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Melphalan

Pronunciation

(MEL fa lan)

Index Terms

  • L-PAM
  • L-Phenylalanine Mustard
  • L-Sarcolysin
  • Phenylalanine Mustard

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

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Solution Reconstituted, Intravenous:

Alkeran: 50 mg (1 ea) [contains alcohol, usp, propylene glycol]

Generic: 50 mg (1 ea)

Tablet, Oral:

Alkeran: 2 mg

Brand Names: U.S.

  • Alkeran

Pharmacologic Category

  • Antineoplastic Agent, Alkylating Agent
  • Antineoplastic Agent, Alkylating Agent (Nitrogen Mustard)

Pharmacology

Alkylating agent which is a derivative of mechlorethamine that inhibits DNA and RNA synthesis via formation of carbonium ions; cross-links strands of DNA; acts on both resting and rapidly dividing tumor cells.

Absorption

Oral: Variable and incomplete

Distribution

Vd: 0.5 L/kg; low penetration into CSF

Metabolism

Hepatic; chemical hydrolysis to monohydroxymelphalan and dihydroxymelphalan

Excretion

Oral: Feces (20% to 50%); urine (~10% as unchanged drug)

Time to Peak

Serum: Oral: ~1-2 hours

Half-Life Elimination

Terminal: IV: 75 minutes; Oral: 1-2 hours

Protein Binding

53% to 92%; primarily to albumin (40% to 60%), ~20% to alpha1-acid glycoprotein

Use: Labeled Indications

Multiple myeloma: Palliative treatment of multiple myeloma (injection and tablets).

Ovarian carcinoma: Palliative treatment of nonresectable epithelial ovarian carcinoma (tablets)

Use: Unlabeled

Treatment of Hodgkin lymphoma (relapsed/refractory), light chain amyloidosis; conditioning regimen for autologous hematopoietic stem cell transplantation in adults with hematologic disorders (eg, multiple myeloma) and autologous marrow or stem cell transplantation in pediatric neuroblastoma

Contraindications

Hypersensitivity to melphalan or any component of the formulation; patients whose disease was resistant to prior melphalan therapy

Dosage

Note: Melphalan is associated with a moderate emetic potential (depending on dose and/or administration route); antiemetics may be recommended to prevent nausea and vomiting (Dupuis, 2011).

Oral: Adults (adjust dose based on patient response and weekly blood counts):

Multiple myeloma (palliative treatment): Note: Response is gradual; may require repeated courses to realize benefit:

Usual dose (as described in the manufacturer’s labeling):

6 mg once daily for 2 to 3 weeks initially, followed by up to 4 weeks rest, then a maintenance dose of 2 mg daily as hematologic recovery begins or

10 mg daily for 7 to 10 days; institute 2 mg daily maintenance dose after WBC >4,000 cells/mm3 and platelets >100,000 cells/mm3 (~4 to 8 weeks); titrate maintenance dose to hematologic response or

0.15 mg/kg/day for 7 days, with a 2 to 6 week rest, followed by a maintenance dose of ≤0.05 mg/kg/day as hematologic recovery begins or

0.25 mg/kg/day for 4 days (or 0.2 mg/kg/day for 5 days); repeat at 4- to 6-week intervals as ANC and platelet counts return to normal

Other dosing regimens in combination therapy (off-label doses):

4 mg/m2/day for 7 days every 4 weeks (in combination with prednisone or with prednisone and thalidomide) (Palumbo, 2006; Palumbo, 2008) or

6 mg/m2/day for 7 days every 4 weeks (in combination with prednisone) (Palumbo, 2004) or

0.25 mg/kg/day for 4 days every 6 weeks (in combination with prednisone [Facon, 2006; Facon, 2007] or with prednisone and thalidomide [Facon, 2007]) or

9 mg/m2/day for 4 days every 6 weeks (in combination with prednisone or with prednisone and bortezomib) (Dimopoulos, 2009; San Miguel, 2008)

Ovarian carcinoma: 0.2 mg/kg/day for 5 days, repeat every 4 to 5 weeks or

Off-label dosing: 7 mg/m2/day in 2 divided doses for 5 days, repeat every 28 days (Wadler, 1996)

Amyloidosis, light chain (off-label use): 0.22 mg/kg/day for 4 days every 28 days (in combination with oral dexamethasone) (Palladini, 2004) or 10 mg/m2/day for 4 days every month (in combination with oral dexamethasone) for 12 to 18 treatment cycles (Jaccard, 2007)

IV:

Children (off-label use): Conditioning regimen for autologous hematopoietic stem cell transplantation:

140 mg/m2 2 days prior to transplantation (combined with busulfan) (Canete, 2009; Oberlin, 2006) or

180 mg/m2 (with pre- and posthydration) 12 to 30 hours prior to transplantation (Pritchard, 2005) or

45 mg/m2/day for 4 days starting 8 days prior to transplantation (combined with busulfan or etoposide and carboplatin) (Berthold, 2005)

Adults:

Multiple myeloma (palliative treatment): 16 mg/m2 administered at 2-week intervals for 4 doses, then administer at 4-week intervals after adequate hematologic recovery.

Conditioning regimen for autologous hematopoietic stem cell transplantation (off-label use):

200 mg/m2 alone 2 days prior to transplantation (Fermand, 2005; Moreau, 2002) or

140 mg/m2 2 days prior to transplantation (combined with busulfan) (Fermand, 2005) or

140 mg/m2 2 days prior to transplantation (combined with total body irradiation [TBI]) (Moreau, 2002) or

140 mg/m2 5 days prior to transplantation (combined with TBI) (Barlogie, 2006)

Hodgkin lymphoma, relapsed/refractory (off-label use): 30 mg/m2 on day 6 of combination chemotherapy (mini-BEAM) regimen (Colwill, 1995; Martin, 2001)

Elderly: Refer to adult dosing; use caution and begin at the lower end of dosing range

Dosage adjustment for toxicity:

Oral:

WBC <3,000/mm3: Withhold treatment until recovery

Platelets <100,000/mm3: Withhold treatment until recovery

IV: Adjust dose based on blood cell count at the nadir and day of treatment

Dosing adjustment in renal impairment:

The manufacturer's labeling contains the following adjustment recommendations (for approved dosing levels) based on route of administration:

Oral: Moderate-to-severe renal impairment: Consider a reduced dose initially

IV: BUN ≥30 mg/dL: Reduce dose by up to 50%

The following adjustments have also been recommended:

Aronoff, 2007: Adults: Oral (based on a 6 mg once-daily dose):

CrCl 10 to 50 mL/minute: Administer 75% of dose

CrCl <10 mL/minute: Administer 50% of dose

Hemodialysis: Administer dose after hemodialysis

Continuous ambulatory peritoneal dialysis (CAPD): Administer 50% of dose

Continuous renal replacement therapy (CRRT): Administer 75% of dose

Carlson, 2005: Oral (for melphalan-prednisone combination therapy; based on a study evaluating toxicity with melphalan dosed at 0.25 mg/kg/day for 4 days/cycle):

CrCl >10 to <30 mL/minute: Administer 75% of dose

CrCl ≤10 mL/minute: Data is insufficient for a recommendation

Kintzel, 1995:

Oral: Adjust dose in the presence of hematologic toxicity

IV:

CrCl 46 to 60 mL/minute: Administer 85% of normal dose

CrCl 31 to 45 mL/minute: Administer 75% of normal dose

CrCl <30 mL/minute: Administer 70% of normal dose

Badros, 2001: IV: Autologous stem cell transplant (single-agent conditioning regimen; no busulfan or irradiation): Serum creatinine >2 mg/dL: Reduce dose from 200 mg/m2 over 2 days (as 100 mg/m2/day for 2 days) to 140 mg/m2 given as a single-dose infusion

Dosing adjustment in hepatic impairment: Melphalan is hepatically metabolized; however, dosage adjustment does not appear to be necessary (King, 2001).

Dosing in obesity:

American Society of Clinical Oncology (ASCO) Guidelines for appropriate chemotherapy dosing in obese adults with cancer (Note: Excludes HSCT dosing): 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).

American Society for Blood and Marrow Transplantation (ASBMT) practice guideline committee position statement on chemotherapy dosing in obesity: Utilize actual body weight (full weight) for calculation of body surface area in melphalan dosing for hematopoietic stem cell transplant conditioning regimens in adults (Bubalo, 2014).

Reconstitution

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Injection: Stability is limited; must be prepared fresh. The time between reconstitution/dilution and administration of parenteral melphalan must be kept to a minimum (manufacturer recommends <60 minutes) because reconstituted and diluted solutions are unstable. Dissolve powder initially with 10 mL of supplied diluent to a concentration of 5 mg/mL; shake immediately and vigorously to dissolve. Immediately dilute dose in NS to a concentration of ≤0.45 mg/mL (manufacturer recommended concentration). Do not refrigerate solution; precipitation occurs if stored at 5°C. The manufacturer recommends administration within 60 minutes of reconstitution.

Administration

Melphalan is associated with a moderate emetic potential (depending on dose and/or administration route); antiemetics may be recommended to prevent nausea and vomiting (Dupuis, 2011).

Oral: Administer on an empty stomach (Schmidt, 2002)

Parenteral: Due to limited stability, complete administration of IV dose should occur within 60 minutes of reconstitution

IV: Infuse over 15 to 20 minutes. Extravasation may cause local tissue damage; administration by slow injection into a fast running IV solution into an injection port or via a central line is recommended; do not administer by direct injection into a peripheral vein.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Compatibility

Incompatible with D5W, LR.

Y-site administration: Incompatible with amphotericin B, chlorpromazine.

Storage

Tablet: Store in refrigerator at 2°C to 8°C (36°F to 46°F). Protect from light.

Injection: Store intact vials at 20°C to 25°C (68°F to 77°F). Protect from light. The manufacturer recommends administration be completed within 60 minutes of reconstitution; immediately dilute dose in NS. Do not refrigerate solution; precipitation occurs.

Drug Interactions

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

Carmustine: Melphalan may enhance the adverse/toxic effect of Carmustine. Specifically, melphalan may sensitize patients to carmustine lung toxicity. Monitor therapy

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

CycloSPORINE (Systemic): Melphalan may enhance the nephrotoxic effect of CycloSPORINE (Systemic). Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

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

Nalidixic Acid: May enhance the adverse/toxic effect of Melphalan. Necrotic enterocolitis has been reported in pediatric patients. Avoid combination

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

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

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

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

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

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. Avoid combination

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

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. Avoid combination

Test Interactions

False-positive Coombs' test [direct]

Adverse Reactions

>10%:

Gastrointestinal: Nausea/vomiting, diarrhea, oral ulceration

Hematologic: Myelosuppression, leukopenia (nadir: 14-21 days; recovery: 28-35 days), thrombocytopenia (nadir: 14-21 days; recovery: 28-35 days), anemia

Miscellaneous: Secondary malignancy (<2% to 20%; cumulative dose and duration dependent, includes acute myeloid leukemia, myeloproliferative syndrome, carcinoma)

1% to 10%: Miscellaneous: Hypersensitivity (IV: 2%; includes bronchospasm, dyspnea, edema, hypotension, pruritus, rash, tachycardia, urticaria)

Infrequent, frequency undefined, postmarketing, and/or case reports: Agranulocytosis, allergic reactions, alopecia, amenorrhea, anaphylaxis (rare), bleeding (with high-dose therapy),, bone marrow failure (irreversible), BUN increased, cardiac arrest, cardiotoxicity (angina, arrhythmia, hypertension, MI; with high-dose therapy), encephalopathy, hemolytic anemia, hemorrhagic cystitis, hepatic sinusoidal obstruction syndrome (SOS; veno-occlusive disease; high-dose IV melphalan), hepatitis, infection, injection site reactions (ulceration, necrosis), interstitial pneumonitis, jaundice, mucositis (with high-dose therapy), ovarian suppression, paralytic ileus (with high-dose therapy), pruritus, pulmonary fibrosis, radiation myelopathy, rash (maculopapular), renal toxicity (with high-dose therapy), seizure (with high-dose therapy), sepsis, SIADH, skin hypersensitivity, sterility, stomatitis, testicular suppression, tingling sensation, transaminases increased, vasculitis, warmth sensation

ALERT: U.S. Boxed Warning

Experienced physician:

Administer melphalan under the supervision of a qualified health care provider experienced in the use of cancer chemotherapeutic agents.

Bone marrow suppression:

Severe bone marrow suppression with resulting infection or bleeding may occur. Controlled trials comparing intravenous (IV) to oral melphalan have shown more myelosuppression with the IV formulation.

Secondary malignancy:

Melphalan is leukemogenic in humans. Melphalan produces chromosomal aberrations in vitro and in vivo and, therefore, should be considered potentially mutagenic in humans.

Hypersensitivity (injection):

Hypersensitivity reactions, including anaphylaxis, have occurred in approximately 2% of patients who received the IV formulation.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: [U.S. Boxed Warning]: Bone marrow suppression is common; may be severe and result in infection or bleeding; has been demonstrated more with the IV formulation (compared to oral). Myelosuppression is dose-related. Monitor blood counts; may require treatment delay or dose modification for thrombocytopenia or neutropenia. Use with caution in patients with prior bone marrow suppression, impaired renal function (consider dose reduction), or who have received prior (or concurrent) chemotherapy or irradiation. Myelotoxicity is generally reversible, although irreversible bone marrow failure has been reported. In patients who are candidates for autologous transplantation, avoid melphalan-containing regimens prior to transplant (due to the effects on stem cell reserve).

• Fertility effects: Suppresses ovarian function and produces amenorrhea; may also cause testicular suppression.

• Gastrointestinal toxicity: Gastrointestinal toxicities, including nausea, vomiting, diarrhea and mucositis are common. When administering high-dose melphalan in autologous transplantation, cryotherapy is recommended to prevent oral mucositis (Lalla, 2014). Melphalan is associated with a moderate emetic potential (depending on dose and/or administration route); antiemetics may be recommended to prevent nausea and vomiting (Dupuis, 2011).

• Hepatotoxicity: Abnormal liver function tests may occur; hepatitis and jaundice have also been reported. Hepatic sinusoidal obstruction syndrome (SOS; formerly called veno-occlusive disease [VOD]) has been reported with IV melphalan.

• Hypersensitivity reactions: [U.S. Boxed Warning]: Hypersensitivity reactions (including anaphylaxis) have occurred in ~2% of patients receiving IV melphalan, usually after multiple treatment cycles. Discontinue infusion and treat symptomatically. Hypersensitivity may also occur (rarely) with oral melphalan. Do not readminister (oral or IV) in patients who experience hypersensitivity to melphalan.

• Pulmonary toxicity: Pulmonary fibrosis (some fatal) and interstitial pneumonitis have been observed with treatment.

• Secondary malignancy: [U.S. Boxed Warning]: Produces chromosomal abnormalities and is leukemogenic and potentially mutagenic. Secondary malignancies (including acute myeloid leukemia, myeloproliferative disease, and carcinoma) have been reported (some patients were receiving combination chemotherapy or radiation therapy); the risk is increased with increased treatment duration and cumulative doses.

Disease-related concerns:

• Infection: Signs of infection, such as fever and WBC rise, may not occur; lethargy and confusion may be more prominent signs of infection.

• Renal impairment: Dosage reduction is recommended with IV melphalan in patients with renal impairment; reduced initial doses may also be recommended with oral melphalan. Closely monitor patients with azotemia.

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 populations:

• Elderly: Toxicity may be increased in elderly; start with lowest recommended adult doses.

Dosage from specific issues:

• Intravenous: Extravasation may cause local tissue damage. Administration by slow injection into a fast running IV solution into an injection port or via a central line is recommended; do not administer directly into a peripheral vein.

• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures and respiratory depression; use caution (AAP, 1997; Zar, 2007).

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Other warnings/precautions:

• Experienced physician: [U.S. Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician.

• Immunizations: Avoid vaccination with live vaccines during treatment if immunocompromised.

Monitoring Parameters

CBC with differential and platelet count, serum electrolytes, serum uric acid

Pregnancy Risk Factor

D

Pregnancy Considerations

Animal studies have demonstrated embryotoxicity and teratogenicity. Therapy may suppress ovarian function leading to amenorrhea. There are no adequate and well-controlled studies in pregnant women. May cause fetal harm if administered during pregnancy. Women of childbearing potential should be advised to avoid pregnancy while on melphalan therapy.

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, alopecia, or stomatitis. Have patient report immediately to prescriber signs of infection, signs of hepatic impairment, severe nausea, ecchymosis, hemorrhaging, significant asthenia, angina, tachycardia, intolerable dizziness, syncope, dyspnea, edema, excessive weight loss, amenorrhea, skin growths, signs of severe pulmonary disorder, or injection site 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 healthcare 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.

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