Melphalan

Dosage Forms

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

Solution Reconstituted, Intravenous:

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

Evomela: 50 mg (1 ea)

Generic: 50 mg (1 ea)

Solution Reconstituted, Intravenous [preservative free]:

Generic: 50 mg (1 ea)

Tablet, Oral:

Alkeran: 2 mg

Generic: 2 mg

Pharmacology

Mechanism of Action

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.

Pharmacokinetics/Pharmacodynamics

Absorption

Oral: Variable and incomplete

Distribution

V_d: 0.5 L/kg; Evomela: Penetrates CSF; Alkeran: 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 to 2 hours

Half-Life Elimination

Terminal: IV: ~75 minutes; Oral: 1.5 ± 0.83 hours

Protein Binding

~50% to 92%; primarily to albumin (~40% to 60%), ~20% to alpha₁-acid glycoprotein

Use in Specific Populations

Special Populations: Renal Function Impairment

A decrease in estimated creatinine clearance from 100 mL/minute to 30 mL/minute results in 28.2% reduction in clearance for a person with an ideal body weight (IBW) of 70 kg receiving IV melphalan.

Special Populations Note

Body weight: A patient with an IBW of 45 kg receiving IV melphalan has a 28% decrease in clearance relative to a patient with IBW of 70 kg, while a patient with an IBW of 100 kg has a 31% increase in clearance as compared to a patient with an IBW of 70 kg.

Use: Labeled Indications

Multiple myeloma: Palliative treatment of multiple myeloma (injection [Alkeran and Evomela] and tablets); high-dose conditioning treatment prior to hematopoietic stem cell transplantation (HSCT) (Evomela only).

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

Use: Off Label

Amyloidosis, light chaina

Data from a randomized study support the use of oral melphalan at a standard dose (in combination with high-dose dexamethasone) for the treatment of light chain amyloidosis Jaccard 2007. Data from another study also supports the use of standard-dose oral melphalan (in combination with high-dose dexamethasone) in the treatment of this condition Palladini 2004.

Lymphomas (Hodgkin or Non-Hodgkin)b

Data from a small clinical trial in patients with relapsed or refractory lymphomas (Hodgkin [HL] or non-Hodgkin [NHL]), as well as clinical experience, support the use of a high-dose chemotherapy regimen (carmustine, etoposide, cytarabine, and melphalan; BEAM regimen) prior to autologous stem cell transplant Anderson 1986. Additionally, data from a small study in patients with either HL or NHL support the use of the propylene glycol-free melphalan formulation (Evomela) as a component of the BEAM regimen in patients with lymphomas eligible for autologous stem cell transplantation Cashen 2016. Data from two studies support the use of melphalan (in combination with carmustine, etoposide and cytarabine [mini-BEAM regimen]) as salvage treatment for HL Colwill 1995, Martin 2001.

Contraindications

Hypersensitivity to melphalan or any component of the formulation; patients whose disease was resistant to prior melphalan therapy (Alkeran only).

Canadian labeling: Additional contraindications (not in US labeling): Recent administration of other similar chemotherapeutic agents or radiotherapy; depressed neutrophil and/or platelet counts; concurrent radiotherapy; breastfeeding

Dosage and Administration

Dosing: Adult

Note: Intravenous melphalan is available in different formulations. Indications for use, product preparation, storage, and dosing differ between formulations. Use caution when selecting melphalan formulations for preparation and administration. Do not mix or combine the formulations. Antiemetics may be recommended to prevent nausea and vomiting; IV melphalan is associated with a moderate emetic potential. Adjust dose based on patient response and weekly blood counts.

Multiple myeloma (conditioning regimen prior to hematopoietic stem cell transplantation): IV (Evomela only): 100 mg/m² daily for 2 days on day -3 and day -2 prior to autologous stem cell transplantation on day 0 (Hari 2015). Note: Per the manufacturer, if patients weigh more than 130% of their ideal body weight, body surface area should be calculated using adjusted ideal body weight.

Off-label dosing (propylene glycol-free formulation [Evomela]): Based on limited data: IV: 200 mg/m² as a single dose on day -2 prior to autologous stem cell transplantation on day 0 (followed by filgrastim starting on day +1 after transplant). Data from a small pharmacokinetic study in multiple myeloma patients undergoing autologous stem cell transplant with propylene glycol-free melphalan conditioning showed acceptable toxicity and efficacy with the single dose regimen, although pharmacokinetic variability between patients was high. Further study is necessary to determine optimal clinical benefit of this dosing regimen (Dhakal 2018).

Multiple myeloma conditioning regimen for autologous hematopoietic stem cell transplantation (off-label doses): IV:

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)

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

Oral: 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

IV (Alkeran and Evomela): 16 mg/m² administered at 2-week intervals for 4 doses, then administer at 4-week intervals after adequate hematologic recovery.

Multiple myeloma (previously untreated; transplant ineligible) (off-label dosing/combinations): Oral: ≥65 years of age and/or transplant ineligible:

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) or

9 mg/m²/day for 4 days (days 1 to 4) every 6 weeks for 9 cycles (in combination with daratumumab, bortezomib and prednisone; after cycle 9, daratumumab is continued as a single agent) (Mateos 2018)

Ovarian cancer: Oral: 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): Oral: 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)

Hodgkin lymphoma, relapsed/refractory, salvage therapy (off-label use): IV: Mini-BEAM regimen: 30 mg/m² over 15 minutes on day 6 (in combination with carmustine, etoposide, and cytarabine); repeat cycle every 4 to 6 weeks (Colwill 1995; Martin 2001)

Lymphomas (Hodgkin and non-Hodgkin) conditioning regimen for autologous hematopoietic stem cell transplantation (off-label use): BEAM regimen: IV: 140 mg/m² on day -1 prior to autologous stem cell transplantation on day 0 (in combination with carmustine, etoposide, and cytarabine) (Anderson 1986). Data from a small phase II study in lymphoma patients receiving the BEAM conditioning regimen containing the propylene glycol-free melphalan formulation (Evomela; at a dose of 140 mg/m² on day -2 prior to transplant) demonstrated acceptable safety and efficacy parameters (Cashen 2016).

Dosing: Geriatric

Refer to adult dosing. Use caution and begin at the lower end of dosing range.

Dosing: Pediatric

Refer to individual protocols; details concerning dosing in combination regimens should also be consulted; adjust dose based on patient response and weekly blood counts.

Note: Intravenous melphalan is available in different formulations. Indications for use, product preparation, storage, and dosing differ between formulations. Use caution when selecting melphalan formulations for preparation and administration. Do not mix or combine the formulations. Melphalan is associated with a moderate emetic potential (depending on dose and/or administration route); antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011).

Hematopoietic stem cell transplantation, conditioning regimen for autologous HSCT: Limited data available: Note: Pediatric dosing data based on experience using Alkeran (or corresponding generic) product formulation. Infants, Children, and Adolescents:

Cantete 2009; Oberlin 2006: IV: 140 mg/m² 2 days prior to transplantation (combined with busulfan)

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

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

Dosing adjustment for toxicity: The presented dosing adjustments are based on experience in adult patients; specific recommendations for pediatric patients are limited. Refer to specific protocol for management in pediatric patients if available.

Adult:

Oral:

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

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

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

Dosing: Adjustment for Toxicity

Oral:

WBC <3000/mm³: Withhold treatment until recovery

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

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

Dosing: 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). Note: The manufacturer of Evomela recommends that if patients weigh more than 130% of their ideal body weight, body surface area should be calculated using adjusted ideal body weight.

Reconstitution

Note: Intravenous melphalan is available in different formulations. Indications for use, product preparation, storage, and dosing differ between formulations. Use caution when selecting melphalan formulations for preparation and administration. Do not mix or combine the formulations.

Alkeran injection: Stability is limited; must be prepared fresh. The time between reconstitution/dilution and administration of parenteral melphalan (Alkeran) 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.

Evomela injection: Reconstitute each vial with 8.6 mL of NS to a 5 mg/mL concentration. Further dilute the appropriate dose in NS to a concentration of 0.45 mg/mL.

Administration

Antiemetics may be recommended to prevent nausea and vomiting; IV melphalan is associated with a moderate emetic potential in adults.

Intravenous melphalan is available in different formulations. Indications for use, product preparation, storage, and dosing differ between formulations. Use caution when selecting melphalan formulations for preparation and administration. Do not mix or combine the formulations.

Oral: Administer on an empty stomach (Schmidt 2002)

IV:

Alkeran: Due to limited stability, complete administration of IV dose should occur within 60 minutes of reconstitution. Infuse over 15 to 20 minutes.

Evomela: Infuse over 15 to 20 minutes (palliative treatment for multiple myeloma) or 30 minutes (conditioning regimen for autologous stem cell transplantation).

Melphalan (IV) is an irritant; local reactions may occur (Perez Fidalgo 2012). 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.

Storage

Alkeran injection: Store intact vials at 15°C to 30°C (59°F to 86°F). Protect from light. The manufacturer recommends administration be completed within 60 minutes of reconstitution; immediately dilute dose in NS. Do not refrigerate reconstituted solution; precipitation occurs.

Evomela injection: Store intact vials at 25°C (77°F); excursions are permitted between 15°C to 30°C (59°F to 86°F). Protect from light (store in original container). The reconstituted solution is stable for 1 hour at room temperature or for 24 hours at 5°C (41°F). Solutions diluted in NS for infusion are stable for 4 hours at room temperature (in addition to the 1 hour at room temperature following reconstitution).

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

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

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

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

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

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

Test Interactions

False-positive Coombs' test [direct]

Adverse Reactions

>10%:

Cardiovascular: Peripheral edema (conditioning: 33%)

Central nervous system: Fatigue (≥50%; conditioning: 77%), dizziness (conditioning: 38%)

Endocrine & metabolic: Hypokalemia (≥50% conditioning: 74%), hypophosphatemia (conditioning: 49%)

Gastrointestinal: Diarrhea (≥50%; conditioning: 93%), nausea (≥50%; conditioning: 90%), vomiting (≥50%; conditioning: 64%), decreased appetite (conditioning: 49%), constipation (conditioning: 48%), mucositis (conditioning: 38%), abdominal pain (conditioning: 28%), dysgeusia (conditioning: 28%), stomatitis (conditioning: 28%), dyspepsia (conditioning: 26%)

Hematologic & oncologic: Anemia (≥50%), decreased absolute lymphocyte count (≥50%), decreased neutrophils (≥50%), decreased platelet count (≥50%; nadir: 14 to 21 days; recovery: 28 to 35 days), decreased white blood cell count (≥50%; nadir: 14 to 21 days; recovery: 28 to 35 days), febrile neutropenia (conditioning: 41%; grades 3/4: 28%)

Miscellaneous: Fever (conditioning: 48%)

1% to 10%:

Gastrointestinal: Hematochezia

Genitourinary: Amenorrhea (9%)

Hypersensitivity: Hypersensitivity reaction (IV: 2%; less common in oral formula; includes bronchospasm, dyspnea, edema, hypotension, pruritus, skin rash, tachycardia, urticaria), anaphylaxis (≤2%)

Renal: Renal failure

Frequency not defined:

Cardiovascular: Vasculitis

Central nervous system: Flushing sensation, tingling sensation

Endocrine & metabolic: SIADH (dose related; Greenbaum-Lefkoe 1985)

Genitourinary: Infertility, inhibition of testicular function

Hematologic & oncologic: Bone marrow depression

Hepatic: Hepatic sinusoidal obstruction syndrome (formerly known as hepatic veno-occlusive disease), hepatitis, increased serum transaminases, jaundice

Renal: Increased blood urea nitrogen

Miscellaneous: Chromosomal abnormality

<1%, postmarketing, and/or case reports: Alopecia, bone marrow failure (irreversible), hemolytic anemia, interstitial pneumonitis, maculopapular rash, pulmonary fibrosis, skin ulceration at injection site, tissue necrosis at injection site (rarely requiring skin grafting)

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: [US 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; myeloablation is expected when used in high doses for conditioning regimens prior to stem cell transplantation. Do not administer melphalan-containing conditioning regimen unless the stem cell product is available for rescue. Monitor blood counts; supportive care for infections, anemia, and thrombocytopenia may be necessary. When used for palliative treatment, 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 induction regimens if future transplant may be necessary (due to the effects on stem cell reserve).
• Extravasation: Melphalan is an irritant; local reactions may occur (Perez Fidalgo 2012). 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.
• Fertility effects: Suppresses ovarian function and produces amenorrhea; may also cause reversible or irreversible testicular suppression.
• Gastrointestinal toxicity: Gastrointestinal toxicities, including nausea, vomiting, diarrhea, and mucositis are common, particularly when used in high doses for conditioning regimens (the incidence of grade 3 or 4 mucositis was 13% in clinical trials). When administering high-dose melphalan in autologous transplantation, cryotherapy is recommended to prevent oral mucositis (Lalla 2014). Antiemetics may be recommended to prevent nausea and vomiting; IV melphalan is associated with a high emetic potential in pediatrics (Paw Cho Sing 2019) and a moderate emetic potential in adults. Nutritional support and/or analgesics may be necessary in patients with severe mucositis.
• 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. Monitor liver function tests.
• Hypersensitivity reactions: [US Boxed Warning]: Hypersensitivity reactions (including anaphylaxis) have occurred in ~2% of patients receiving IV melphalan, usually after multiple treatment cycles. Symptoms may include urticaria, pruritus, edema, skin rashes, tachycardia, bronchospasm, dyspnea, and hypotension. 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: [US Boxed Warning]: Produces chromosomal abnormalities in vitro and in vivo. Melphalan should be considered potentially leukemogenic in humans. 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:

• Renal impairment: Dosage reduction is recommended with IV melphalan in patients with renal impairment (when used for palliative treatment); reduced initial doses may also be recommended with oral melphalan. Closely monitor patients with azotemia. High-dose melphalan with autologous stem cell transplant is feasible in patients with multiple myeloma and renal impairment (Dimopoulos 2016). Prolonged mucositis has occurred when standard melphalan doses were administered to patients with chronic kidney disease (Bodge 2014).

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 form specific issues:

• Formulations: Intravenous melphalan is available in different formulations. Evomela (melphalan for injection) is a lyophilized powder which is reconstituted with normal saline to a 5 mg/mL concentration. Alkeran (melphalan hydrochloride for injection) and generic melphalan hydrochloride are also powder formulations which are reconstituted with the supplied diluent (which contains propylene glycol and ethanol) to a 5 mg/mL concentration. Indications for use, product preparation, storage, and dosing differ between formulations. Use caution when selecting melphalan formulations for preparation and administration. Do not mix or combine the formulations.
• 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).

Other warnings/precautions:

• Experienced physician: [US 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, renal/liver function tests, serum uric acid; signs/symptoms of hypersensitivity reaction, pulmonary toxicity, and gastrointestinal toxicity; monitor infusion site.

Pregnancy

Pregnancy Considerations

May cause fetal harm if administered during pregnancy. Females of reproductive potential should be advised to avoid pregnancy. Treatment with melphalan may suppress ovarian function leading to amenorrhea. Reversible and irreversible testicular suppression has been reported in male patients after melphalan administration.

Patient Education

What is this drug used for?

• It is used to treat multiple myeloma.
• It is used to treat cancer of the ovary.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Diarrhea
• Constipation
• Lack of appetite
• Change in taste
• Mouth irritation
• Hair loss
• Abdominal pain
• Mouth sores

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
• Electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting.
• Severe nausea
• Vomiting
• Bruising
• Bleeding
• Severe loss of strength and energy
• Pale skin
• Chest pain
• Fast heartbeat
• Dizziness
• Passing out
• Shortness of breath
• Swelling
• Excessive weight loss
• No menstrual periods
• Skin growths
• Blurred vision
• Severe pulmonary disorder like lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse.
• Severe injection site redness, pain, swelling, or irritation
• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.