Melphalan hydrochloride is a bifunctional alkylating agent. Melphalan tablets are approved for use in the palliative treatment of multiple myeloma; the injectable melphalan formulation for IV use is reserved for patients with multiple myeloma who cannot take oral therapy. Oral melphalan is also indicated for the palliative treatment of unresectable, epithelial ovarian cancer. A propylene glycol-free injectable formulation of melphalan (Evomela) is approved for use as a high-dose conditioning treatment prior to an autologous stem-cell transplant in patients with multiple myeloma. Melphalan injection for intra-arterial use, as a component of the Hepzato Kit Hepatic Delivery System, is approved as liver-directed therapy for use in adult patients with uveal melanoma who have 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. Boxed warnings include myelosuppression, hypersensitivity, and leukemogenicity in the IV melphalan products. Melphalan for use with hepatic delivery system has a black box warning for severe peri-procedural complications and myelosuppression. It is available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the HEPZATO KIT REMS. Information for this program enrollment is available at www.HEPZATOKITREMS.com or 1-833-632-0457.
General Administration Information
For storage information, see the specific product information within the How supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 1
-NIOSH (Draft) 2020 List: Table 1
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Oral Tablets/Capsules: Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
-Injectables: Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
Emetic Risk
Pediatrics
-IV Doses: High
-Oral Doses: 0.2 mg/kg: Low
Adults
-IV Doses: Low/Minimal
Administer routine antiemetic prophylaxis prior to treatment for high risk of emetogenicity.
Extravasation Risk
-Irritant
Route-Specific Administration
Oral Administration
-Take melphalan on an empty stomach (i.e., at least 1 hour prior to or 2 hours after a meal).
Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
-Melphalan is available as a lyophilisate powder.
-Alkeran and generic melphalan are reconstituted with a supplied propylene glycol-containing diluent; Evomela does not require a propylene glycol-containing diluent.
-Product formulations have different reconstitution and storage requirements; do NOT mix or combine Evomela with other melphalan products.
Evomela
Reconstitution:
-Add 8.6 mL of 0.9% Sodium Chloride injection to the 50-mg melphalan vial for a final vial concentration of 5 mg/mL.
-Storage following reconstitution: Store at room temperature for up to 1 hour or refrigerated up to 24 hours.
Dilution:
-Calculate the dose and add to an appropriate amount of 0.9% Sodium Chloride injection to a final diluted admixture concentration of 0.45 mg/mL.
-Storage following dilution: Store at room temperature for up to 4 hours (in addition to 1 hour following reconstitution).
IV infusion:
-Administer IV over 30 minutes.
-Infuse into an injection port or by injecting slowly into a fast-running IV infusion via a central venous line to avoid extravasation.
Alkeran and Generic Melphalan
Reconstitution:
-Using a syringe with a 20-gauge or larger needle, rapidly inject 10 mL of the supplied diluent into the melphalan 50-mg vial for a final vial concentration of 5 mg/mL.
-Immediately shake the vial well until the solution becomes clear and all material is dissolved.
-Dilute the reconstituted melphalan immediately; the solution is unstable.
-Do NOT refrigerate the reconstituted vial; a precipitate forms if the solution is stored at 5 degrees C.
Dilution:
-Dilute the appropriate dose of melphalan in 0.9% Sodium Chloride injection to a final concentration not to exceed 0.45 mg/mL.
-The diluted melphalan solution is unstable; about 1% of the labeled dose hydrolyzes every 10 minutes after dilution with sodium chloride.
IV infusion:
-Administer IV over 15 to 20 minutes; do NOT give over less than 15 minutes and complete the infusion within 60 minutes from vial reconstitution.
-Infuse melphalan through a central line to avoid extravasation.
Other Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intra-arterial Administration
-Melphalan for injection is a component of the Hepzato Kit Hepatic Delivery System (HDS) which contains:
-5 single-dose 50-mg melphalan for injection lyophilized glass vials
-5 single-dose sterile 10-mL glass vials of diluent for reconstitution
-2 plastic 250-mL 0.9% Sodium Chloride injection containers for dilution
-Melphalan for injection must only be administered with the HDS device supplied with the Hepzato Kit and components; it is infused into the hepatic artery.
-Use the ideal body weight equation provided by the manufacturer to calculate the dosage.
-Reconstituted and diluted solutions are unstable due to the formation of citrate derivative of melphalan. The citrate derivative is formed within 30 minutes of reconstitution; 1% of the labeled strength of melphalan hydrolyzes every 10 minutes following dilution in 0.9% Sodium Chloride injection.
Reconstitution:
-Using a sterile needle (20 gauge or larger) and syringe, rapidly inject 10 mL of the supplied diluent into the 50-mg melphalan vial for a final vial concentration of 5 mg/mL.
-Immediately shake the vial vigorously until a clear solution is obtained; do not allow more than 5 seconds to elapse between the discharge of the syringe and the start of shaking.
-Dilute the reconstituted solution immediately. Do not refrigerate; a precipitate forms if the reconstituted solution is stored at 5 degrees C.
Dilution:
-Add the calculated dose volume to the supplied 0.9% Sodium Chloride injection container(s) to a final diluted admixture concentration not to exceed 0.45 mg/mL as follows:
-Doses up to 110 mg: Dilute in 250 mL of 0.9% Sodium Chloride injection.
-Doses 111 mg to 220 mg: Divide the total dose equally into 2 doses and dilute each in 250 mL of 0.9% Sodium Chloride injection.
-Use immediately following dilution; complete the intra-hepatic infusion of the diluted solution within 60 minutes from reconstitution. Do not refrigerate.
Intra-arterial hepatic infusion:
-Refer to Hepzato Kit HDS Instructions for Use prior to the intra-arterial infusion into the hepatic artery.
-Administer the diluted solution into the hepatic artery; complete the infusion within 30 minutes.
-Follow the infusion with a 30-minute washout period.
Contusion was reported in 17% of patients with uveal melanoma who received intra-arterial melphalan with a hepatic delivery system in a clinical trial (n = 95).
Severe bone marrow suppression/myelosuppression is common with melphalan therapy; infection and hemorrhage may occur. Administer supportive care for infections, hemorrhage, and symptomatic anemia as indicated until hematopoietic recovery. Obtain complete blood counts (CBC) with differential prior to each IV melphalan dose; obtain CBC prior to each course of oral therapy and then periodically to monitor for toxicity and to determine the optimal dosage. Dose adjustments based on nadir and day of treatment blood counts may be considered in patients receiving palliative treatment with oral or IV melphalan. Severe myelosuppression (defined as WBC count 1,000 cells/mm3 or less and/or platelet count 25,000 cells/mm3 or less) occurred more often with IV melphalan therapy (28%) compared with oral melphalan therapy (11%) in patients with multiple myeloma who received palliative therapy. In patients who had a BUN of 30 mg/dL or higher, the incidence of severe leukopenia was 50%; however, the incidence of severe leukopenia decreased to 11% after a protocol amendment requiring a 50% dose reduction of IV melphalan in these patients. Hemolytic anemia has also occurred in patients who received melphalan as palliative treatment. WBC count and platelet count nadirs usually occur 2 to 3 weeks after melphalan therapy with recovery at 4 to 5 weeks after treatment. Anemia (50% or higher), neutropenia (50% or higher), febrile neutropenia (41%; grade 3 or 4, 28%), lymphopenia (50% or higher), white blood cell (WBC) count decreased/leukopenia (50% or higher), and thrombocytopenia (50% or higher) were reported in multiple myeloma patients who received IV melphalan (Evomela) as part of conditioning treatment prior to an autologous stem-cell transplant in a clinical study (n = 61). Monitor CBCs until hematopoietic recovery. A dose reduction may be necessary in patients who receive melphalan with the hepatic delivery system and develop severe myelosuppression. Administer transfusions or growth factors as appropriate. Decreased platelet count/thrombocytopenia (65%; grade 3 or 4, 55%), decreased hemoglobin level/anemia (63%; grade 3 or 4, 33%), decreased leukocyte count/leukopenia (46%; grade 3 or 4, 34%), decreased neutrophil count/neutropenia (35%; grade 3 or 4, 30%), and febrile neutropenia (7%) occurred in patients with uveal melanoma who received intra-arterial melphalan with a hepatic delivery system in a clinical trial (n = 95).
Gastrointestinal (GI) adverse events occurred infrequently when melphalan was used as palliative therapy for multiple myeloma. GI events such as nausea (90%; grade 3 or 4, 2%), vomiting (64%), mucositis/oral ulceration (38%; grade 3 or 4, 10%), diarrhea (93%; grade 3 or 4, 3%), decreased appetite/anorexia (49%), constipation (48%), stomatitis (28%; grade 3 or 4, 5%), abdominal pain (28%), dysgeusia (28%), and dyspepsia (26%) were reported in multiple myeloma patients who received IV melphalan (Evomela) as part of conditioning treatment prior to an autologous stem-cell transplant in a clinical study (n = 61). Give prophylactic antiemetics prior to each IV melphalan dose. Administer supportive care for nausea, vomiting, diarrhea, and mucositis including nutritional support and analgesics in patients with severe mucositis. Gastrointestinal toxicity (84%), including nausea (57%), abdominal pain (39%; grade 3 or 4, 1%), vomiting (35%), diarrhea (17%; grade 3 or 4, 1%), and decreased appetite/anorexia (16%), occurred in patients with uveal melanoma who received intra-arterial melphalan with a hepatic delivery system in a clinical trial (n = 95). Fatal bacterial peritonitis was reported in 1 patient in this trial.
Evaluate renal function (e.g., serum creatinine or blood urea nitrogen (BUN) concentration) prior to starting melphalan therapy; monitor renal function closely in patients with azotemia. In patients receiving IV melphalan for the palliative treatment of multiple myeloma, consider up to a 50% dose reduction in patients with a BUN concentration of 30 mg/dL or greater. Do not reduce the dose or omit therapy in patients with multiple myeloma who are receiving melphalan (Evomela) as conditioning treatment prior to an autologous stem-cell transplant. Renal failure (unspecified) was reported in more than 1.6% of multiple myeloma patients who received Evomela as part of conditioning treatment prior to an autologous stem-cell transplant in a clinical study (n = 61). In patients receiving oral melphalan, consider an initial dose adjustment in patients with moderate to severe renal impairment.
Serious hypersensitivity reactions or anaphylaxis have occurred in about 2% of patients who received IV melphalan. Discontinue melphalan in patients who develop a serious reaction. Patients experiencing an acute allergic reaction may respond to treatment with antihistamine and corticosteroid therapy; administer volume expanders and pressor agents as necessary. Reactions typically occur after multiple courses of melphalan treatment. Symptoms of an allergic reaction include anaphylactoid reactions, bronchospasm, cardiac arrest, dyspnea, edema, hypotension, pruritus, rash and maculopapular rash, sinus tachycardia, and urticaria. Acute hypersensitivity reactions were reported in 2.4% of patients with multiple myeloma who received IV melphalan (n = 425).
Pulmonary toxicities including interstitial pneumonitis and fatal cases of pulmonary fibrosis have been reported in patients who received melphalan therapy. Dyspnea (23%; grade 3 or 4, 2%), cough (15%), hypoxia (2.1%), pleural effusion (2.1%), and pulmonary edema (2.1%) occurred in patients with uveal melanoma who received intra-arterial melphalan with a hepatic delivery system in a clinical trial (n = 95).
A new primary malignancy (e.g., myeloproliferative syndrome, acute myelogenous leukemia, and carcinomas) has been reported in multiple myeloma patients treated with melphalan-containing regimens. In clinical studies, the 10-year cumulative risk of developing acute leukemia or myeloproliferative syndrome after oral melphalan therapy was 19.5% for cumulative doses of 730 mg to 9,652 mg and less than 2% for cumulative doses less than 600 mg.
Suppression of ovarian function resulting in persistent amenorrhea has been reported in about 9% of premenopausal women who received melphalan. Additionally, testicular suppression/spermatogenesis inhibition has been reported with melphalan use in men.
Injection site reaction (e.g., skin hypersensitivity, skin ulcer, and skin necrosis rarely requiring skin grafting) has occurred with IV melphalan. Additionally, vasculitis and a subjective and transient sensation of warmth and/or tingling have been reported in patients who received melphalan.
Hepatic toxicity including (e.g., hepatitis, jaundice, elevated hepatic enzymes) has been reported with melphalan therapy. Serious toxicity, including sinusoidal obstruction syndrome (SOS), previously termed veno-occlusive disease (VOD), has also occurred. Monitor liver function tests during therapy. Hepatotoxicity/hepatocellular injury has occurred in patients receiving intra-arterial administration of melphalan with the hepatic delivery system. Elevated hepatic enzymes including increased ALT (32%; grade 3 or 4, 3%), AST (28%; grade 3 or 4, 4%), and alkaline phosphatase (27%; grade 3 or 4, 2%) levels and increased bilirubin level/hyperbilirubinemia (11%; grade 3 or 4, 3%) were reported in patients with uveal melanoma who received intra-arterial melphalan with a hepatic delivery system in a clinical trial (n = 95). Fatal acute hepatic failure was reported in 1 patient in this trial.
Alopecia has been reported in patients who received melphalan.
Fatigue was reported in 77% (grade 3 or 4, 2%) of multiple myeloma patients who received IV melphalan (Evomela) as part of conditioning treatment prior to an autologous stem-cell transplant in a clinical study (n = 61). Fatigue was reported in 65% of patients with uveal melanoma who received intra-arterial melphalan with a hepatic delivery system in a clinical trial (n = 95).
Hypokalemia (74%; grade 3 or 4, 28%) and hypophosphatemia (49%; grade 3 or 4, 48%) were reported in multiple myeloma patients who received IV melphalan (Evomela) as part of conditioning treatment prior to an autologous stem-cell transplant in a clinical study (n = 61). Decreased calcium level/hypocalcemia was reported in 13% (grade 3 or 4, 3%) of patients with uveal melanoma who received intra-arterial melphalan with a hepatic delivery system in a clinical trial (n = 95).
Fever was reported in 48% of multiple myeloma patients who received IV melphalan (Evomela) as part of conditioning treatment prior to an autologous stem-cell transplant in a clinical study (n = 61); grade 3 or 4 fever was reported in 3% of these patients. Fever was reported in 16% of patients with uveal melanoma who received intra-arterial melphalan with a hepatic delivery system in a clinical trial (n = 95).
Dizziness was reported in 38% of multiple myeloma patients who received IV melphalan (Evomela) as part of conditioning treatment prior to an autologous stem-cell transplant in a clinical study (n = 61). Headache (19%), lethargy (12%), and dizziness (11%) occurred in patients with uveal melanoma who received intra-arterial melphalan with a hepatic delivery system in a clinical trial (n = 95).
Peripheral edema was reported in 33% of multiple myeloma patients who received IV melphalan (Evomela) as part of conditioning treatment prior to an autologous stem-cell transplant in a clinical study (n = 61).
Musculoskeletal pain (46%; grade 3 or 4, 1%) and groin pain (11%) occurred in patients with uveal melanoma who received intra-arterial melphalan with a hepatic delivery system in a clinical trial (n = 95).
Thromboembolism/thromboembolic events have occurred in patients receiving melphalan with the hepatic delivery system. Deep vein thrombosis was reported in 2.1% of patients with uveal melanoma who received intra-arterial melphalan with a hepatic delivery system in a clinical trial (n = 95).
Treatment-related hematochezia/GI bleeding occurred in 3% of multiple myeloma patients who received IV melphalan (Evomela) as part of conditioning treatment prior to an autologous stem-cell transplant in a clinical study (n = 61). Bleeding (15%; grade 3 or 4, 1%) and prolonged bleeding time, including increased INR value (31%; grade 3 or 4, 8%) and prolonged activated partial thromboplastin time (28%; grade 3 or 4, 8%), occurred in patients with uveal melanoma who received intra-arterial melphalan with a hepatic delivery system in a clinical trial (n = 95). If serious bleeding occurs during the procedure, reverse anticoagulation and correct coagulopathy as appropriate.
Hypotension was reported in 13% (grade 3 or 4, 3%) of patients with uveal melanoma who received intra-arterial melphalan with a hepatic delivery system in a clinical trial (n = 95). Closely monitor blood pressure during the procedure; patients may require fluid support and vasopressors.
Cardiac arrest (including 1 fatal case) occurred in 3.2% of patients with uveal melanoma who received intra-arterial melphalan with a hepatic delivery system in a clinical trial (n = 95). Additionally, increased troponin I level was reported in 13% (grade 3 or 4, 2%) of patients.
Peri procedural complications including bleeding, hepatotoxicity/hepatocellular injury, and thromboembolic disease/events have been reported in patients receiving intra-arterial administration of melphalan with the hepatic delivery system. Special requirements for use with the hepatic delivery system include pre-infusion evaluation, hydration, premedication, anticoagulation, supportive care, and monitoring during and for at least 72 hours after the procedure.
Use of melphalan is contraindicated in patients with a melphalan hypersensitivity. Discontinue melphalan in patients who develop a serious hypersensitivity reaction. There is a risk of serious hypersensitivity reactions or anaphylaxis with the use of melphalan; hypersensitivity reactions, including anaphylaxis, tachycardia, bronchospasm, and dyspnea, have occurred in patients who received the IV formulation. Do not use melphalan in patients whose disease has demonstrated prior melphalan resistance. Melphalan for use with the hepatic delivery system is contraindicated in patients with natural rubber latex hypersensitivity, heparin hypersensitivity or history of heparin-induced thrombocytopenia (HIT), or history of iodinated radiopaque contrast media hypersensitivity not controlled by premedication with antihistamines and steroids. Administer premedications prior to melphalan for use with the hepatic delivery system in patients with a history of iodinated contrast hypersensitivity.
Melphalan causes chromosome damage in humans; a new primary malignancy including myeloproliferative syndrome or acute leukemia has been reported in multiple myeloma patients treated with melphalan-containing regimens. Patients on long-term melphalan treatment or who receive high cumulative doses may be at increased risk of developing leukemia. Prior to starting melphalan, weigh the benefits of therapy with the risk of developing a secondary malignancy.
Severe bone marrow suppression/myelosuppression (e.g., anemia, neutropenia, leukopenia, thrombocytopenia) is common with melphalan therapy; infection and hemorrhage may occur. Administer supportive care for infections, hemorrhage, and symptomatic anemia as indicated until hematopoietic recovery. Patients receiving IV melphalan or who have had prior chemotherapy or radiation therapy are at increased risk for developing severe myelosuppression. Obtain complete blood counts (CBC) with differential prior to each IV melphalan dose and prior to each course of oral therapy and periodically during therapy to monitor for toxicity and to determine the optimal dosage. Dose adjustments based on nadir and day of treatment blood counts may be considered in patients receiving palliative treatment with oral or IV melphalan. Myeloablation occurs in all patients who receive melphalan for conditioning treatment prior to an autologous stem-cell transplant; do not start melphalan unless stem cells are available for rescue. Monitor CBCs until hematopoietic recovery. Monitor CBC with differential and for signs of severe infection and hemorrhage in patients who are receiving melphalan for use with the hepatic delivery system. Do not initiate therapy unless the following hematologic parameters are met: hemoglobin level of 10 g/dL or more, platelet count of 100,000 cells/microliters (mcL) or more, and neutrophil count of more than 2,000 cells/mcL. Administer transfusions or growth factors as appropriate.
Melphalan for use with the hepatic delivery system is contraindicated in patients with uncorrectable coagulopathy, active brain metastases or brain lesions that may bleed, or who have had surgery or medical treatment involving the liver within the previous 4 weeks. Because of the risk of severe peri procedural complications including bleeding, hepatotoxicity/hepatocellular injury, and thromboembolic disease/events in patients receiving intra-arterial administration of melphalan with the hepatic delivery system, use requires an experienced clinician with training in the management of these toxicities. Melphalan for use with the hepatic delivery system also requires a specialized care setting that is enrolled in the HEPZATO KIT REMS program and can comply with all program requirements (i.e., pre-infusion evaluation, hydration, premedication, anticoagulation, and supportive care) and monitoring during and for at least 72 hours after the procedure. Discontinue oral anticoagulation (e.g., warfarin) prior to the procedure; resume anticoagulation as appropriate once homeostasis has been restored. Discontinue drugs affecting platelet function (e.g., aspirin, nonsteroidal anti-inflammatory drugs [NSAIDs]) 1 week before the procedure. Because platelets and clotting factors may be removed during the procedure, monitor platelets and coagulation parameters. Patients with abnormal hepatic vascular or biliary anatomy or gastric acid hypersecretion syndromes (e.g., Zollinger-Ellison syndrome) may be at increased risk of peri-procedural complications. Screen patients for a history of prior bile duct surgery.
Patients with renal impairment or renal disease (e.g. elevated serum creatinine or blood urea nitrogen (BUN)) may have a higher risk of developing severe myelosuppression, primarily leukopenia, with melphalan therapy; evaluate kidney function prior to starting therapy. Do not reduce the dose or omit therapy in patients with multiple myeloma who are receiving melphalan (Evomela) as conditioning treatment prior to an autologous stem-cell transplant. In patients receiving IV melphalan for the palliative treatment of multiple myeloma, consider up to a 50% dose reduction in patients with a BUN concentration of 30 mg/dL or greater. In patients receiving oral melphalan, consider an initial dose adjustment in patients with moderate to severe renal impairment.
Hepatotoxicity has been reported with melphalan therapy. Serious toxicity, including sinusoidal obstruction syndrome (SOS), previously termed veno-occlusive disease (VOD), has also occurred; use melphalan cautiously in patients with pre-existing hepatic disease. Monitor liver function tests during therapy. Melphalan for use with the hepatic delivery system is contraindicated in patients with hepatic failure, portal hypertension, or known esophageal varices.
Melphalan for use with the hepatic delivery system is contraindicated in patients who cannot safely undergo general anesthesia with the procedure, including patients with active cardiac disease/conditions (e.g., unstable coronary syndromes/coronary artery disease such as unstable or severe angina or myocardial infarction, worsening or new-onset congestive heart failure, significant cardiac arrhythmias, severe valvular heart disease).
Due to the risk of extravasation and local tissue damage, melphalan should not be administered intravenously (IV) by direct injection into a peripheral vein. Administer the diluted melphalan solution slowly into a fast-running IV infusion via an injection port or a central venous line.
The administration of live vaccines to immunocompromised patients should be avoided. Vaccination should be avoided during myelosuppressive chemotherapy because the antibody response is suboptimal. When chemotherapy is being planned, vaccination should precede the initiation of chemotherapy by 2 weeks or longer. Those undergoing chemotherapy should not be exposed to others who have recently received the oral poliovirus vaccine (OPV). Measles-mumps-rubella (MMR) vaccination is not contraindicated for the close contacts, including health care professionals, of immunocompromised patients. Passive immunoprophylaxis with immune globulins may be indicated for immunocompromised persons instead of, or in addition to, vaccination. When exposed to a vaccine-preventable disease such as measles, severely immunocompromised children should be considered susceptible regardless of their vaccination history.
Gastrointestinal adverse events such as nausea/vomiting, severe mucositis, and diarrhea have been commonly reported in patients who received melphalan as part of conditioning treatment prior to an autologous stem-cell transplant. Give prophylactic antiemetic prior to each IV melphalan dose. Administer supportive care for nausea, vomiting, diarrhea, and mucositis including nutritional support and analgesics in patients with severe mucositis. In patients who receive melphalan for use with the hepatic delivery system, administer a proton pump inhibitor the day prior to and the morning of the procedure; if antiemetic treatment is required, pre-medicate patients with an antiemetic agent in subsequent cycles.
Procedure-related severe hypotension may occur in patients who receive melphalan for use with the hepatic delivery system. Closely monitor blood pressure during the procedure; patients may require fluid support and vasopressors. Prior to administration, assess hypothalamic-pituitary-adrenal axis function and discontinue ACE-inhibitors, calcium channel blockers, or alpha-1-adrenergic blockers for at least 5 half-lives. Short-acting antihypertensive drugs may be used to manage blood pressure during the peri-procedure period if needed.
Engraftment syndrome occurred more often with melphalan (Evomela) in geriatric patients over the age of 65 years compared with younger patients.
Melphalan may cause fetal harm when administered during pregnancy. It caused fetal death and birth defects in animal studies. Advise females of reproductive potential to avoid pregnancy while taking melphalan. Discuss the potential hazard to the fetus if melphalan is used during pregnancy or if a patient becomes pregnant while taking this drug. Embryo-fetal toxicities including malformation (e.g., meningocele, encephalocele, anophthalmia, microphthalmos, and mandible and tail reduction) and hepatocele were observed in the offspring or pregnant rats who received oral (6 to 18 mg/m2/day for 10 days) or intraperitoneal (18 mg/m2) melphalan.
Counsel patients about the reproductive risk and contraception requirements during melphalan treatment. Patients of reproductive potential should use effective contraception during and after treatment with melphalan. Additionally, patients with a partner of reproductive potential should use effective contraception during and after treatment with melphalan due to the potential for male-mediated teratogenicity. Women who become pregnant while receiving melphalan should be apprised of the potential hazard to the fetus. Melphalan may cause infertility in male and female patients. Suppression of ovarian function resulting in amenorrhea has been reported in premenopausal women who received melphalan. Testicular suppression has been reported with melphalan use in men. Male and female patients should continue using effective contraception for 3 months and 6 months, respectively, after the last melphalan dose. Perform pregnancy testing prior to initiating melphalan for use with the hepatic delivery system.
Patients should avoid breast-feeding during melphalan therapy because of the potential for serious adverse reactions in nursing children from melphalan. It is not known if melphalan is excreted into human milk. Do not resume breastfeeding until 1 week after the last melphalan dose.
For the treatment of multiple myeloma:
NOTE: Melphalan injection for intravenous administration has been designated by the FDA as an orphan drug for the treatment of patients with multiple myeloma for whom oral therapy is inappropriate.
-for the palliative treatment of multiple myeloma:
NOTE: The manufacturer removed the palliative treatment of multiple myeloma indication from the Evomela label in August 2021.
Oral dosage:
Adults: 6 mg (three 2-mg tablets) orally daily; adjust the dose as required approximately every week based on blood counts. Hold melphalan therapy for a leukocyte count less than 3,000 cells/mm3 or a platelet count less than 100,000 cells/mm3. After 2 to 3 weeks of therapy, discontinue melphalan for up to 4 weeks; monitor blood counts during this time. Begin maintenance therapy with melphalan 2 mg orally daily when the white blood cell (WBC) and platelet counts begin increasing; consider cautious dose escalation until some myelosuppression occurs to assure that potentially therapeutic levels of the drug have been reached. Another regimen is melphalan 10 mg (five 2-mg tablets) orally daily for 7 to 10 days. When the WBC count is greater than 4,000 cells/mm3 and the platelet count is greater than 100,000 cells/mm3 (typically within 4 to 8 weeks), maintenance therapy is initiated with melphalan 2 mg orally daily; the maintenance dosage is adjusted between 1 mg/day and 3 mg/day based on the hematological response (target leukocyte count of 3,000 to 3,500 cells/mm3). A third regimen consists of melphalan 0.15 mg/kg orally daily for 7 days followed by maintenance therapy started when the WBC and platelet counts begin increasing (no sooner than 2 weeks and typically within 5 to 6 weeks). Maintenance therapy is melphalan 0.05 mg/kg orally daily (or less) adjusted based on blood count. In a randomized study, the overall response rate at week 22 was 44% in 100 evaluable patients with multiple myeloma who received oral melphalan 0.15 mg/kg/day PO for 7 days followed by 0.05 mg/kg/day PO when the WBC count began to rise. All patients received prednisone 0.8 mg/kg/day PO initially; prednisone was tapered over 6 weeks. Of patients who received oral melphalan in this study, 58% of patients had poor-risk cytogenetics and 51% of patients had a high tumor load.
Intravenous dosage:
Intravenous melphalan is indicated in patients for whom oral therapy is not appropriate.
Adults: 16 mg/m2 IV over 15 to 20 minutes every 2 weeks for 4 doses. After adequate recovery from toxicity, give melphalan 16 mg/m2 IV once every 4 weeks. Consider dose adjustment based on blood cell counts at the nadir and day of treatment. The overall response rate at week 22 was 38% in evaluable patients with multiple myeloma who received IV melphalan (n = 195) in a randomized study. All patients received prednisone 0.8 mg/kg/day PO; prednisone was tapered over 6 weeks. Of patients who received IV melphalan in this study, 44% of patients had poor-risk cytogenetics and 34% of patients had a high tumor load. In this study, IV melphalan doses were adjusted as follows: full dose for white blood cell (WBC) count of 4,000 cells/mm3 or greater and platelet count of 100,000 cells/mm3 or greater; 75% of dose for WBC count 3,000 to 3,999 cells/mm3 or platelet count of 75,000 to 99,999 cells/mm3; and 50% of dose for WBC count 2,000 to 2,999 cells/mm3 or platelet count of 50,000 to 74,999 cells/mm3. Doses were omitted if the WBC count was less than 2,000 cells/mm3 or the platelet count was less than 50,000 cells/mm3.
-for the palliative treatment of multiple myeloma, in combination with prednisone:
Oral dosage:
Adults: 0.25 mg/kg/day orally for 4 days (or 0.2 mg/kg/day orally for 5 days) in combination with prednisone (2 mg/kg/day orally for 4 days) repeated every 4 to 6 weeks when the granulocyte and platelet counts returned to normal. Response may be gradual over several months.
-for newly diagnosed multiple myeloma in elderly or transplant ineligible patients, in combination with thalidomide and prednisone*:
Oral dosage:
Elderly patients: The optimal dosage of melphalan and prednisone plus thalidomide has not been clearly established and dosages have varied in randomized controlled trials. Melphalan 0.25 mg/kg PO daily for 4 days and prednisone 2 mg/kg PO daily for 4 days repeated every 6 weeks for 12 cycles plus thalidomide 200 mg/day PO for 2 to 4 weeks escalated up to a maximum dose of 400 mg/day if no severe adverse events occurred was studied in previously untreated patients with multiple myeloma who were between 65 and 75 years of age in one study. Thalidomide was stopped after day 4 of the last cycle. Most patients in this study took a thalidomide dose of 200 mg/day or less. In another study, patients aged 75 years and older received melphalan 0.2 mg/kg PO daily for 4 days and prednisone 2 mg/kg PO daily for 4 days repeated every 6 weeks for 12 cycles plus thalidomide 100 mg/day PO at bedtime.
-for previously untreated multiple myeloma, in combination with bortezomib and prednisone*:
Bortezomib is FDA approved in combination with melphalan and prednisone for use in previously untreated multiple myeloma.
Oral dosage:
Adults: 9 mg/m2/day orally on days 1, 2, 3, and 4 and prednisone 60 mg/m2/day orally on days 1, 2, 3, and 4 plus bortezomib repeated every 6 weeks for 9 cycles. In cycles 1 to 4, IV or subcutaneous bortezomib 1.3 mg/m2 is given on days 1, 4, 8, and 11 followed by a 10-day rest period (on days 12 to 21) and again on days 22, 25, 29, and 32 followed by a 10-day rest period (on days 33 to 42); this 6-week cycle is considered one course. In cycles 5 to 9, IV or subcutaneous bortezomib 1.3 mg/m2 is given on days 1, 8, 22, and 29; this 6-week cycle is considered one course.
-for the treatment of newly diagnosed multiple myeloma in patients ineligible for autologous stem-cell transplant, in combination with daratumumab, bortezomib, and prednisone*:
NOTE: Daratumumab is FDA approved in combination with bortezomib, melphalan, and prednisone for the treatment of newly diagnosed multiple myeloma in patients ineligible for autologous stem-cell transplant.
Oral dosage:
Adults: 9 mg/m2 orally daily on days 1, 2, 3, and 4; bortezomib 1.3 mg/m2 subcutaneously twice weekly on weeks 1, 2, 4, and 5 of cycle 1 followed by bortezomib 1.3 mg/m2 subcutaneously once weekly on weeks 1, 2, 4, and 5 of cycles 2 to 9; and prednisone 60 mg/m2 orally daily on days 1, 2, 3, and 4 (VMP regimen) repeated every 6 weeks for 9 cycles in combination with daratumumab was evaluated in a randomized, phase 3 trial. The manufacturer recommends the following daratumumab dosage in combination with VMP: 16 mg/kg (actual body weight) IV weekly on weeks 1 to 6, 16 mg/kg IV every 3 weeks on weeks 7 to 54, and then 16 mg/kg IV every 4 weeks starting on week 55 until disease progression. In the ALCYONE trial (median follow-up of 40.1 months), the primary endpoint of PFS time was significantly higher with daratumumab plus VMP compared VMP alone (36.4 months vs. 19.3 months; hazard ratio (HR) = 0.42; 95% CI, 0.34 to 0.51; p less than 0.0001) in adult patients (n = 706; median age, 71 years; range, 40 to 93 years) with multiple myeloma who were ineligible for high-dose chemotherapy with stem-cell transplant (SCT) due to coexisting conditions or age of 65 years or older and who had not received prior systemic therapy or SCT. At the time of this analysis, the median overall survival time was significantly improved in patients in the daratumumab plus VMP arm compared with the VMP alone arm (median time not reached in either arm; HR = 0.6; 95% CI, 0.46 to 0.8; p = 0.0003).
-for the treatment of newly diagnosed multiple myeloma in patients ineligible for autologous stem-cell transplant, in combination with daratumumab/hyaluronidase, bortezomib, and prednisone*:
NOTE: Daratumumab; hyaluronidase is FDA approved in combination with bortezomib, melphalan, and prednisone for the treatment of newly diagnosed multiple myeloma in patients ineligible for autologous stem-cell transplant.
Oral dosage:
Adults: 9 mg/m2 PO daily on days 1, 2, 3, and 4 repeated every 6 weeks on cycles 1 to 9 in combination with prednisone 60 mg/m2 PO daily on days 1, 2, 3, and 4 repeated every 6 weeks on cycles 1 to 9; bortezomib 1.3 mg/m2 subcutaneously twice weekly on weeks 1, 2, 4, and 5 for the first 6-week cycle (8 doses in cycle 1) followed by bortezomib 1.3 mg/m2 subcutaneously once weekly on weeks 1, 2, 4, and 5 for 8 more 6-week cycles (4 doses/cycle in cycles 2 to 9); and 1,800 mg daratumumab and 30,000 units hyaluronidase subcutaneously weekly on weeks 1 to 6 (6 doses), every 3 weeks on weeks 7 to 54 (16 doses), and then every 4 weeks starting on week 55 until disease progression was evaluated in a single-arm cohort (n = 67) of a multicohort, open-label trial (the PLEIADES trial). The overall response rate was 88% in patients with newly diagnosed multiple myeloma who were ineligible for transplant who received daratumumab/hyaluronidase, bortezomib, melphalan, and prednisone.
-for the treatment of newly diagnosed multiple myeloma in patients ineligible for autologous stem-cell transplant, in combination with carfilzomib and prednisone*:
Oral dosage:
Adults: Dosage not established. The progression-free survival time was not significantly improved with carfilzomib, melphalan, and prednisone compared with bortezomib, melphalan, and prednisone in a randomized, phase 3 trial (the CLARION trial); additionally, serious and fatal adverse reactions occurred more often in the carfilzomib-containing arm. There is not sufficient evidence to support the use of this drug combination for this indication.
For the palliative treatment of nonresectable epithelial ovarian cancer:
Oral dosage:
Adults: 200 mcg/kg/day PO for 5 days, repeated every 4 to 5 weeks depending upon hematologic tolerance. If the leukocyte count falls below 3,000 cells/mm3, or the platelet count below 100,000 cells/mm3, discontinue melphalan until the peripheral blood cell counts have recovered.
For stem cell transplant preparation:
NOTE: Melphalan has been designated by the FDA as an orphan drug for high-dose conditioning treatment prior to hematopoietic stem-cell transplantation.
-for high-dose conditioning treatment prior to an autologous stem-cell transplant in patients with multiple myeloma:
Intravenous dosage (Evomela; propylene glycol-free formulation):
Adults: 100 mg/m2 IV over 30 minutes daily for 2 consecutive days (on day -3 and day -2) prior to an autologous stem-cell transplant (ASCT) (on day 0). Use adjusted ideal body weight to calculate the dose in patients who weigh more than 130% of their ideal body weight. Administer prophylactic antiemetic agents prior to each melphalan dose. The overall response rate (assessed in an independent, blinded review) was 100% in patients with multiple myeloma who received IV melphalan (Evomela) as high-dose conditioning treatment prior to an ASCT in a multicenter, phase IIb study (n = 61); the complete response rate was 21%. All patients achieved myeloablation at a median time of 5 days post-ASCT; the median times to neutrophil and platelet engraftment post-ASCT were 12 days (range, 10 to 16 days) and 13 days (range, 10 to 28 days), respectively. Treatment-related mortality at day 100 was 0%. Patients with symptomatic multiple myeloma and an adequate stem-cell collection yield (greater than 2 X 106 CD34+ cells/kg) were eligible. In this study, the median age was 62 years (range, 32 to 73 years), 87% of patients had newly diagnosed multiple myeloma, and 48% of patients had standard-risk cytogenetics.
-for allogeneic stem cell transplant preparation as a reduced intensity conditioning regimen*:
Intravenous dosage (Alkeran or generic melphalan with propylene glycol-containing diluent):
Adults: Studies have used melphalan 140 mg/m2 IV as a single dose or 90 mg/m2/day IV for 2 days in combination with fludarabine in reduced intensity conditioning regimens prior to allogeneic SCT for hematologic malignancies.
-for stem cell transplant preparation prior to tandem autologous stem cell transplantation in the treatment of newly diagnosed multiple myeloma*:
Intravenous dosage (Alkeran or generic melphalan with propylene glycol-containing diluent):
Adults: 200 mg/m2 IV on day -2, followed by autologous stem cell transplant on day 0. Treatment with melphalan and autologous stem cell transplant was repeated to complete a total of two sequential transplant courses (tandem transplant).
-prior to autologous hematopoietic stem-cell transplantation in patients with high-risk neuroblastoma, in combination with busulfan*:
Intravenous dosage:
Adults less than 21 years, Adolescents, Children, and Infants: 140 mg/m2 IV over 15 minutes once (4 mg/kg IV in patients who weighed less than 12 kg) given 24 hours after the completion of busulfan (0.8 to 1.2 mg/kg IV every 6 hours for 16 doses) was evaluated in a randomized, phase III trial (n = 598; HR-NBL1/SIOPEN trial). Busulfan doses were based on bodyweight as follows: 1 mg/kg for weight less than 9 kg; 1.2 mg/kg for 9 kg to less than 16 kg; 1.1 mg/kg for 16 to 23 kg; 0.95 mg/kg for weight greater than 23 kg to 34 kg; and 0.8 mg/kg for weight greater than 34 kg. Stem-cell rescue was administered at least 24 hours after melphalan. Prior to high dose chemotherapy with busulfan and melphalan, patients had received multi-agent induction chemotherapy and surgery. Post-transplant, all patients received radiation and maintenance therapy. Recommended supportive therapy included granulocyte-colony stimulating factors and ursodeoxycholic acid (for veno-occlusive disease prophylaxis).
-prior to autologous hematopoietic stem-cell transplantation in patients with newly diagnosed multiple myeloma, in combination with IV busulfan*:
Intravenous dosage:
Adults 70 years or younger: 70 mg/m2 (use adjusted body weight to calculate BSA in patients who are more than 20% above ideal body weight) IV over 30 minutes daily on days -2 and -1 in combination with intravenous busulfan was evaluated as conditioning therapy prior to an autologous hematopoietic stem-cell transplant in a randomized, open-label, phase 3 trial (n = 202). Busulfan was administered as follows: test dose of 32 mg/m2 (use actual body weight to calculate BSA) IV over 45 minutes once on either day -8 or -9 followed by either a pharmacokinetically-adjusted busulfan dose for target daily AUC of 5,000 micromolar x minute) or 130 mg/m2 (use adjusted body weight to calculate BSA in patients who are more than 20% above ideal body weight) IV over 3 hours daily on days -7, -6, -5, and -4. Patients received induction chemotherapy and supportive care per standard institutional practice including granulocyte colony-stimulating factor 5 micrograms/kg subcutaneously daily starting on day 5 and continuing until an absolute neutrophil count of 0.5 x 109 cells/L or greater. Most patients received maintenance therapy until disease progression with a lenalidomide-containing regimen.
For the treatment of amyloidosis*:
-for the treatment of primary amyloidosis in patients who are ineligible for stem cell transplantation, in combination with dexamethasone*:
Oral dosage:
Adults: 0.22 mg/kg PO in combination with dexamethasone 40 mg PO on days 1 to 4, every 28 days. Prophylactic omeprazole 20 mg PO daily, ciprofloxacin 250 mg PO twice daily, and itraconazole 100 mg PO daily were also prescribed on days 1 to 10.
-for the treatment of primary amyloidosis, prior to autologous stem cell transplant*:
Intravenous dosage:
Adults: Multiple melphalan dosage regimens have been used prior to autologous stem cell transplant. These include melphalan 140 mg/m2 IV in combination with total body irradiation (12 Gy), melphalan 200 mg/m2 IV, melphalan 140 mg/m2 IV, and melphalan 100 mg/m2 IV.
-for the treatment of systemic amyloid light-chain amyloidosis, in combination with lenalidomide and dexamethasone*:
Oral dosage:
Adults: Oral melphalan in combination with lenalidomide (10 mg PO daily on days 1 to 21) and dexamethasone (40 mg PO on days 1, 8, 15, and 22) repeated every 28 days has been evaluated in nonrandomized studies. Treatment duration, the melphalan dosage, and thromboprophylaxis agents/recommendations varied in these studies. In one study, melphalan (0.18 mg/kg PO daily on days 1, 2, 3, and 4), lenalidomide, and dexamethasone therapy was given for a maximum of 9 cycles; single-agent lenalidomide was continued in responding patients. In another study, lenalidomide, melphalan (5 mg/m2 PO daily on days 1, 2, 3, and 4), and dexamethasone were continued until disease progression, unacceptable toxicity, or up to 12 cycles.
-for the treatment of newly diagnosed systemic amyloid light-chain amyloidosis in patients who are ineligible for stem-cell transplantation, in combination with bortezomib and dexamethasone*:
Oral dosage:
Adults: 0.22 mg/kg orally daily on days 1, 2, 3, and 4 repeated every 28 days on cycles 1 and 2 and then melphalan 0.22 mg/kg orally daily on days 1, 2, 3, and 4 repeated every 35 days up to a maximum of 8 cycles in combination with bortezomib and dexamethasone (BMdex regimen) was evaluated in a multicenter, randomized, open-label, phase 3 trial (n = 109). Patients were evaluated for response after 3 and 6 cycles of therapy; patients with a partial response (PR) or better after cycle 3 received an additional 3 cycles of therapy. Patients with a complete response (CR) or a PR and organ response stopped treatment after cycle 6.
For the treatment of unresectable hepatic metastases affecting less than 50% of the liver in patients with uveal melanoma and no extrahepatic disease, or extrahepatic disease limited to bone, lymph nodes, subcutaneous tissues, or lung) that is amenable to resection or radiation:
NOTE: Melphalan for use with a hepatic delivery system has been designated an orphan drug by the FDA for this indication.
NOTE: Refer to Hepzato Kit Hepatic Delivery System Instructions for Use for information regarding pre-infusion evaluation, hydration, premedication, anticoagulation, and supportive care.
Use the following ideal body weight (IBW) equations to calculate the dose:
Male
152 cm or more: IBW = 52 kg + (0.75 kg/cm of height greater than 152 cm); Less than 152 cm: IBW = 52 kg - (0.75 kg/cm of height less than 152 cm);
Female
152 cm or more: IBW = 49 kg + (0.67 kg/cm of height greater than 152 cm);
Less than 152 cm: IBW = 49 kg - (0.67 kg/cm of height less than 152 cm.
Intra-arterial dosage:
Adults weighing 35 kg or more: 3 mg/kg (use IBW; maximum dose of 220 mg) as an intra-arterial infusion into the hepatic artery (using a hepatic delivery system) repeated every 6 to 8 weeks for up to 6 total infusions. Prior to starting therapy, verify the following baseline hematologic parameters are met: hemoglobin level of 10 g/dL or more, platelet count of 100,000 cells/microliters (mcL) or more, and neutrophil count of more than 2,000 cells/mcL. Do not administer in patients weighing less than 35 kg due to potential size limitations of percutaneous catheterization. A dose reduction or therapy discontinuation may be necessary in patients who develop severe or persistent toxicity. The objective response rate was 36.3% (complete response, 7.7%) in patients with uveal melanoma with metastases predominately involving the liver who received melphalan for use with a hepatic delivery system (n = 91) in a multicenter, single-arm (FOCUS) trial. The median duration of response was 14 months. In this study, 30% of patients had extrahepatic lesions at study enrollment and 43% of patients had received prior therapy for metastatic disease (systemic therapy, 25%; surgery/procedures, 14%; radiation, 11%).
Therapeutic Drug Monitoring:
Management of Treatment-Related Toxicity
Melphalan Used with the Hepzato Kit Hepatic Delivery System
-Hematologic Toxicity
Grade 4 neutropenia lasting more than 5 days despite growth factor support or associated with neutropenic fever: Reduce the dose to 2 mg/kg for subsequent treatment.
Grade 4 thrombocytopenia lasting more than 5 days or associated with a hemorrhage that required a transfusion: Reduce the dose to 2 mg/kg for subsequent treatment.
-Life-Threatening or Persistent Toxicity
Toxicity that does not resolve to grade 2 or less by 8 weeks: Discontinue therapy.
Maximum Dosage Limits:
-Adults
IV: 100 mg/m2 for 2 consecutive days (Evomela), use adjusted ideal body weight (IBW) in patients weighing greater than 130% of their IBW or 200 mg/m2 once (Alkeran) as conditioning therapy prior to an autologous stem-cell transplant; 16 mg/m2 IV repeated every 2 to 4 weeks as palliative therapy for multiple myeloma.
Oral: The maximum dose depends on the indication and on drug-related toxicity.
Intra-arterial: 3 mg/kg (using IBW; max of 220 mg) into the hepatic artery repeated every 6 to 8 weeks.
-Geriatric
IV: 100 mg/m2 for 2 consecutive days (Evomela), use adjusted ideal body weight (IBW) in patients weighing greater than 130% of their IBW or 200 mg/m2 once (Alkeran) as conditioning therapy prior to an autologous stem-cell transplant; 16 mg/m2 IV repeated every 2 to 4 weeks as palliative therapy for multiple myeloma.
Oral: The maximum dose depends on the indication and on drug-related toxicity.
Intra-arterial: 3 mg/kg (using IBW; max of 220 mg) into the hepatic artery repeated every 6 to 8 weeks.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
For conditioning treatment prior to an autologous stem-cell transplant: No melphalan (Evomela) dose adjustment is necessary.
For palliative treatment of multiple myeloma: IV therapy, consider an up to 50% dose reduction in patients with a blood urea nitrogen concentration of 30 mg/dL or greater. Oral therapy, consider an initial dose adjustment in patients with moderate to severe renal impairment.
*non-FDA-approved indication
Bacillus Calmette-Guerin Vaccine, BCG: (Contraindicated) Avoid administration of live virus vaccines in patients who are receiving melphalan. Patients with altered immunocompetence, including those receiving or those that have recently received immunosuppressive drug therapy, may be at increased risk for an adverse reaction because of uninhibited growth of the attenuated live virus. Additionally, vaccines may be less effective if administered during a period or altered immunocompetence.
Carmustine, BCNU: (Moderate) Concomitant use of intravenous melphalan and carmustine may result in additive pulmonary toxicity. Fatal cases of pulmonary fibrosis have been reported with both melphalan and carmustine. If these agents are used together, monitor patients for signs and symptoms of pulmonary toxicity.
Chikungunya Vaccine, Live: (Contraindicated) Avoid administration of live virus vaccines in patients who are receiving melphalan. Patients with altered immunocompetence, including those receiving or those that have recently received immunosuppressive drug therapy, may be at increased risk for an adverse reaction because of uninhibited growth of the attenuated live virus. Additionally, vaccines may be less effective if administered during a period or altered immunocompetence.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Cisplatin: (Moderate) Concomitant use of melphalan and cisplatin may result in increased melphalan levels. Cisplatin induced-renal dysfunction may alter the clearance of melphalan. Melphalan clearance is decreased in patients with renal impairment.
Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Cyclosporine: (Major) Concomitant use of melphalan and cyclosporine may result in additive nephrotoxicity. Severe renal impairment was reported in patients who received a single dose of melphalan 140 to 250 mg/m2 IV followed by standard oral doses of cyclosporine. If these agents are used together, closely monitor renal function (e.g., serum creatinine, BUN); consider a dosage reduction of cyclosporine or melphalan or switch to alternate treatment in patients who develop renal impairment.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Digoxin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa. For the digoxin tablets, there was a significant reduction in the AUC after chemotherapy to 54.4% +/- 35.5% (mean plus/minus SD) of the value before chemotherapy (p = 0.02), whereas for lanoxin capsules there was an insignificant reduction in AUC to 85.1% +/- 42.7% of the value before chemotherapy. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin tablets while they are receiving chemotherapy.
Febuxostat: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Intranasal Influenza Vaccine: (Contraindicated) Avoid administration of live virus vaccines in patients who are receiving melphalan. Patients with altered immunocompetence, including those receiving or those that have recently received immunosuppressive drug therapy, may be at increased risk for an adverse reaction because of uninhibited growth of the attenuated live virus. Additionally, vaccines may be less effective if administered during a period or altered immunocompetence.
Live Vaccines: (Contraindicated) Avoid administration of live virus vaccines in patients who are receiving melphalan. Patients with altered immunocompetence, including those receiving or those that have recently received immunosuppressive drug therapy, may be at increased risk for an adverse reaction because of uninhibited growth of the attenuated live virus. Additionally, vaccines may be less effective if administered during a period or altered immunocompetence.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Contraindicated) Avoid administration of live virus vaccines in patients who are receiving melphalan. Patients with altered immunocompetence, including those receiving or those that have recently received immunosuppressive drug therapy, may be at increased risk for an adverse reaction because of uninhibited growth of the attenuated live virus. Additionally, vaccines may be less effective if administered during a period or altered immunocompetence.
Measles/Mumps/Rubella Vaccines, MMR: (Contraindicated) Avoid administration of live virus vaccines in patients who are receiving melphalan. Patients with altered immunocompetence, including those receiving or those that have recently received immunosuppressive drug therapy, may be at increased risk for an adverse reaction because of uninhibited growth of the attenuated live virus. Additionally, vaccines may be less effective if administered during a period or altered immunocompetence.
Mycophenolate: (Minor) Bone marrow suppression is the most significant toxicity associated with melphalan in most patients. The bone marrow depressant effects of melphalan can be potentiated by concurrent or sequential administration of other bone marrow depressants and immunosuppressives.
Rotavirus Vaccine: (Contraindicated) Avoid administration of live virus vaccines in patients who are receiving melphalan. Patients with altered immunocompetence, including those receiving or those that have recently received immunosuppressive drug therapy, may be at increased risk for an adverse reaction because of uninhibited growth of the attenuated live virus. Additionally, vaccines may be less effective if administered during a period or altered immunocompetence.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Contraindicated) Avoid administration of live virus vaccines in patients who are receiving melphalan. Patients with altered immunocompetence, including those receiving or those that have recently received immunosuppressive drug therapy, may be at increased risk for an adverse reaction because of uninhibited growth of the attenuated live virus. Additionally, vaccines may be less effective if administered during a period or altered immunocompetence.
Smallpox Vaccine, Vaccinia Vaccine: (Contraindicated) Avoid administration of live virus vaccines in patients who are receiving melphalan. Patients with altered immunocompetence, including those receiving or those that have recently received immunosuppressive drug therapy, may be at increased risk for an adverse reaction because of uninhibited growth of the attenuated live virus. Additionally, vaccines may be less effective if administered during a period or altered immunocompetence.
Tacrolimus: (Minor) Bone marrow suppression is the most significant toxicity associated with melphalan in most patients. The bone marrow depressant effects of melphalan can be potentiated by concurrent or sequential administration of other bone marrow depressants and immunosuppressives.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
Typhoid Vaccine: (Contraindicated) Avoid administration of live virus vaccines in patients who are receiving melphalan. Patients with altered immunocompetence, including those receiving or those that have recently received immunosuppressive drug therapy, may be at increased risk for an adverse reaction because of uninhibited growth of the attenuated live virus. Additionally, vaccines may be less effective if administered during a period or altered immunocompetence.
Varicella-Zoster Virus Vaccine, Live: (Contraindicated) Avoid administration of live virus vaccines in patients who are receiving melphalan. Patients with altered immunocompetence, including those receiving or those that have recently received immunosuppressive drug therapy, may be at increased risk for an adverse reaction because of uninhibited growth of the attenuated live virus. Additionally, vaccines may be less effective if administered during a period or altered immunocompetence.
Yellow Fever Vaccine, Live: (Contraindicated) Avoid administration of live virus vaccines in patients who are receiving melphalan. Patients with altered immunocompetence, including those receiving or those that have recently received immunosuppressive drug therapy, may be at increased risk for an adverse reaction because of uninhibited growth of the attenuated live virus. Additionally, vaccines may be less effective if administered during a period or altered immunocompetence.
Chemotherapeutic agents interfere with DNA synthesis by acting on the enzymes or the enzyme substrates involved in cell replication. Thus, cells are most susceptible to these drugs during mitosis. The actions of antineoplastic agents are dependent on or independent of the cell cycle and are focused on the biochemical pathways of both normal and neoplastic cells. These agents are thus cytotoxic rather than tumoricidal and also may be mutagenic, carcinogenic, or teratogenic.
As an alkylating agent, melphalan exerts its chemotherapeutic effects by causing DNA base-pair code misreading (resulting in scission), depurination, and DNA-strand crosslinking. These actions lead to interference with DNA replication, transcription of RNA, and nucleic acid function, resulting in cell death.
Melphalan is administered orally, intravenously (IV), or as an intra-arterial infusion into the hepatic artery. Its volume of distribution at steady state is 0.5 L/kg or approximately 35.3 to 185.7 L/m2; it does penetrate into the cerebrospinal fluid. Melphalan demonstrates variable protein binding (50% to 90%); about 30% of drug is irreversibly bound to plasma proteins. It is mostly bound to serum albumin (40% to 60%) and has some alpha-1-acid glycoprotein binding (20%). The terminal half-life is about 75 minutes following IV administration and about 1 to 1.5 hours following oral administration. Following intra-arterial infusion of melphalan, the median terminal elimination phase half-life is 1.07 hours; systemic melphalan is eliminated by renal excretion of parent drug and metabolites. Melphalan is primarily metabolized via hydrolysis in the plasma to form monohydroxymelphalan and dihydroxymelphalan (inactive) metabolites. Following IV administration, the average total body clearance was variable among studies and ranged from 5.5 to 9 mL/min/kg or approximately 250 to 325 mL/min/m2. Renal excretion via the kidneys appears to be low with 5.8% to 21.3% excreted as unchanged drug in the urine. Following a single, radiolabeled, oral dose of melphalan 0.6 mg/kg in 18 patients, 10% +/- 4.5% of the radioactivity from the parent drug was recovered in the urine at 24 hours. In another study, less radioactivity was recovered in the urine following radiolabeled oral melphalan (30% of administered dose in 9 days) compared with IV melphalan (35% to 65% of administered dose in 7 days); most radioactivity was recovered in the first 24 hours.
-Route-Specific Pharmacokinetics
Oral Route
The absorption of oral melphalan is highly variable; the time to absorption takes up to 6 hours following a dose. The average absolute bioavailability ranges from 56% to 93%; the high variability in bioavailability may be due to incomplete intestinal absorption, first-pass hepatic metabolism, or rapid hydrolysis. Following an adjusted mean oral dose of melphalan 14 mg, the mean Cmax and AUC values were 212 +/- 74 nanograms (ng)/mL and 498 +/- 137 ng/mL X hour, respectively. The time to peak radioactivity (Tmax) was 2 hours following a radiolabeled oral melphalan dose in another study.
Effects of food: Compared with the fasted state, administration of oral melphalan with a high-fat meal reduces melphalan exposure by 36% to 54%.
Intravenous Route
Following melphalan 10 mg/m2 or 20 mg/m2 IV, the mean Cmax values were 1.2 +/- 0.4 micrograms (mcg)/mL and 2.8 +/- 1.9 mcg/mL, respectively, in patients with multiple myeloma. The mean Cmax and AUC(0-inf) values were 5.8 +/- 1.5 mcg/mL and 451 +/- 109 mcg X min/mL, respectively, following melphalan 100 mg/m2 IV in patients with multiple myeloma. In a randomized, cross-over design phase 2a study (n = 24), bioequivalence was demonstrated with an IV formulation of melphalan that does not require a proplylene-glycol containing diluent (Evomela) compared with a standard IV formulation of melphalan (Alkeran) in transplant-eligible patients with multiple myeloma (n = 24). In this study, the Cmax level (including 90% confidence intervals (CI)) following Evomela administration was 112% of the Cmax level achieved after Alkeran administration; additionally the AUC(0 to inf) value (including 90% CIs) achieved after Evomela was 110.9% of the AUC(0 to inf) value following Alkeran administration.
Other Route(s)
Intra-Arterial Route
Following the intra-arterial administration of melphalan via the hepatic delivery system (HDS), the geometric mean systemic melphalan Cmax and AUC(0-last) values were 2.4 mcg/mL and 1.8 mcg X hr/mL, respectively, and the median Tmax was 0.57 (range, 0.05 to 1.18) hours. Following intra-arterial administration into the hepatic artery, melphalan is eliminated systemically by liver uptake and removal by isolation of hepatic venous blood and subsequent filtration by the HDS. During the total filtration period, the systemic exposure of melphalan is reduced with a mean filter efficiency of 82.7%.
-Special Populations
Hepatic Impairment
The hepatic parameters of ALT (7 to 157 international units/L), AST (11 to 90 international units/L), and bilirubin (0.06 to 1.5 mg/dL) levels have no clinically significant impact on the pharmacokinetic parameters of intra-arterially administered melphalan.
Renal Impairment
Melphalan clearance is decreased in patients with renal impairment who receive IV melphalan. In a patient with an ideal body weight (IBW) of 70 kg, melphalan clearance is decreased by 28.2% in a patient with an estimated creatinine clearance (CrCl) of 30 mL/min compared with a patient with an estimated CrCl of 100 mL/min. A CrCl of more than 50 mL/min has no clinically significant impact on the pharmacokinetic parameters of intra-arterially administered melphalan.
Obesity
Melphalan clearance is increased with higher body weight in patients who receive IV melphalan. Compared with a patient with an ideal body weight (IBW) of 70 kg, melphalan clearance is decreased by 28% in a patient with an IBW of 45 kg and is increased by 31% in a patient with an IBW of 100 kg. Body weight (range, 43 to 150 kg) has no clinically significant impact on the pharmacokinetic parameters of intra-arterially administered melphalan.