Evomela

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Evomela

Classes

Nitrogen Mustard Analogs

Administration

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

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.

Adverse Reactions
Severe

hypophosphatemia / Delayed / 48.0-48.0
leukopenia / Delayed / 0-34.0
anemia / Delayed / 0-33.0
neutropenia / Delayed / 0-30.0
hypokalemia / Delayed / 28.0-28.0
anaphylactoid reactions / Rapid / 2.0-22.4
new primary malignancy / Delayed / 0-19.5
oral ulceration / Delayed / 0-10.0
stomatitis / Delayed / 0-5.0
elevated hepatic enzymes / Delayed / 0-4.0
cardiac arrest / Early / 3.2-3.2
diarrhea / Early / 0-3.0
hyperbilirubinemia / Delayed / 0-3.0
hypocalcemia / Delayed / 3.0-3.0
fever / Early / 0-3.0
GI bleeding / Delayed / 3.0-3.0
hypotension / Rapid / 3.0-3.0
hypoxia / Early / 2.1-2.1
pleural effusion / Delayed / 2.1-2.1
pulmonary edema / Early / 2.1-2.1
thrombosis / Delayed / 2.1-2.1
nausea / Early / 0-2.0
dyspnea / Early / 2.0-2.0
fatigue / Early / 0-2.0
abdominal pain / Early / 0-1.0
hepatic failure / Delayed / 0-1.0
musculoskeletal pain / Early / 1.0-1.0
bleeding / Early / 0-1.0
renal failure (unspecified) / Delayed / 1.6
hemolytic anemia / Delayed / Incidence not known
azotemia / Delayed / Incidence not known
bronchospasm / Rapid / Incidence not known
serious hypersensitivity reactions or anaphylaxis / Rapid / Incidence not known
pulmonary fibrosis / Delayed / Incidence not known
skin necrosis / Early / Incidence not known
vasculitis / Delayed / Incidence not known
sinusoidal obstruction syndrome (SOS) / Delayed / Incidence not known
veno-occlusive disease (VOD) / Delayed / Incidence not known
hepatotoxicity / Delayed / Incidence not known
thromboembolism / Delayed / Incidence not known

Moderate

constipation / Delayed / 0-48.0
peripheral edema / Delayed / 33.0-33.0
thrombocytopenia / Delayed / 50.0
lymphopenia / Delayed / 50.0
bone marrow suppression / Delayed / Incidence not known
edema / Delayed / Incidence not known
sinus tachycardia / Rapid / Incidence not known
pneumonitis / Delayed / Incidence not known
skin ulcer / Delayed / Incidence not known
hepatitis / Delayed / Incidence not known
jaundice / Delayed / Incidence not known
prolonged bleeding time / Delayed / Incidence not known

Mild

vomiting / Early / 0-64.0
anorexia / Delayed / 0-49.0
dizziness / Early / 11.0-38.0
dysgeusia / Early / 0-28.0
dyspepsia / Early / 0-26.0
headache / Early / 19.0-19.0
cough / Delayed / 15.0-15.0
lethargy / Early / 12.0-12.0
amenorrhea / Delayed / 0-9.0
infection / Delayed / Incidence not known
maculopapular rash / Early / Incidence not known
pruritus / Rapid / Incidence not known
rash / Early / Incidence not known
urticaria / Rapid / Incidence not known
spermatogenesis inhibition / Delayed / Incidence not known
injection site reaction / Rapid / Incidence not known
alopecia / Delayed / Incidence not known

Boxed Warning
Heparin hypersensitivity, heparin-induced thrombocytopenia (HIT), latex hypersensitivity, melphalan hypersensitivity, radiopaque contrast media hypersensitivity, serious hypersensitivity reactions or anaphylaxis

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.

New primary malignancy

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.

Anemia, bone marrow suppression, infection, leukopenia, neutropenia, radiation therapy, thrombocytopenia

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.

Bleeding, coagulopathy, hepatotoxicity, requires a specialized care setting, requires an experienced clinician, surgery, thromboembolic disease

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.

Common Brand Names

Alkeran, Evomela

Dea Class

Rx

Description

Alkylating agent
Used in the palliative treatment of unresectable epithelial ovarian cancer (Alkeran tablets), the palliative treatment of multiple myeloma (Alkeran tablets or injection), and as a high-dose conditioning treatment prior to an autologous stem-cell transplant in patients with multiple myeloma (Evomela); also used as liver-directed therapy with a hepatic delivery system in adults with unresectable hepatic metastases due to uveal melanoma (Hepzato)
Boxed warnings for severe myelosuppression resulting in infection or bleeding (IV and intra-arterial use products)

Dosage And Indications
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 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.[64061]

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 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 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).

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.

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 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%).

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.

†Indicates off-label use

Dosing Considerations
Hepatic Impairment

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Renal Impairment

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.

Drug Interactions

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.
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.
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.
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.
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.
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.
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.

How Supplied

Alkeran/Evomela/Melphalan Intravenous Inj Pwd F/Sol: 50mg
Alkeran/Melphalan Oral Tab: 2mg

Maximum Dosage
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.

Mechanism Of Action

Mechanism of Action: 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.

Pharmacokinetics

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.

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%.

Pregnancy And Lactation
Pregnancy

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.