with 2% sodium thiosulfate solution. Medical attention should be sought immediately. Ocular exposure to mechlorethamine in any formulation causes pain, burns, inflammation, photophobia, and blurred vision. Blindness and severe irreversible anterior eye injury may occur. The topical gel does not contain a boxed warning regarding accidental exposure, but should only be applied to the skin, and several warnings regarding proper application and need for care in handling during administration apply. If accidental eye contact occurs to mechlorethamine topical gel or other dosage forms, rinse the exposed eye(s) with copious amounts of water, normal saline, or a balanced salt solution for at least 15 minutes; promptly seek emergency care, which should include consult of an ophthalmologist. If oral mucous membrane exposure occurs with topical mechlorethamine gel use, immediately rinse the area for at least 15 minutes with water and promptly seek medical attention. Individuals other than the patient should avoid direct skin contact with mechlorethamine gel due to the risks of secondary exposure including dermatitis, mucosal injury, and secondary cancers.

    Secondary malignancy

    The risk of secondary malignancy is increased with the use of alkylating agents such as mechlorethamine, particularly when alkylating agents are used in combination with other antineoplastic agents or radiation therapy. Thymic lymphomas, pulmonary adenomas, and squamous cell tumors have been observed in the animal studies. Additionally, non-melanoma skin cancer has been reported in patients who received mechlorethamine topical gel. Some non-melanoma skin cancers occurred in patients who had received prior therapies known to cause non-melanoma skin cancer. Monitor patients for non-melanoma skin cancers during and after treatment with mechlorethamine topical gel.

    Pregnancy

    Mechlorethamine may cause fetal harm when administered during pregnancy based on its mechanism of action, data from animal studies, and reports in humans; pregnant women should avoid exposure to mechlorethamine. There are case reports of children born with malformations following systemic mechlorethamine use. Females of reproductive potential should avoid pregnancy. If mechlorethamine is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Fetal malformations including fetal death and growth retardation occurred in animals after a single subcutaneous 1 mg/kg dose.

    DEA CLASS

    Rx

    DESCRIPTION

    Bifunctional alkylating agent.
    IV formulation approved for use in the palliative treatment of many malignancies including Hodgkin's disease, chronic lymphocytic leukemia, chronic myelogenous leukemia, and mycosis fungoides; topical gel approved to treat recurrent mycosis fungoides.
    Strong adherence to cytotoxic handling, administration, and disposal procedures is advised due to corrosive, carcinogenic, mutagenic, and teratogenic properties of mechlorethamine.

    COMMON BRAND NAMES

    Mustargen, VALCHLOR

    HOW SUPPLIED

    Mustargen Intracavitary Inj Pwd F/Sol: 10mg
    Mustargen Intravenous Inj Pwd F/Sol: 10mg
    VALCHLOR Topical Gel: 0.016%

    DOSAGE & INDICATIONS

    For the treatment of chronic lymphocytic leukemia (CLL).
    Intravenous dosage
    Adults

    6 mg/m2 IV every 4 weeks as a part of the ProMACE-MOPP regimen.

    For the treatment of chronic myelogenous leukemia (CML).
    Intravenous dosage
    Adults

    0.4 mg/kg or 6 mg/m2 as a single IV dose monthly or as necessary to lower the white blood cell count.

    For the treatment of Hodgkin's disease.
    For the treatment of Hodgkin's disease as part of the Stanford V regimen.
    Intravenous dosage
    Adults and Adolescents >= 15 years

    6 mg/m2 IV on weeks 1, 5, and 9 in combination with doxorubicin (25 mg/m2 IV on weeks 1, 3, 5, 7, 9, and 11), vinblastine (6 mg/m2 IV on weeks 1, 3, 5, 7, 9, and 11), vincristine (1.4 mg/m2 (max: 2 mg) IV on weeks 2, 4, 6, 8, 10, and 12), bleomycin (5 units/m2 IV on weeks 2, 4, 6, 8, 10, and 12), etoposide (60 mg/m2/day IV on 2 consecutive days in weeks 3, 7, and 11), and prednisone (40 mg/m2 PO every other day for 10 weeks then tapered by 10 mg PO every other day between weeks 10 and 12). Total duration of Stanford V regimen is 12 weeks; three 4-week cycles. Doses of mechlorethamine, doxorubicin, vinblastine, and etoposide have been reduced to 65% if ANC < 1000/mm3 (treatment delayed if ANC < 500/mm3). Prophylactic sulfamethoxazole-trimethoprim, acyclovir, and ranitidine were given throughout the treatment period. G-CSF has also been used to maintain dose intensity as needed after the first dose reduction. Alternative prophylactic medications have also been used.

    As a single agent or as part of a regimen.
    Intravenous dosage
    Adults

    0.2 mg/kg or 6 mg/m2 given as a single IV dose on day 1 or on days 1 and 8 of a regimen. Alternatively, it may be given as 0.1 mg/kg IV once daily for 4 successive days every 3—6 weeks. This dosage should be reduced to 0.2—0.4 mg/kg in those patients who have received prior radiation or chemotherapy.

    Children† and Adolescents†

    As part of the MOPP regimen, 6 mg/m2 IV on days 1 and 8 of a 28 day cycle.

    For the treatment of lung cancer.
    Intravenous dosage
    Adults

    6 mg/m2 IV every 2 weeks in combination with doxorubicin and methotrexate or every 4 weeks with doxorubicin, methotrexate, fluorouracil, hydroxyurea, and procarbazine.

    For intracavitary administration for neoplastic effusions including pericardial effusion, pleural effusion, and peritoneal effusion.
    Intracavitary dosage
    Adults

    0.2—0.4 mg/kg as a single, intracavitary injection. Pericardial effusions are usually treated with 0.2 mg/kg. Pleural effusions are sometimes treated with fixed doses of 10, 15, 20 or 30 mg.

    For the treatment of polycythemia vera (PCV).
    Intravenous dosage
    Adults

    0.4 mg/kg or 6 mg/m2 as a single IV dose monthly or as necessary to lower the red blood cell count.

    For the treatment of cutaneous T-cell lymphoma (CTCL), including mycosis fungoides.
    For the palliative treatment of mycosis fungoides.
    Intravenous dosage
    Adults

    0.2 mg/kg or 6 mg/m2 given as a single IV dose on day 1 or on days 1 and 8 of a regimen. Alternatively, it may be given as 0.1 mg/kg IV once daily for 4 successive days every 3—6 weeks. This dosage should be reduced to 0.2—0.4 mg/kg in those patients who have received prior radiation or chemotherapy.

    For the treatment of of stage IA and IB mycosis fungoides in patients who have received prior skin directed therapy.
    Topical dosage
    Adults

    Apply a thin film of mechlorethamine topical gel once daily to affected skin. If skin ulceration, blistering, or moderate to severe or severe dermatitis occurs, interrupt treatment and restart at a reduced application frequency of every 3 days when symptoms improve. If the reduced frequency schedule is tolerated for 1 week, increase the application frequency to once every other day for 1 week and then to once daily as tolerated. Once-daily application of mechlorethamine 0.02% topical gel (Valchlor; n = 130) or a compounded, petrolatum-based mechlorethamine 0.02% topical ointment (n = 130) for 12 months was evaluated in patients who had recurrent stage IA, IB, or IIA mycosis fungoides following at least 1 prior therapy (median of 2 prior therapies; range, 1—12 therapies) in a multicenter, randomized, phase II non-inferiority trial. Patients who had previously received topical carmustine, topical mechlorethamine within 2 years, or radiation therapy within 1 year were excluded from this trial. Valchlor gel was noninferior to compounded mechlorethamine ointment for the primary endpoint of Composite Assessment of Index Lesion Severity (CAILS) response rate in the intention-to-treat population (59% vs 48%; response ratio = 1.23; 95% CI, 0.97—1.55; lower limit of CI met criteria of >= 0.75) and the per-protocol population (77% vs 59%; response ratio = 1.3; 95% CI, 1.06—1.61). The CAILS evaluated the response in up to 5 index lesions identified at baseline. The CAILS complete response rates for patients who received Valchlor gel were 14% in the ITT population and 19% in the per-protocol population. The modified Severity Weighted Assessment Tool (mSWAT) response rate (secondary endpoint) was similar with Valchlor and compounded mechlorethamine ointment (47% vs 46%).

    MAXIMUM DOSAGE

    Adults

    IV: 0.4 mg/kg/dose or 6 mg/m2/dose.
    Intracavitary: 0.4 mg/kg/dose.
    Topical gel: 1 application/day to affected area(s).

    Geriatric

    IV: 0.4 mg/kg/dose or 6 mg/m2/dose.
    Intracavitary: 0.4 mg/kg/dose.
    Topical gel: 1 application/day to affected area(s).

    Adolescents

    IV: Safety and efficacy have not been established, although 6 mg/m2/dose has been used off-label for Hodgkin's disease.
    Topical gel: Safety and efficacy have not been established.

    Children

    IV: Safety and efficacy have not been established, although 6 mg/m2/dose has been used off-label for Hodgkin's disease.
    Topical gel: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    For storage information, see specific product information within the How Supplied section.
     
    CAUTION: Observe and exercise usual cautions for handling, preparing, and disposing of cytotoxic drugs.

    Injectable Administration
    Intravenous Administration

    Avoid inhalation of mechlorethamine dust or vapors, and contact with skin or mucous membranes, especially those of the eyes.
    If eye exposure occurs, immediately rinse the affected area with copious amounts of water, normal saline, or a balanced salt ophthalmic irrigating solution for at least 15 minutes; promptly consult an ophthalmologist.
    If skin contact occurs, immediately rinse the affected area with copious amounts of water for at least 15 minutes and then irrigate with a 2% sodium thiosulfate solution; remove and destroy contaminated clothing and shoes; promptly seek medical attention.
    Neutralization (with a solution of equal volume of sodium thiosulfate 5% and sodium bicarbonate 5%) is required for equipment exposed to mechlorethamine (e.g, rubber gloves, tubing, glassware) and for unused mechlorethamine injection; allow solution to stand for 45 minutes.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
     
    Reconstitution:
    Add 10 ml of sterile water for injection or 0.9% sodium chloride injection into the 10 mg mechlorethamine powder vial for a final concentration of 1 mg/ml.
    With the needle still in the rubber stopper (minimizes the risk of skin contact with mechlorethamine), shake the vial several times to ensure complete dissolution.
     
    Direct intravenous injection:
    Using a sterile needle, withdraw the dose from the vial containing the reconstituted solution.
    Using another sterile needle, inject the reconstituted solution over a few minutes directly into any suitable vein.
     
    Intravenous bolus injection:
    Inject 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. Following administration, flush the vein with the running IV infusion for 2—5 minutes and/or inject 5—10 ml of IV solution into the sidearm to flush any remaining drug from the tubing.
    For patients with elevated venous pressure due to mediastinal tumor compression of major blood vessels, mechlorethamine may be administered via an indwelling catheter inserted into the femoral vein.

    Topical Administration
    Other Topical Formulations

    Gel Formulation
    Patients should wash hands thoroughly with soap and water after handling or applying mechlorethamine gel.
    Caregivers must wear disposable nitrile gloves when applying mechlorethamine gel to patients and wash hands thoroughly with soap and water after glove removal. For accidental skin exposure, immediately wash exposed areas thoroughly with soap and water for at least 15 minutes and remove contaminated clothing.
    If eye exposure occurs, immediately rinse the affected area with copious amounts of water, normal saline, or a balanced salt ophthalmic irrigating solution for at least 15 minutes; promptly consult an ophthalmologist.
    Store mechlorethamine topical gel in the refrigerator at 2—8 degrees Celsius (36—46 degrees Fahrenheit); keep separated from food.
    Discard unused product after 60 days.
    Apply immediately or within 30 minutes after removal from the refrigerator; return mechlorethamine gel to the refrigerator immediately after each use.
    Apply to completely dry skin at least 4 hours before or 30 minutes after showering or washing; allow treated areas to dry for 5—10 minutes after application before covering with clothing.
    Emollients or moisturizers may be applied to the treated areas 2 hours before or 2 hours after application.
    Do not use occlusive dressings on areas of the skin where mechlorethamine gel was applied.
    Avoid fire, flame, and smoking until mechlorethamine gel has dried.

    Extemporaneous Compounding-Topical

    NOTE: Mechlorethamine 0.02% topical gel (Valchlor) is available and approved for use by the FDA. Other extemporaneous compounded formulations are not FDA approved.
     
    Mechlorethamine topical solution:
    Dissolve 10 mg of mechlorethamine in 50—60 ml of water.
    Mechlorethamine topical ointment:
    Dissolve mechlorethamine in dehydrated alcohol.
    Filter the solution to remove the insoluble sodium chloride present in the commercial preparation.
    Mix the mechlorethamine-alcohol solution into petrolatum or another anhydrous ointment base. The usual concentration is 0.01%.

    Other Administration Route(s)

    Intracavitary Administration
    Specialized references should be consulted because techniques for intracavitary administration vary.
    Further dilute the reconstituted solution in up to 100 ml of NS injection.
    Before intrapleural or intraperitoneal instillation, paracentesis is performed to remove most of the fluid which facilitates contact of mechlorethamine with pleura or peritoneum.
     
    Method of injection:
    Inject slowly with frequent aspiration to ensure that a free flow of fluid is present; if fluid cannot be aspirated, injection outside the cavity may occur, resulting in pain and necrosis. Free flow of fluid prevents injection into a pocket and ensures adequate dissemination of mechlorethamine.
    Change the position of patient every 5—10 minutes for 1 hour following injection to uniformly distribute mechlorethamine throughout the body cavity.
    Remaining fluid may be removed from the pleural or peritoneal cavity by paracentesis 24—36 hours later.
     
    Intrapleural or intrapericardial injection
    Administer directly through the thoracentesis needle.
     
    Intraperitoneal injection
    Administer through a rubber catheter inserted into the trocar used for paracentesis or through an 18-gauge needle inserted at another site.

    STORAGE

    Mustargen:
    - Avoid excessive humidity
    - Protect from light
    - Store at room temperature (between 59 to 86 degrees F)
    VALCHLOR:
    - After dispensing, store refrigerated (36 to 46 degrees F)
    - Flammable, keep away from heat and flame
    - Prior to dispensing, store in freezer (-13 to 5 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Hypersensitivity reactions have been reported with IV and topical mechlorethamine therapy. Use is contraindicated in patients with a previous or known history of severe hypersensitivity reaction (e.g., anaphylaxis) to mechlorethamine.

    Anemia, bleeding, bone marrow suppression, herpes infection, immunosuppression, infection, leukopenia, neutropenia, radiation therapy, requires an experienced clinician, thrombocytopenia, varicella, viral infection

    Hematologic toxicity (e.g., anemia, neutropenia, leukopenia, and thrombocytopenia) has been reported with mechlorethamine therapy. This drug requires an experienced clinician knowledgeable in the use of cancer chemotherapy. Infection and bleeding may occur as a result of bone marrow suppression. Intravenous (IV) mechlorethamine should be used cautiously in patients receiving other myelosuppressive therapy (e.g., radiation therapy). Monitor hematologic parameters (e.g., complete blood count panel) frequently during therapy. Bone morrow function should be recovered prior to administering IV mechlorethamine and/or radiation therapy. Use of IV mechlorethamine is contraindicated in patients who have an infectious disease. Immunosuppression has been reported with IV mechlorethamine therapy and bacterial, fungal, or viral infection (e.g., varicella, herpes infection) may occur. Herpes zoster infection may occur during or be precipitated by mechlorethamine treatment. Discontinue therapy in patients with herpes zoster infection.

    Dental disease, dental work

    Myelosuppressive effects of mechlorethamine can increase the risk of infection or bleeding; therefore, dental work should be delayed until blood counts have returned to normal. Patients, especially those with dental disease, should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks.

    Extravasation

    Extravasation resulting in severe tissue damage (e.g., inflammation, induration, or sloughing of tissue) has been reported with mechlorethamine therapy. If extravasation or signs of drug leakage occur, promptly treat with sterile isotonic sodium thiosulfate (1/6 molar) and apply an ice compress for 6 to 12 hours. 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. Alternatively, dilute 4 mL of 10% sodium thiosulfate injection with 6 mL of Sterile Water for Injection.

    Accidental exposure, ocular exposure

    Mechlorethamine is highly toxic and the powder, solution must be handled and administered with care; all injectable forms contain a boxed warning against accidental exposure. Review and diligently follow special handling procedures before and during mechlorethamine handling because of the toxic properties of the drug such as corrosivity, carcinogenicity, mutagenicity, and teratogenicity. Appropriate protective equipment should be worn to avoid accidental exposure to mechlorethamine during preparation, handling, and administration. Avoid exposure to the eyes, avoid inhalation of dust or vapors, and avoid accidental contact with the skin or mucous membranes. Contaminated clothing should be destroyed. To clean gloves, tubing, surfaces, etc., after contact with mechlorethamine, soak in aqueous solution containing equal parts sodium thiosulfate 5% and sodium bicarbonate 5% for 45 minutes. Any unused solution and vials should be neutralized by mixing with an equal volume of sodium thiosulfate/sodium bicarbonate solution prior to disposal. Accidental skin contact with parenteral mechlorethamine should be treated with thorough rinsing of the area with water for at least 15 minutes, while removing contaminated clothing and shoes, followed by rinsing with 2% sodium thiosulfate solution. Medical attention should be sought immediately. Ocular exposure to mechlorethamine in any formulation causes pain, burns, inflammation, photophobia, and blurred vision. Blindness and severe irreversible anterior eye injury may occur. The topical gel does not contain a boxed warning regarding accidental exposure, but should only be applied to the skin, and several warnings regarding proper application and need for care in handling during administration apply. If accidental eye contact occurs to mechlorethamine topical gel or other dosage forms, rinse the exposed eye(s) with copious amounts of water, normal saline, or a balanced salt solution for at least 15 minutes; promptly seek emergency care, which should include consult of an ophthalmologist. If oral mucous membrane exposure occurs with topical mechlorethamine gel use, immediately rinse the area for at least 15 minutes with water and promptly seek medical attention. Individuals other than the patient should avoid direct skin contact with mechlorethamine gel due to the risks of secondary exposure including dermatitis, mucosal injury, and secondary cancers.

    Hyperuricemia, tumor lysis syndrome (TLS)

    Hyperuricemia may occur with IV mechlorethamine use. Take measures to prevent tumor lysis syndrome (TLS) and hyperuricemia (e.g., fluids) prior to starting mechlorethamine, especially in patients with highly chemosensitive disease (e.g., lymphoma).

    Inflammation, skin disease

    Dermatitis has been commonly reported with mechlorethamine topical gel use. Monitor patients for redness, swelling, inflammation, itchiness, blisters, ulceration, and secondary skin infections. Applying mechlorethamine topical gel to the face, genitalia, anus, and intertriginous skin increase the risk of dermatitis. Therapy interruption and application frequency reduction is necessary in patients who develop skin disease such as skin ulceration, blistering, or moderate to severe or severe dermatitis.

    Suppurative inflammation

    Intravenous mechlorethamine should not be used in patients with foci of acute or chronic suppurative inflammation because the drug can cause the rapid development of amyloidosis.

    Vaccination

    Vaccination during chemotherapy or radiation therapy should be avoided because the antibody response is suboptimal. When chemotherapy is being planned, vaccination should precede the initiation of chemotherapy by >= 2 weeks. The administration of live vaccines to immunocompromised patients should be avoided. Those undergoing chemotherapy (such as mechlorethamine) should not be exposed to others who have recently received the oral poliovirus vaccine (OPV). Measles-mumps-rubella (MMR) vaccination is not contraindicated for the close contacts, including health care professionals, of immunocompromised patients. Passive immunoprophylaxis with immune globulins may be indicated for immunocompromised persons instead of, or in addition to, vaccination. When exposed to a vaccine-preventable disease such as measles, severely immunocompromised children should be considered susceptible regardless of their vaccination history.

    Secondary malignancy

    The risk of secondary malignancy is increased with the use of alkylating agents such as mechlorethamine, particularly when alkylating agents are used in combination with other antineoplastic agents or radiation therapy. Thymic lymphomas, pulmonary adenomas, and squamous cell tumors have been observed in the animal studies. Additionally, non-melanoma skin cancer has been reported in patients who received mechlorethamine topical gel. Some non-melanoma skin cancers occurred in patients who had received prior therapies known to cause non-melanoma skin cancer. Monitor patients for non-melanoma skin cancers during and after treatment with mechlorethamine topical gel.

    Children, infants, neonates

    The safety and efficacy of mechlorethamine topical gel have not been established in adolescents, children, infants, and neonates. There has been limited experience in using IV mechlorethamine (e.g., MOPP regimen for Hodgkin lymphoma) in pediatric patients; the safety and efficacy of IV mechlorethamine have not been established in well controlled trials in this patient population.

    Pregnancy

    Mechlorethamine may cause fetal harm when administered during pregnancy based on its mechanism of action, data from animal studies, and reports in humans; pregnant women should avoid exposure to mechlorethamine. There are case reports of children born with malformations following systemic mechlorethamine use. Females of reproductive potential should avoid pregnancy. If mechlorethamine is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Fetal malformations including fetal death and growth retardation occurred in animals after a single subcutaneous 1 mg/kg dose.

    Infertility, reproductive risk

    Counsel patients about the reproductive risk with mechlorethamine treatment. Infertility or impaired fertility may occur in female (e.g., delayed catamenia, oligomenorrhea, temporary or permanent amenorrhea) or male (e.g., impaired spermatogenesis, azoospermia, and total germinal aplasia) patients who receive alkylating agents such as mechlorethamine; the risk may increase when mechlorethamine is used in combination with other drugs. Spermatogenesis may return following treatment with alkylating agents, sometimes several years after therapy.

    Breast-feeding

    It is not known whether mechlorethamine is excreted in human milk. Because many drugs are
    excreted in human milk and because of the potential for topical or systemic maternal exposure from mechlorethamine to cause serious adverse reactions in nursing infants, a decision should be made to discontinue breast-feeding or discontinue the drug, taking into account the importance of the drug to the mother.

    ADVERSE REACTIONS

    Severe

    exfoliative dermatitis / Delayed / 56.0-56.0
    pruritus / Rapid / 4.0-4.0
    skin ulcer / Delayed / 3.0-3.0
    infection / Delayed / 2.0-2.0
    thrombosis / Delayed / Incidence not known
    tissue necrosis / Early / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    hearing loss / Delayed / Incidence not known

    Moderate

    anemia / Delayed / 0-13.0
    thrombocytopenia / Delayed / 0-13.0
    neutropenia / Delayed / 0-13.0
    secondary malignancy / Delayed / 2.0-2.0
    phlebitis / Rapid / Incidence not known
    lymphopenia / Delayed / Incidence not known
    bleeding / Early / Incidence not known
    leukopenia / Delayed / Incidence not known
    hyperuricemia / Delayed / Incidence not known
    infertility / Delayed / Incidence not known
    clastogenesis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    immunosuppression / Delayed / Incidence not known

    Mild

    skin hyperpigmentation / Delayed / 5.0-5.0
    injection site reaction / Rapid / Incidence not known
    petechiae / Delayed / Incidence not known
    diarrhea / Early / Incidence not known
    vomiting / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    nausea / Early / Incidence not known
    gonadal suppression / Delayed / Incidence not known
    oligomenorrhea / Delayed / Incidence not known
    amenorrhea / Delayed / Incidence not known
    azoospermia / Delayed / Incidence not known
    spermatogenesis inhibition / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    alopecia / Delayed / Incidence not known
    weakness / Early / Incidence not known
    vertigo / Early / Incidence not known
    tinnitus / Delayed / Incidence not known

    DRUG INTERACTIONS

    Aldesleukin, IL-2: (Moderate) The safety and efficacy of aldesleukin, IL 2 in combination with any antineoplastic agents have not been established. Hypersensitivity reactions have been reported in patients receiving combination regimens containing sequential high dose aldesleukin, IL 2 and dacarbazine. Aldesleukin, IL 2 can decrease dacarbazine serum concentrations by increasing the volume of distribution of dacarbazine by 36 percent via an unknown mechanism.
    Carbamazepine: (Moderate) Myelosuppressive antineoplastic agents and radiation therapy possess hematologic toxicities similar to carbamazepine, and should be used concomitantly with caution. Dosage adjustments may be necessary. Monitor patient closely. Carbamazepine may potentially accelerate the hepatic metabolism of dacarbazine, DTIC.
    Celecoxib: (Major) Mechlorethamine, nitrogen mustard is highly toxic and is associated with lymphocytopenia, granulocytopenia, and thrombocytopenia. Due to the thrombocytopenic effects of mechlorethamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Diclofenac: (Major) Mechlorethamine, nitrogen mustard is highly toxic and is associated with lymphocytopenia, granulocytopenia, and thrombocytopenia. Due to the thrombocytopenic effects of mechlorethamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diclofenac; Misoprostol: (Major) Mechlorethamine, nitrogen mustard is highly toxic and is associated with lymphocytopenia, granulocytopenia, and thrombocytopenia. Due to the thrombocytopenic effects of mechlorethamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diflunisal: (Major) Mechlorethamine, nitrogen mustard is highly toxic and is associated with lymphocytopenia, granulocytopenia, and thrombocytopenia. Due to the thrombocytopenic effects of mechlorethamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Digoxin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Diphenhydramine; Ibuprofen: (Major) Mechlorethamine, nitrogen mustard is highly toxic and is associated with lymphocytopenia, granulocytopenia, and thrombocytopenia. Due to the thrombocytopenic effects of mechlorethamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diphenhydramine; Naproxen: (Major) Mechlorethamine, nitrogen mustard is highly toxic and is associated with lymphocytopenia, granulocytopenia, and thrombocytopenia. Due to the thrombocytopenic effects of mechlorethamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to drugs that alter immune system activity like antineoplastic drugs. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    Esomeprazole; Naproxen: (Major) Mechlorethamine, nitrogen mustard is highly toxic and is associated with lymphocytopenia, granulocytopenia, and thrombocytopenia. Due to the thrombocytopenic effects of mechlorethamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Etodolac: (Major) Mechlorethamine, nitrogen mustard is highly toxic and is associated with lymphocytopenia, granulocytopenia, and thrombocytopenia. Due to the thrombocytopenic effects of mechlorethamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Famotidine; Ibuprofen: (Major) Mechlorethamine, nitrogen mustard is highly toxic and is associated with lymphocytopenia, granulocytopenia, and thrombocytopenia. Due to the thrombocytopenic effects of mechlorethamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Febuxostat: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
    Fenoprofen: (Major) Mechlorethamine, nitrogen mustard is highly toxic and is associated with lymphocytopenia, granulocytopenia, and thrombocytopenia. Due to the thrombocytopenic effects of mechlorethamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Flucytosine: (Minor) Flucytosine can cause significant hematologic toxicity. It should be used cautiously with all antineoplastic agents, especially those that cause bone marrow depression.
    Flurbiprofen: (Major) Mechlorethamine, nitrogen mustard is highly toxic and is associated with lymphocytopenia, granulocytopenia, and thrombocytopenia. Due to the thrombocytopenic effects of mechlorethamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Hydrocodone; Ibuprofen: (Major) Mechlorethamine, nitrogen mustard is highly toxic and is associated with lymphocytopenia, granulocytopenia, and thrombocytopenia. Due to the thrombocytopenic effects of mechlorethamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ibuprofen: (Major) Mechlorethamine, nitrogen mustard is highly toxic and is associated with lymphocytopenia, granulocytopenia, and thrombocytopenia. Due to the thrombocytopenic effects of mechlorethamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ibuprofen; Oxycodone: (Major) Mechlorethamine, nitrogen mustard is highly toxic and is associated with lymphocytopenia, granulocytopenia, and thrombocytopenia. Due to the thrombocytopenic effects of mechlorethamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ibuprofen; Pseudoephedrine: (Major) Mechlorethamine, nitrogen mustard is highly toxic and is associated with lymphocytopenia, granulocytopenia, and thrombocytopenia. Due to the thrombocytopenic effects of mechlorethamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Indomethacin: (Major) Mechlorethamine, nitrogen mustard is highly toxic and is associated with lymphocytopenia, granulocytopenia, and thrombocytopenia. Due to the thrombocytopenic effects of mechlorethamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ketoprofen: (Major) Mechlorethamine, nitrogen mustard is highly toxic and is associated with lymphocytopenia, granulocytopenia, and thrombocytopenia. Due to the thrombocytopenic effects of mechlorethamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ketorolac: (Major) Mechlorethamine, nitrogen mustard is highly toxic and is associated with lymphocytopenia, granulocytopenia, and thrombocytopenia. Due to the thrombocytopenic effects of mechlorethamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Lansoprazole; Naproxen: (Major) Mechlorethamine, nitrogen mustard is highly toxic and is associated with lymphocytopenia, granulocytopenia, and thrombocytopenia. Due to the thrombocytopenic effects of mechlorethamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Live Vaccines: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Meclofenamate Sodium: (Major) Mechlorethamine, nitrogen mustard is highly toxic and is associated with lymphocytopenia, granulocytopenia, and thrombocytopenia. Due to the thrombocytopenic effects of mechlorethamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Mefenamic Acid: (Major) Mechlorethamine, nitrogen mustard is highly toxic and is associated with lymphocytopenia, granulocytopenia, and thrombocytopenia. Due to the thrombocytopenic effects of mechlorethamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Meloxicam: (Major) Mechlorethamine, nitrogen mustard is highly toxic and is associated with lymphocytopenia, granulocytopenia, and thrombocytopenia. Due to the thrombocytopenic effects of mechlorethamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Nabumetone: (Major) Mechlorethamine, nitrogen mustard is highly toxic and is associated with lymphocytopenia, granulocytopenia, and thrombocytopenia. Due to the thrombocytopenic effects of mechlorethamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Naproxen: (Major) Mechlorethamine, nitrogen mustard is highly toxic and is associated with lymphocytopenia, granulocytopenia, and thrombocytopenia. Due to the thrombocytopenic effects of mechlorethamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Naproxen; Pseudoephedrine: (Major) Mechlorethamine, nitrogen mustard is highly toxic and is associated with lymphocytopenia, granulocytopenia, and thrombocytopenia. Due to the thrombocytopenic effects of mechlorethamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Naproxen; Sumatriptan: (Major) Mechlorethamine, nitrogen mustard is highly toxic and is associated with lymphocytopenia, granulocytopenia, and thrombocytopenia. Due to the thrombocytopenic effects of mechlorethamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Nonsteroidal antiinflammatory drugs: (Major) Mechlorethamine, nitrogen mustard is highly toxic and is associated with lymphocytopenia, granulocytopenia, and thrombocytopenia. Due to the thrombocytopenic effects of mechlorethamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Oxaprozin: (Major) Mechlorethamine, nitrogen mustard is highly toxic and is associated with lymphocytopenia, granulocytopenia, and thrombocytopenia. Due to the thrombocytopenic effects of mechlorethamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Piroxicam: (Major) Mechlorethamine, nitrogen mustard is highly toxic and is associated with lymphocytopenia, granulocytopenia, and thrombocytopenia. Due to the thrombocytopenic effects of mechlorethamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Rofecoxib: (Major) Mechlorethamine, nitrogen mustard is highly toxic and is associated with lymphocytopenia, granulocytopenia, and thrombocytopenia. Due to the thrombocytopenic effects of mechlorethamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Sipuleucel-T: (Major) Concomitant use of sipuleucel-T and antineoplastic agents should be avoided. Concurrent administration of antineoplastic agents with the leukapheresis procedure that occurs prior to sipuleucel-T infusion has not been studied. Sipuleucel-T stimulates the immune system and patients receiving antineoplastic agents may have a diminished response to sipuleucel-T. When appropriate, consider discontinuing or reducing the dose of antineoplastic agents prior to initiating therapy with sipuleucel-T.
    Sulindac: (Major) Mechlorethamine, nitrogen mustard is highly toxic and is associated with lymphocytopenia, granulocytopenia, and thrombocytopenia. Due to the thrombocytopenic effects of mechlorethamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Tolmetin: (Major) Mechlorethamine, nitrogen mustard is highly toxic and is associated with lymphocytopenia, granulocytopenia, and thrombocytopenia. Due to the thrombocytopenic effects of mechlorethamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Valdecoxib: (Major) Mechlorethamine, nitrogen mustard is highly toxic and is associated with lymphocytopenia, granulocytopenia, and thrombocytopenia. Due to the thrombocytopenic effects of mechlorethamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.

    PREGNANCY AND LACTATION

    Pregnancy

    Mechlorethamine may cause fetal harm when administered during pregnancy based on its mechanism of action, data from animal studies, and reports in humans; pregnant women should avoid exposure to mechlorethamine. There are case reports of children born with malformations following systemic mechlorethamine use. Females of reproductive potential should avoid pregnancy. If mechlorethamine is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Fetal malformations including fetal death and growth retardation occurred in animals after a single subcutaneous 1 mg/kg dose.

    It is not known whether mechlorethamine is excreted in human milk. Because many drugs are
    excreted in human milk and because of the potential for topical or systemic maternal exposure from mechlorethamine to cause serious adverse reactions in nursing infants, a decision should be made to discontinue breast-feeding or discontinue the drug, taking into account the importance of the drug to the mother.

    MECHANISM OF ACTION

    Mechanism of Action: Mechlorethamine is a bifunctional alkylating agent and exerts its chemotherapeutic effects by substituting alkyl groups for hydrogen ions in a number of organic compounds. Mechlorethamine reacts readily with phosphate, amino, hydroxyl, sulfhydryl, carboxyl, and imidazole groups on amino acids. DNA-DNA interstrand and DNA-protein crosslinking occur, leading to DNA strand breakage and interference in DNA replication, transcription of RNA, and nucleic acid function. Cellular functions such as protein synthesis and glycolysis are impaired. Besides being an antineoplastic, mechlorethamine also is a mutagen and radiomimetic.

    PHARMACOKINETICS

    Mechlorethamine is administered via intravenous, intracavitary and topical administration. The active form of mechlorethamine reacts with various components of the cell before becoming inactivated by the body fluids. Metabolites of the drug are excreted in the urine.

    Intravenous Route

    Following IV administration, mechlorethamine is rapidly transformed to its active form; unchanged drug is undetectable in the blood a few minutes after administration.

    Topical Route

    Systemic exposure was undetectable in 16 patients who received mechlorethamine 0.016% topical gel (equivalent to mechlorethamine hydrochloride 0.02%). In these patients, no detectable plasma mechlorethamine concentrations were found in blood samples obtained after 1 day and 1 month of topical use.

    Other Route(s)

    Intracavitary Route
    Intracavitary injection results in incomplete absorption of mechlorethamine, probably due to rapid inactivation of the drug by the body fluids.