Version May 2024
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. Monitor hematologic laboratory parameters. Myelosuppression with resulting severe infection, bleeding, or symptomatic anemia may occur with melphalan administered intra-arterially as a percutaneous hepatic perfusion (PHP) (Hepzato). Monitor hematologic laboratory parameters and delay additional cycles of melphalan administered intra-arterially via PHP until blood counts have improved.
Melphalan produces chromosomal aberrations in vitro and in vivo. Melphalan should be considered potentially leukemogenic in humans.
Hypersensitivity reactions, including anaphylaxis, have occurred in approximately 2% of patients who received the IV formulation of melphalan. Discontinue treatment with melphalan for serious hypersensitivity reactions.
Administer melphalan under the supervision of a qualified health care provider experienced in the use of cancer chemotherapeutic agents.
Severe periprocedural complications, including hemorrhage, hepatocellular injury, and thromboembolic events may occur via hepatic intra-arterial administration of melphalan. Assess patients for these adverse reactions during and for at least 72 hours following administration of melphalan.
Melphalan for intra-arterial infusion via PHP is available only through a restricted program under a Risk Evaluation and Mitigation Strategy called the Hepzato Kit REMS.
Note: IV melphalan is available as different salt forms and different IV 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. Do not substitute melphalan hydrochloride for melphalan flufenamide. Antiemetics are recommended with IV melphalan to prevent nausea and vomiting; IV melphalan is associated with a moderate or high emetic potential (depending on dose). Adjust dose based on patient response and weekly blood counts.
Amyloidosis, light chain (off-label use): Oral: 0.22 mg/kg/day for 4 days every 28 days (in combination with bortezomib and oral dexamethasone) for up to 6 to 8 cycles; refer to protocol for further information (Ref) or 0.22 mg/kg/day for 4 days every 28 days (in combination with oral dexamethasone) (Ref) or 10 mg/m2/day for 4 days every month (in combination with oral dexamethasone) for 12 to 18 treatment cycles (Ref).
Amyloidosis, light chain, conditioning regimen for autologous hematopoietic cell transplantation (off-label use): IV: 200 mg/m2 (or 140 mg/m2 if >65 years of age, left ventricular ejection fraction 40% to 45%, or hematopoietic cell collection ≥2 to <2.5 × 106 cells/kg) as a one-time dose prior to hematopoietic cell infusion; some patients received a further reduced dose of 100 mg/m2 (Ref). Data from a small retrospective analysis demonstrated acceptable safety and efficacy when propylene glycol-free melphalan formulation (Evomela; dose not specified) was used for conditioning prior to autologous hematopoietic cell transplant for light chain amyloidosis (Ref).
Hematopoietic cell transplant, allogeneic, reduced intensity conditioning regimen for hematologic malignancies (off-label use): IV: 140 mg/m2 (in combination with fludarabine) prior to allogeneic hematopoietic cell transplant. In clinical studies, the melphalan dose ranged from 100 to 180 mg/m2 (administered either as a one-time dose or divided over 2 days) (Ref). Refer to protocols for further details.
Hematopoietic cell transplant, autologous, conditioning regimen for lymphomas (off-label use):
BEAM regimen: IV: 140 mg/m2 on day -1 prior to autologous hematopoietic cell transplantation on day 0 (in combination with carmustine, etoposide, and cytarabine) (Ref). 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 (Ref).
BuMelTT regimen: IV: 50 mg/m2/day on days -5 and -4 (total dose 100 mg/m2) prior to autologous hematopoietic cell transplantation (in combination with oral busulfan and thiotepa) (Ref).
GemBuMel regimen: IV: 60 mg/m2/day for 2 days (in combination with gemcitabine and busulfan) prior to autologous hematopoietic cell transplantation (Ref).
Hodgkin lymphoma, relapsed or refractory, salvage therapy (off-label use): Mini-BEAM regimen: IV: 30 mg/m2 over 15 minutes on day 6 (in combination with carmustine, etoposide, and cytarabine); repeat cycle every 4 to 6 weeks (Ref).
Multiple myeloma, conditioning regimen prior to hematopoietic cell transplantation (Evomela only): IV: 100 mg/m2 daily for 2 days on day -3 and day -2 prior to autologous hematopoietic cell transplantation on day 0 (Ref). 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 hematopoietic 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 hematopoietic 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 (Ref).
Multiple myeloma, conditioning regimen for autologous hematopoietic cell transplantation (off-label doses):
IV: 200 mg/m2 alone 2 days prior to transplantation (Ref) or
IV: 140 mg/m2 2 days prior to transplantation (combined with busulfan) (Ref) or
IV: 140 mg/m2 2 days prior to transplantation (combined with total body irradiation [TBI]) (Ref) or
IV: 140 mg/m2 5 days prior to transplantation (combined with TBI) (Ref).
Multiple myeloma, previously untreated; transplant ineligible (off-label dosing/combinations): ≥65 years of age and/or transplant ineligible:
Oral: 9 mg/m2/day for 4 days (days 1 to 4) every 6 weeks for 9 cycles (in combination with daratumumab/hyaluronidase, bortezomib and prednisone; after cycle 9, daratumumab/hyaluronidase is continued as a single agent) (Ref) or
Oral: 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) (Ref) or
Oral: 9 mg/m2/day for 4 days every 6 weeks (in combination with prednisone or with prednisone and bortezomib) (Ref) or
Oral: 4 mg/m2/day for 7 days every 4 weeks (in combination with prednisone or with prednisone and thalidomide) (Ref) or
Oral: 6 mg/m2/day for 7 days every 4 weeks (in combination with prednisone) (Ref) or
Oral: 0.25 mg/kg/day for 4 days every 6 weeks (in combination with prednisone (Ref) or with prednisone and thalidomide (Ref)).
Multiple myeloma, palliative treatment: Note: Response is gradual; may require repeated courses to realize benefit:
Usual dose (as described in the manufacturer's labeling):
Oral: 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
Oral: 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
Oral: 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
Oral: 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.
Alkeran: IV: 16 mg/m2 administered at 2-week intervals for 4 doses, then administer at 4-week intervals after adequate hematologic recovery.
Ovarian cancer: Oral: 0.2 mg/kg/day for 5 days, repeat every 4 to 5 weeks or
Off-label dosing: Oral: 7 mg/m2/day in 2 divided doses for 5 days, repeat every 28 days (Ref).
Regional perfusion in solid tumors, melanoma and soft tissue sarcoma (off-label use): Isolated limb infusion (ILI) protocol: 5 to 10 mg/L of limb volume (maximum: 100 mg) over 20 minutes (in combination with dactinomycin) (Ref) or 5 to 10 mg/L of tissue in 400 mL warmed, heparinized NS (in combination with dactinomycin) over 20 to 30 minutes (Ref).
Uveal melanoma, unresectable hepatic metastases (Hepzato only): Note: Dose is based on ideal body weight (see manufacturer’s labeling for ideal body weight calculations). Melphalan administered intra-arterially via percutaneous hepatic perfusion (PHP) using the Hepzato Kit should only be administered to patients ≥35 kg (due to size limitations of percutaneous catheterization). Screen patients for history of previous surgery of the bile duct to determine appropriateness of treatment with melphalan administered intra-arterially via PHP. Discontinue oral anticoagulation (warfarin or other anticoagulants) prior to procedure and drugs affecting platelets (eg, aspirin, nonsteroidal anti-inflammatory drugs, or other antiplatelets) 1 week prior to procedure. Discontinue ACE inhibitors, calcium channel blockers, or alpha-1-adrenergic blockers at least 5 half-lives prior to treatment. Ensure patient is euvolemic prior to procedure. Only administer melphalan via percutaneous hepatic perfusion if baseline ANC >2,000/mm3, hemoglobin ≥10 g/dL, and platelets ≥100,000/mm3.
Premedication: Administer a proton pump inhibitor the day prior to and the morning of the procedure. Premedicate patients with a history of allergic reaction to iodinated contrast prior to treatment. If antiemetic treatment is required, premedicate with antiemetics in subsequent cycles.
Patients ≥35 kg: Intra-arterial infusion via PHP: 3 mg/kg (using ideal body weight; maximum dose: 220 mg) once every 6 to 8 weeks for up to 6 total infusions (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
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:
Conditioning regimen for multiple myeloma: No dosage adjustment is necessary.
Palliative treatment of multiple myeloma: BUN ≥30 mg/dL: Reduce dose by up to 50%.
Hemodialysis: Melphalan is not removed (to any significant degree) by hemodialysis.
The following adjustments have also been recommended:
Aronoff 2007: Oral (based on a 6 mg once-daily dose):
CrCl 10 to 50 mL/minute: Reduce dose to 75% of normal dose.
CrCl <10 mL/minute: Reduce dose to 50% of normal dose.
Hemodialysis: Administer dose after hemodialysis.
Continuous ambulatory peritoneal dialysis (CAPD): Reduce dose to 50% of normal dose.
Continuous renal replacement therapy (CRRT): Reduce dose to 75% of normal 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: Reduce dose to 75% of normal 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: Reduce dose to 85% of normal dose.
CrCl 31 to 45 mL/minute: Reduce dose to 75% of normal dose.
CrCl <30 mL/minute: Reduce dose to 70% of normal dose.
Badros 2001: IV: Autologous hematopoietic 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
International Myeloma Working Group (IMWG) Recommendations (Ref):
The IMWG recommends the use of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (preferred) or the Modification of Diet in Renal Disease (MDRD) formula to evaluate renal function estimation in multiple myeloma patients with a stable serum creatinine.
Oral:
CrCl >60 mL/minute: Usual dose: 0.15 to 0.25 mg/kg/day for 4 to 7 days
CrCl 15 to 59 mL/minute: Reduce dose to 75% of usual dose
CrCl <15 mL/minute: Reduce dose to 50% of usual dose
Hemodialysis: Reduce dose to 50% of usual dose
IV (high-dose melphalan for autologous hematopoietic cell transplant conditioning regimen):
CrCl >60 mL/minute: Usual dose: 200 mg/m2 per treatment course
CrCl <15 to 59 mL/minute: Reduce dose to 140 mg/m2 per treatment course; 100 mg/m2 (per treatment course) may be appropriate in some patients
Hemodialysis: Reduce dose to 100 to 140 mg/m2 per treatment course
IV, Oral: Melphalan is hepatically metabolized; however, dosage adjustment does not appear to be necessary (Ref).
American Society of Clinical Oncology guidelines for appropriate systemic therapy dosing in adults with cancer with a BMI ≥30 kg/m2 (Note: Excludes hematopoietic cell transplantation dosing): Utilize patient's actual body weight for calculation of BSA- or weight-based dosing; manage regimen-related toxicities in the same manner as for patients with a BMI <30 kg/m2; if a dose reduction is utilized due to toxicity, may consider resumption of full, weight-based dosing (or previously tolerated dose level) with subsequent cycles, only if dose escalations are allowed in the prescribing information, if contributing underlying factors (eg, hepatic or kidney impairment) are sufficiently resolved, AND if performance status has markedly improved or is considered adequate (Ref). Note: The manufacturer of Hepzato (melphalan hydrochloride for intra-arterial infusion via percutaneous hepatic perfusion injection) recommends the dose be calculated based on ideal body weight.
American Soc iety for Blood and Marrow Transplantation practice guideline committee position statement on chemotherapy dosing in obesity: Utilize actual body weight for calculation of BSA in melphalan dosing for hematopoietic cell transplant conditioning regimens in adults (Ref). Note: The manufacturer of Evomela recommends that if patients weigh >130% of their ideal body weight, BSA should be calculated using adjusted ideal body weight.
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.
Hypersensitivity reactions: Discontinue melphalan (do not rechallenge [oral or IV]).
Provide supportive care as clinically necessary for infections, bleeding, symptomatic anemia, and GI adverse reactions.
Intra-arterial infusion via percutaneous hepatic perfusion (Hepzato only):
ANC <500/mm3 (grade 4 neutropenia) for >5 days despite growth factor support or associated with febrile neutropenia: Reduce dose to 2 mg/kg with subsequent infusions. Administer growth factors as clinically indicated.
Platelets <25,000/mm3 (grade 4 thrombocytopenia) for >5 days or associated with hemorrhage requiring transfusion: Reduce dose to 2 mg/kg with subsequent infusions. Administer transfusions as clinically indicated.
Life-threatening or persistent toxicity that has not resolved to ≤ grade 2 by 8 weeks following treatment: Permanently discontinue therapy.
Hypersensitivity reactions: Immediately terminate infusion of melphalan; administer supportive care.
Refer to adult dosing. Use caution and begin at the lower end of dosing range.
(For additional information see "Melphalan: Pediatric drug information")
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 (IV) is associated with a high emetic potential; antiemetics are recommended with IV melphalan to prevent nausea and vomiting (Ref). Refer to individual protocols; details concerning dosing in combination regimens should also be consulted; adjust dose based on patient response and weekly blood counts.
Hematopoietic stem cell transplantation (HSCT), 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:
Canete 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).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
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.
There are no pediatric specific recommendations available; refer to individual protocols. Based on experience in adult patients, dosing adjustment suggested.
There are no pediatric specific recommendations; refer individual protocols; based on experience in adult patients, dosage adjustment does not appear to be necessary (Ref).
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Cardiovascular: Peripheral edema (33%)
Endocrine & metabolic: Hypokalemia (74%), hypophosphatemia (49%)
Gastrointestinal: Abdominal pain (28%), constipation (48%), decreased appetite (49%), diarrhea (93%), dysgeusia (28%), dyspepsia (26%), nausea (90%), stomatitis (28% to 38%; grades 3/4: 5% to 13%), vomiting (64%)
Hematologic & oncologic: Anemia (≥50%), decreased neutrophils (≥50%), decreased platelet count (≥50%), decreased white blood cell count (≥50%), febrile neutropenia (41%; grades 3/4: 28%), lymphocytopenia (≥50%)
Nervous system: Dizziness (38%), fatigue (77%)
Miscellaneous: Fever (48%)
1% to 10%:
Genitourinary: Amenorrhea (9%)
Hypersensitivity: Anaphylaxis (≤2%), hypersensitivity reaction (≤2%)
Frequency not defined:
Endocrine & metabolic: SIADH (Greenbaum-Lefkoe 1985)
Gastrointestinal: Hematochezia
Genitourinary: Infertility, inhibition of testicular function
Hematologic & oncologic: Bone marrow depression, bone marrow failure (can be irreversible)
Renal: Increased blood urea nitrogen, renal failure syndrome
Miscellaneous: Chromosomal abnormality
Postmarketing:
Cardiovascular: Vasculitis
Dermatologic: Allergic skin reaction, alopecia, maculopapular rash, skin necrosis, skin ulceration at injection site
Hematologic & oncologic: Acute leukemia, carcinoma, hemolytic anemia, myelodysplastic syndrome
Hepatic: Abnormal hepatic function tests, hepatic sinusoidal obstruction syndrome, hepatitis, jaundice
Nervous system: Flushing sensation, tingling sensation
Respiratory: Interstitial pneumonitis, pulmonary fibrosis
Melphalan (IV and oral): Hypersensitivity to melphalan or any component of the formulation; patients whose disease was resistant to prior melphalan therapy (Alkeran only).
Melphalan (intra-arterially as a percutaneous hepatic perfusion [PHP]): History of allergies or hypersensitivity to melphalan or any component of the Hepzato Kit; history of hypersensitivity/allergy to heparin or the presence of heparin-induced thrombocytopenia; history of severe allergic reaction to iodinated contrast not controlled by premedication with antihistamines and steroids; active intracranial metastases or brain lesions with a propensity to bleed; liver failure, portal hypertension, or known varices at risk for bleeding; surgery or medical treatment of the liver in the previous 4 weeks; uncorrectable coagulopathy; inability to safely undergo general anesthesia, including active cardiac conditions which include (but are not limited to) unstable coronary syndromes (unstable or severe angina or myocardial infarction), worsening or new-onset congestive heart failure, significant arrhythmias, or severe valvular disease.
Canadian labeling (IV and oral): Additional contraindications (not in the US labeling): Recent administration of other similar chemotherapeutic agents or radiotherapy; depressed neutrophil and/or platelet counts; concurrent radiotherapy; breastfeeding.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Concerns related to adverse effects:
• Bone marrow suppression: Severe bone marrow suppression (including thrombocytopenia, anemia, and neutropenia) may occur, which could result in infection or bleeding; myelosuppression has been shown 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 hematopoietic cell transplantation. Do not administer a melphalan-containing conditioning regimen unless the hematopoietic cell product is available for rescue. 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). Myelosuppression (including grade 3 or 4) has also been commonly reported with the melphalan administered intra-arterially via percutaneous hepatic perfusion (PHP).
• Extravasation: Melphalan is an irritant; local reactions may occur (ESMO/EONS [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.
• GI toxicity: GI 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). 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.
• Hypersensitivity reactions: 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. Hypersensitivity may also occur (rarely) with oral melphalan.
• Periprocedural complications: Hemorrhage, hepatocellular injury, and thromboembolic events have occurred with the administration of melphalan intra-arterially via PHP (Hepzato). Life-threatening or fatal adverse effects may occur; administration of melphalan intra-arterially via PHP requires general anesthesia and extracorporeal bypass of circulation. Patients with abnormal hepatic vascular (especially arterial) or biliary anatomy or gastric acid hypersecretion syndromes may have a higher risk of periprocedural complications or severe adverse events. Reductions in BP, including hypotension, related to the intra-arterial infusion procedure may occur; hypotension may require fluid support or vasopressors.
• Pulmonary toxicity: Pulmonary fibrosis (some fatal) and interstitial pneumonitis have been observed with treatment.
• Secondary malignancy: Melphalan 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:
• Kidney impairment: High-dose melphalan with autologous hematopoietic cell transplant is feasible in patients with multiple myeloma and kidney impairment (Dimopoulos 2016). Prolonged mucositis has occurred when standard melphalan doses were administered to patients with chronic kidney disease (Bodge 2014).
Special populations:
• Older adult: Toxicity may be increased in patients ≥65 years of age.
Dosage form specific issues:
• Formulations: IV melphalan is available as different salt forms and different IV 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), Hepzato (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. Melphalan flufenamide (Pepaxto) is a prodrug of melphalan. Indications for use, product preparation, storage, and dosing differ between salt forms and formulations. Use caution when selecting melphalan formulations for preparation and administration. Do not mix or combine the formulations. Do not substitute melphalan hydrochloride for melphalan flufenamide.
• Latex (Hepzato only): The double balloon catheter component of the Hepzato Kit delivery system contains natural rubber latex. Use of melphalan through the delivery system is contraindicated in patients with a history of allergy to natural rubber latex.
• Propylene glycol: Some dosage forms or diluents 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:
• Immunizations: Avoid vaccination with live vaccines during treatment if immunocompromised.
• REMS program (Hepzato only): Melphalan for intra-arterial infusion via PHP is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Hepzato Kit REMS Program. Further information is available at 1-833-632-0457.
Some dosage forms may contain propylene glycol; in neonates large amounts of propylene glycol delivered orally, intravenously (eg, >3,000 mg/day), or topically have been associated with potentially fatal toxicities which can include metabolic acidosis, seizures, renal failure, and CNS depression; toxicities have also been reported in children and adults including hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Shehab 2009).
Hepzato: FDA approved August 2023; availability anticipated in the 4th quarter of 2023. Information pertaining to this product within the monograph is pending revision. Hepzato injection, as a component of the Hepzato Kit, is indicated as a liver-directed treatment for adult patients with uveal melanoma with unresectable hepatic metastases affecting less than 50% of the liver and no extrahepatic disease or extrahepatic disease limited to the bone, lymph nodes, subcutaneous tissues, or lung that is amenable to resection or radiation. Consult the prescribing information for additional information.
Melphalan 90 mg/mL multiple-dose vial: FDA approved August 2023; anticipated availability currently unknown. Information pertaining to this product within the monograph is pending revision. Melphalan multiple-dose vial is indicated for palliative treatment of patients with multiple myeloma for whom oral therapy is not appropriate. Consult the prescribing information for additional information.
Different formulations of intravenous melphalan are available. Alkeran (melphalan hydrochloride for injection) and generic melphalan hydrochloride are reconstituted with the supplied diluent (which contains propylene glycol and ethanol). Evomela (melphalan for injection) is reconstituted with normal saline. Melphalan flufenamide (Pepaxto) is a prodrug of melphalan. Use caution when selecting melphalan formulations for preparation and administration. Do not mix or combine the formulations. Do not substitute melphalan hydrochloride for melphalan flufenamide.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution Reconstituted, Intravenous:
Alkeran: 50 mg (1 ea [DSC]) [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 [DSC]
Generic: 2 mg
Yes
Solution (reconstituted) (Evomela Intravenous)
50 mg (per each): $1,918.80
Solution (reconstituted) (Melphalan HCl Intravenous)
50 mg (per each): $240.00 - $3,007.65
Tablets (Melphalan Oral)
2 mg (per each): $12.21
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Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous:
Alkeran: 50 mg (1 ea) [contains alcohol, usp, povidone (polyvinylpyrrolidone), propylene glycol]
Generic: 50 mg (1 ea)
Tablet, Oral:
Alkeran: 2 mg
Antiemetics are recommended with IV melphalan to prevent nausea and vomiting; IV melphalan is associated with a moderate or high emetic potential (depending on dose).
IV melphalan is available as different salts and different IV 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. Do not substitute melphalan hydrochloride for melphalan flufenamide.
Oral: Administer on an empty stomach (Ref).
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 30 minutes (conditioning regimen for autologous cell transplantation).
Melphalan (IV) is an irritant; local reactions may occur (Ref). 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.
When administering high-dose melphalan in autologous transplantation, cryotherapy is recommended to prevent oral mucositis (Ref).
Regional perfusion: Technique may vary by institution; consult protocol for details (Ref).
Intra-arterial infusion via percutaneous hepatic perfusion (Hepzato only): Consult the Hepzato Kit delivery system instructions for use for details (Ref). If antiemetic treatment is required, premedicate with antiemetics in subsequent cycles.
Parenteral: Note: Melphalan (IV) is associated with a high emetic potential; antiemetics are recommended with IV melphalan to prevent nausea and vomiting (Ref). 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.
IV:
Alkeran: Must be prepared fresh; the time between reconstitution/dilution and administration of parenteral melphalan must be kept to a minimum (manufacturer recommends completing infusion within <60 minutes of reconstitution) because reconstituted and diluted solutions are unstable. Administer by IV infusion typically over 15 to 20 minutes and some centers suggest at a rate not to exceed 10 mg/minute.
Evomela: In adults, doses are infused over 30 minutes (conditioning regimen for autologous stem cell transplantation); refer to pediatric-specific protocols.
Melphalan (IV) is an irritant; local reactions may occur (Ref). 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 (NIOSH 2016 [group 1]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Multiple myeloma:
Palliative treatment of multiple myeloma (injection [Alkeran] and tablets).
High-dose conditioning treatment prior to hematopoietic cell transplantation in patients with multiple myeloma (Evomela only).
Ovarian cancer: Palliative treatment of nonresectable epithelial ovarian carcinoma (tablets).
Uveal melanoma, unresectable hepatic metastases: Treatment of uveal melanoma (as a liver-directed therapy) in adults with unresectable hepatic metastases affecting <50% of the liver and no extrahepatic disease or extrahepatic disease limited to the bone, lymph nodes, SUBQ tissues, or lung that is amenable to resection or radiation (Hepzato only).
Amyloidosis, light chain; Hematopoietic cell transplant (allogeneic), reduced intensity conditioning regimen (hematologic malignancies); Hematopoietic cell transplant (autologous), conditioning regimen (lymphomas); Hodgkin lymphoma (relapsed or refractory); Regional perfusion in solid tumors (melanoma and soft tissue sarcoma)
Melphalan may be confused with melphalan flufenamide, Mephyton, Myleran
Alkeran may be confused with Alferon, Leukeran, Myleran
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
Different formulation issues: IV melphalan is available as different salt forms and different IV 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), Hepzato (melphalan hydrochloride for intra-arterial infusion via percutaneous hepatic perfusion), 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. Melphalan flufenamide (Pepaxto) is a prodrug of melphalan. Indications for use, product preparation, storage, and dosing differ between salt forms and formulations. Use caution when selecting melphalan formulations for preparation and administration. Do not mix or combine the formulations. Do not substitute melphalan hydrochloride for melphalan flufenamide.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Antithymocyte Globulin (Equine): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Antithymocyte Globulin (Equine). Specifically, these effects may be unmasked if the dose of cytotoxic chemotherapy is reduced. Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Antithymocyte Globulin (Equine). Specifically, infections may occur with greater severity and/or atypical presentations. Risk C: Monitor therapy
Baricitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
BCG Products: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination
Brincidofovir: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy
Brivudine: May enhance the adverse/toxic effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Carmustine: Melphalan may enhance the adverse/toxic effect of Carmustine. Specifically, melphalan may sensitize patients to carmustine lung toxicity. Risk C: Monitor therapy
Chikungunya Vaccine (Live): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Chikungunya Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Chikungunya Vaccine (Live). Risk X: Avoid combination
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy
Chloramphenicol (Systemic): Myelosuppressive Agents may enhance the myelosuppressive effect of Chloramphenicol (Systemic). Risk X: Avoid combination
CISplatin: May increase the serum concentration of Melphalan. Risk C: Monitor therapy
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination
Cladribine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy
Coccidioides immitis Skin Test: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing cytotoxic chemotherapy several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification
COVID-19 Vaccine (Adenovirus Vector): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector). Management: Administer a 2nd dose using an mRNA COVID-19 vaccine (at least 4 weeks after the primary vaccine dose) and a bivalent booster dose (at least 2 months after the additional mRNA dose or any other boosters). Risk D: Consider therapy modification
COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor therapy
COVID-19 Vaccine (mRNA): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (mRNA). Management: Give a 3-dose primary series for all patients aged 6 months and older taking immunosuppressive medications or therapies. Booster doses are recommended for certain age groups. See CDC guidance for details. Risk D: Consider therapy modification
COVID-19 Vaccine (Subunit): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit). Risk C: Monitor therapy
COVID-19 Vaccine (Virus-like Particles): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Virus-like Particles). Risk C: Monitor therapy
CycloSPORINE (Systemic): Melphalan may enhance the nephrotoxic effect of CycloSPORINE (Systemic). Risk C: 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. Risk D: Consider therapy modification
Dengue Tetravalent Vaccine (Live): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination
Denosumab: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and cytotoxic chemotherapy. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modification
Deucravacitinib: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination
Etrasimod: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination
Filgotinib: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Inebilizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy
Influenza Virus Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating chemotherapy if possible. If vaccination occurs less than 2 weeks prior to or during chemotherapy, revaccinate at least 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modification
Leflunomide: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents, such as cytotoxic chemotherapy. Risk D: 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. Risk D: 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. Risk D: Consider therapy modification
Mumps- Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Mumps- Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Mumps- Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination
Nadofaragene Firadenovec: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Nadofaragene Firadenovec. Specifically, the risk of disseminated adenovirus infection may be increased. Risk X: Avoid combination
Nalidixic Acid: May enhance the adverse/toxic effect of Melphalan. Necrotic enterocolitis has been reported in pediatric patients. Risk C: Monitor therapy
Natalizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination
Ocrelizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy
Ofatumumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy
Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. Risk C: 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. Risk D: Consider therapy modification
Pidotimod: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy
Pimecrolimus: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Pneumococcal Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy
Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination
Polymethylmethacrylate: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Rabies Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modification
Ritlecitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ritlecitinib. Risk X: Avoid combination
Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification
Ruxolitinib (Topical): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination
Sipuleucel-T: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants, such as cytotoxic chemotherapy, prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification
Sphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk C: Monitor therapy
Tacrolimus (Topical): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination
Talimogene Laherparepvec: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination
Tertomotide: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination
Tofacitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Tofacitinib. Risk X: Avoid combination
Typhoid Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination
Ublituximab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ublituximab. Risk C: Monitor therapy
Upadacitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination
Vaccines (Inactivated/Non-Replicating): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of chemotherapy when possible. Patients vaccinated less than 14 days before initiating or during chemotherapy should be revaccinated at least 3 months after therapy is complete. Risk D: Consider therapy modification
Vaccines (Live): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Vaccines (Live) may diminish the therapeutic effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Yellow Fever Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination
Food interferes with oral absorption. Management: Administer on an empty stomach.
Patients who could become pregnant should use effective contraception during treatment and for 6 months after the last melphalan dose.
Melphalan may damage spermatozoa and testicular tissue, resulting in potential fetal abnormalities. Patients with partners who could become pregnant should use effective contraception during treatment and for 3 months after the last melphalan dose.
Treatment with melphalan may suppress ovarian function, leading to amenorrhea. Reversible and irreversible testicular suppression has been reported in patients after melphalan administration. Prior to melphalan treatment, the European Society for Medical Oncology recommends referral to a fertility specialist for patients who wish to preserve fertility (ESMO [Lambertini 2020]).
Based on the mechanism of action, melphalan may cause fetal harm if administered during pregnancy.
It is not known if melphalan is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during treatment and for 1 week after the last melphalan dose.
CBC with differential and platelet count, serum electrolytes, renal/liver function tests, serum uric acid. Monitor for signs/symptoms of hypersensitivity reaction, pulmonary toxicity, and GI toxicity; monitor infusion site. Monitor adherence (oral melphalan).
Hepzato only: Monitor for periprocedural complications during procedure and for at least 72 hours after procedure. Monitor BP during the periprocedural period. Monitor platelets and coagulation parameters as clinically indicated. Monitor patients for severe infections, bleeding, and symptomatic anemia.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Melphalan is an alkylating agent, which is a derivative of mechlorethamine that inhibits DNA and RNA synthesis via formation of carbonium ions; cross-links strands of DNA. Melphalan acts on both resting and rapidly dividing tumor cells.
Absorption: Oral: Variable and incomplete.
Distribution: Vd: 0.5 L/kg or 35.5 to 185.7 L/m2; Evomela: Penetrates CSF; Alkeran: Low penetration into CSF.
Protein binding: ~50% to 92%; primarily to albumin (~40% to 60%), ~20% to alpha1-acid glycoprotein.
Metabolism: Hepatic; chemical hydrolysis to monohydroxymelphalan and dihydroxymelphalan.
Bioavailability: Oral: Variable; 56% to 93%; exposure is reduced by 36% to 54% with a high-fat meal.
Half-life elimination: Terminal: IV: ~75 minutes; Oral: 1.5 ± 0.83 hours.
Time to peak, serum: Oral: ~1 to 2 hours; Intra-arterial infusion via percutaneous hepatic perfusion (PHP) (Hepzato only): 0.57 hours (range: 0.05 to 1.18 hours).
Excretion: Oral: Feces (20% to 50%); urine (~10% as unchanged drug); IV: urine: (6% to 21%); Intra-arterial infusion via PHP: Via isolation of hepatic venous blood flow and filtration by the Hepzato delivery system (HDS); HDS filter efficiency: 82.7%.
Clearance: IV: 250 to 325 mL/minute/m2.
Altered kidney function: 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.
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.
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