Mechlorethamine (Systemic)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution Reconstituted, Injection, as hydrochloride:

Mustargen: 10 mg (1 ea [DSC])

Pharmacology

Mechanism of Action

Mechlorethamine is a bifunctional alkylating agent that inhibits DNA and RNA synthesis via formation of carbonium ions; produces interstrand and intrastrand cross-links in DNA resulting in miscoding, breakage, and failure of replication. Although not cell phase-specific per se, mechlorethamine effect is most pronounced in the S phase, and cell proliferation is arrested in the G₂ phase.

Pharmacokinetics/Pharmacodynamics

Metabolism

Rapid hydrolysis in the plasma to active metabolites (Perry 2012)

Half-Life Elimination

15 to 20 minutes (Perry 2012)

Use: Labeled Indications

Hodgkin lymphoma: Palliative treatment of Hodgkin lymphoma

Use: Off Label

Hodgkin lymphoma (previously untreated)b

Data from multiple studies support the use of mechlorethamine (in combination with doxorubicin, vinblastine, vincristine, bleomycin, etoposide, prednisone, and radiation therapy [Stanford V regimen]) for management previously untreated Hodgkin lymphoma in patients with either early stage (favorable) or advanced stage (unfavorable) disease Advani 2013, Bartlett 1995, Horning 2000, Horning 2002.

Contraindications

Hypersensitivity (prior anaphylactic reaction) to mechlorethamine or any component of the formulation; presence of known infectious diseases

Dosage and Administration

Dosing: Adult

Note: Mustargen has been discontinued in the United States for >1 year.

Dosage should be based on ideal dry weight (evaluate the presence of edema or ascites so that dosage is based on actual weight unaugmented by edema/ascites). Mechlorethamine is associated with a high emetic potential (Hesketh 2017; Roila 2016); antiemetics are recommended to prevent nausea and vomiting. Dosing in the prescribing information does not reflect current clinical practice.

Hodgkin lymphoma, previously untreated (off-label use/dose): IV:

Stanford V regimen:

Favorable/early stage disease: 6 mg/m² as a single dose on day 1 every 4 weeks (in combination with doxorubicin, vinblastine, vincristine, bleomycin, etoposide, prednisone, and radiation therapy) for a total of 2 cycles (Advani 2013)

Unfavorable/advanced stage disease: 6 mg/m² as a single dose on day 1 every 4 weeks (in combination with doxorubicin, vinblastine, vincristine, bleomycin, etoposide, prednisone, and radiation therapy) for a total of 3 cycles (Bartlett 1995; Horning 2000; Horning 2002)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Mustargen has been discontinued in the US for >1 year.

Note: Dosing and frequency may vary by protocol and/or treatment phase; refer to specific protocol. Meclorethamine is associated with a high emetic potential (Dupuis 2011); antiemetics are recommended to prevent nausea and vomiting (Dupuis 2013).

Hodgkin lymphoma:

MOPP regimen: Note: The MOPP (with or without ABVD) regimen is generally no longer used due to improved toxicity profiles with other combination regimens used in the treatment of Hodgkin lymphoma (Kelly 2012). Children and Adolescents: IV: 6 mg/m² on days 1 and 8 of a 28-day cycle in combination with vincristine, procarbazine, and prednisone, may or may not alternate with doxorubicin, bleomycin, vinblastine, dacarbazine (MOPP/ABVD) (Kung 2006; Longo 1986)

Stanford V regimen: Adolescents ≥16 years: IV: 6 mg/m² as a single dose on day 1 in weeks 1, 5, and 9 (Horning 2000; Horning 2002; Metzger 2012)

Dosing: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: In general, utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs 2012). Note: The manufacturer recommends dosing be based on ideal dry body weight and the presence of edema or ascites should be considered so the dose will be based on unaugmented weight.

Reconstitution

Must be prepared immediately before use; degradation begins shortly after dilution. Reconstitute powder with 10 mL SWFI or NS to a final concentration of 1 mg/mL. Shake vial several times to dissolve completely.

Administration

IV: Administer as a slow IV push over a few minutes into a free-flowing IV solution. Mechlorethamine is associated with a high emetic potential (Dupuis 2011; Hesketh 2017; Roila 2016); antiemetics are recommended to prevent nausea and vomiting.

Prepare immediately prior to administration.

Vesicant; ensure proper needle or catheter placement prior to and during infusion; avoid extravasation.

Extravasation management: If extravasation occurs, stop infusion immediately and disconnect (leave cannula/needle in place); gently aspirate extravasated solution (do NOT flush the line); remove needle/cannula; elevate extremity.

Sodium thiosulfate 1/6 M solution: Inject subcutaneously into extravasation area using 2 mL for each mg of mechlorethamine suspected to have extravasated (Perez Fidalgo 2012; Polovich 2009). Apply ice for 6 to 12 hours after sodium thiosulfate administration (Mustargen prescribing information 2013; Polovich 2009) or may apply dry cold compresses for 20 minutes 4 times daily for 1 to 2 days (Perez Fidalgo 2012).

Storage

Store intact vials at room temperature of 15°C to 30°C (59°F to 86°F). Protect from light. Protect from humidity. Must be prepared immediately before use; degradation begins shortly after dilution.

Drug Interactions

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Adverse Reactions

Frequency not defined.

Cardiovascular: Local thrombophlebitis

Central nervous system: Brain disease (high dose), drowsiness, headache, lethargy, metallic taste, sedation, vertigo

Dermatologic: Alopecia, diaphoresis, erythema multiforme, maculopapular rash, skin rash

Endocrine & metabolic: Amenorrhea, hyperuricemia, oligomenorrhea

Gastrointestinal: Anorexia, diarrhea, mucositis, nausea, vomiting

Genitourinary: Inhibition of spermatogenesis

Hematologic & oncologic: Agranulocytosis, granulocytopenia (onset: 6 to 8 days; recovery: 10 to 21 days), hemolytic anemia, leukopenia, lymphocytopenia, pancytopenia, petechia, thrombocytopenia

Hepatic: Jaundice

Hypersensitivity: Anaphylaxis, hypersensitivity reaction

Infection: Herpes zoster

Neuromuscular & skeletal: Weakness

Ophthalmic: Lacrimation

Otic: Deafness, tinnitus

Miscellaneous: Fever, tissue necrosis (extravasation)

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Mechlorethamine may cause hematologic toxicity, including leukopenia, neutropenia, thrombocytopenia, anemia, and lymphopenia. The onsets for neutropenia and thrombocytopenia occur within 6 to 8 days and last for 10 to 21 days. Anemia typically has an onset within 2 weeks and is generally mild. The lymphocytopenia onset occurs within 1 day. Agranulocytopenia or hemolytic anemia may rarely occur. Severe hematologic toxicity may occur in patients with widespread disease, poor performance status, and/or those previously treated with other antineoplastic agents or radiation therapy. Bone marrow suppression may be prolonged (up to 50 days or longer); persistent pancytopenia has also been reported. Monitor blood counts. Bleeding due to severe thrombocytopenia may occur. Use with caution in patients with preexisting leukopenia, thrombocytopenia, and anemia or with tumor invasion of the bone marrow; treatment response (as defined by the absence of tumor in the bone marrow) may be associated with improvement of bone marrow function. However, in nonresponders or heavily pretreated patients, hematopoietic function may be further compromised, leading to more severe (and potentially fatal) leukopenia, thrombocytopenia, and anemia. Bone marrow function should recover after mechlorethamine administration prior to initiating radiation therapy or other chemotherapy regimens.
• Extravasation: Mechlorethamine is a vesicant. [US Boxed Warning]: Extravasation results in painful inflammation with induration and sloughing. If extravasation occurs, promptly manage by infiltrating area with 1/6 molar sodium thiosulfate solution, followed by dry cold compresses for 6 to 12 hours to minimize the 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. Ensure proper needle or catheter placement prior to and during infusion. Avoid extravasation.
• Gastrointestinal toxicities: Mechlorethamine is associated with a high emetic potential (Dupuis 2011; Hesketh 2017; Roila 2016); antiemetics are recommended to prevent nausea and vomiting. Nausea may persist for up to 24 hours.
• Hypersensitivity: Hypersensitivity reactions, including anaphylaxis, have been reported.
• Immunosuppression: Mechlorethamine has immunosuppressant properties. May predispose patients to infections (bacterial, viral, or fungal).
• Secondary malignancies: Alkylating agents, including mechlorethamine, are associated with an increased incidence of secondary malignancies; concurrent radiation therapy or combination chemotherapy may increase the risk.
• Tumor lysis syndrome: Hyperuricemia may occur, especially with lymphomas; ensure adequate hydration; consider antihyperuricemic therapy if appropriate.

Disease-related concerns:

• Amyloidosis: Nitrogen mustards may contribute to extensive/rapid development of amyloidosis. Mechlorethamine should only be used if foci of suppurative inflammation (acute and chronic) are absent.
• Nonresponding tumors: Bone and nervous system tumors typically respond poorly to mechlorethamine. The routine use of mechlorethamine in widely disseminated tumors is discouraged.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special handling:

• Hazardous agent: [US Boxed Warning]: Mechlorethamine is a highly toxic nitrogen mustard; avoid inhalation of vapors or dust; avoid dust or vapor contact with skin or eyes; review and follow special handling procedures. If accidental skin exposure occurs, wash/irrigate thoroughly with water for at least 15 minutes, followed by 2% sodium thiosulfate solution; remove and destroy any contaminated clothing. If exposure to eye(s) occurs, promptly irrigate for at least 15 minutes with copious amounts of water, normal saline, or balanced salt ophthalmic irrigating solution; obtain ophthalmology consultation. The manufacturer recommends neutralizing remaining unused mechlorethamine, empty or partial vials, gloves, tubing, glassware, etc., after mechlorethamine administration; soak in an aqueous solution containing equal volumes of sodium thiosulfate (5%) and sodium bicarbonate (5%) for 45 minutes; rinse with water; dispose of properly.

Other warnings/precautions:

• Experienced physician: [US Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician.
• Topical application: A gel formulation is commercially approved for topical treatment of cutaneous T-cell lymphoma (mycosis fungoides-type); refer to Mechlorethamine (Topical) monograph.

Monitoring Parameters

CBC with differential and platelet count; renal and hepatic function. Monitor for signs/symptoms of hypersensitivity reactions and infection. Monitor infusion site for extravasation.

Pregnancy

Pregnancy Risk Factor

D

Pregnancy Considerations

[US Boxed Warning]: Mechlorethamine 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 (eg, teratogenicity), special handling procedures should be reviewed prior to handling and followed diligently.

Mechlorethamine may cause fetal harm if administered to a pregnant female. Females of reproductive potential are advised not to become pregnant during mechlorethamine treatment.

Delayed menses, oligomenorrhea, or temporary or permanent amenorrhea may be observed in female patients treated with mechlorethamine. Impaired spermatogenesis, azoospermia, and total germinal aplasia may occur in male patients treated with mechlorethamine, particularly when used in combination with other chemotherapy agents.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience diarrhea, lack of appetite, nausea, or vomiting. Have patient report immediately to prescriber signs of infection, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), severe loss of strength and energy, or severe injection site redness, burning, edema, pain, or irritation (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.