melphalan
{{Short description|Chemical compound}}
{{Use dmy dates|date=September 2019}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Infobox drug
| Watchedfields = changed
| verifiedrevid = 462248349
| image = Melphalan.svg
| image_class = skin-invert-image
| width = 240
| alt =
| image2 = Melphalan ball-and-stick.png
| image_class2 = bg-transparent
| alt2 =
| pronounce =
| tradename = Alkeran, Evomela, Phelinun, others
| Drugs.com = {{drugs.com|monograph|melphalan}}
| MedlinePlus = a682220
| DailyMedID = Melphalan
| pregnancy_AU =
| pregnancy_AU_comment =
| pregnancy_category =
| routes_of_administration = By mouth, intravenous, intra-arterial
| class =
| ATC_prefix = L01
| ATC_suffix = AA03
| ATC_supplemental =
| legal_AU = S4
| legal_BR =
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| legal_NZ =
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| legal_UK =
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| legal_US = Rx-only
| legal_US_comment = {{cite web | title=Alkeran- melphalan tablet, film coated | website=DailyMed | date=18 November 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ff913271-0090-4832-a0fe-5154fe8f97b9 | access-date=23 April 2022}}[https://web.archive.org/web/20230816003745/https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/201848s000lbl.pdf fda.gov] {{Bare URL PDF|date=August 2024}}
| legal_EU = Rx-only
| legal_UN =
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| bioavailability = 25–89% (By mouth)
| protein_bound =
| metabolism = Hydrolysis to inactive metabolites
| metabolites =
| onset =
| elimination_half-life = 1.5 ± 0.8 hours
| duration_of_action =
| excretion = Kidney (IV: 5.8–21.3%)
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 148-82-3
| CAS_supplemental =
| PubChem = 460612
| IUPHAR_ligand = 7620
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01042
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 405297
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = Q41OR9510P
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00369
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 28876
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 852
| NIAID_ChemDB =
| PDB_ligand =
| synonyms = (2S)-2-amino-3-
| IUPAC_name = 4-[bis(2-Chloroethyl)amino]-L-phenylalanine
| C=13 | H=18 | Cl=2 | N=2 | O=2
| SMILES = c1cc(ccc1C[C@@H](C(=O)O)N)N(CCCl)CCCl
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C13H18Cl2N2O2/c14-5-7-17(8-6-15)11-3-1-10(2-4-11)9-12(16)13(18)19/h1-4,12H,5-9,16H2,(H,18,19)/t12-/m0/s1
| StdInChI_comment =
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = SGDBTWWWUNNDEQ-LBPRGKRZSA-N
| density =
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Melphalan, sold under the brand name Alkeran among others, is a chemotherapy medication used to treat multiple myeloma; malignant lymphoma; lymphoblastic and myeloblastic leukemia; childhood neuroblastoma; ovarian cancer; mammary adenocarcinoma; and uveal melanoma. It is taken by mouth or by injection into a vein.
Common side effects include nausea and bone marrow suppression. Other severe side effects may include anaphylaxis and the development of other cancers. Use during pregnancy may result in harm to the fetus.{{cite web |title=Melphalan Use During Pregnancy |url=https://www.drugs.com/pregnancy/melphalan.html |website=Drugs.com |access-date=9 October 2019}} Melphalan belongs to the class of nitrogen mustard alkylating agents. It works by interfering with the creation of DNA and RNA.
Melphalan was approved for medical use in the United States in 1964.{{cite web |title=Melphalan Monograph for Professionals |url=https://www.drugs.com/monograph/melphalan.html |website=Drugs.com |publisher=American Society of Health-System Pharmacists |access-date=9 October 2019}} It is on the World Health Organization's List of Essential Medicines.{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }} It is available as a generic medication.{{cite book|title=British national formulary : BNF 76|date=2018|publisher=Pharmaceutical Press|isbn=9780857113382|pages=873–874|edition=76}}
Medical uses
In the European Union, melphalan is indicated for the treatment of multiple myeloma; malignant lymphoma (Hodgkin, non-Hodgkin lymphoma); acute lymphoblastic and myeloblastic leukemia; childhood neuroblastoma; ovarian cancer; and mammary adenocarcinoma.
In the United States, melphalan is used as a high-dose conditioning treatment prior to hematopoietic progenitor (stem) cell transplantation in people with multiple myeloma.{{cite web | title=Evomela- melphalan injection, powder, lyophilized, for solution | website=DailyMed | date=31 December 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c5d68b96-14bd-4605-b6d2-2bf8b0c5ca8a | access-date=23 April 2022}}{{cite web | title=Evomela (Captisol-enabled melphalan HCl) for Injection | website=U.S. Food and Drug Administration (FDA) | date=30 November 2016 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/207155Orig1s000_Orig2s000TOC.cfm | access-date=7 September 2023}}{{dead link|date=May 2025|bot=medic}}{{cbignore|bot=medic}} In the European Union, it is indicated, in combination with other cytotoxic medicinal products, as reduced intensity conditioning treatment prior to allogeneic haematopoietic stem cell transplantation in malignant haematological diseases in adults.
In August 2023, the US Food and Drug Administration approved melphalan (Hepzato) as a liver-directed treatment for adults with uveal melanoma with unresectable hepatic metastases affecting less than 50% of the liver and no extrahepatic disease, or extrahepatic disease limited to the bone, lymph nodes, subcutaneous tissues, or lung that is amenable to resection or radiation.{{cite web | title=Oncology (Cancer) / Hematologic Malignancies Approval Notifications | website=U.S. Food and Drug Administration (FDA) | date=14 August 2023 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-approval-notifications | access-date=7 September 2023}}{{dead link|date=May 2025|bot=medic}}{{cbignore|bot=medic}} {{PD-notice}}{{cite press release | title=Delcath Systems, Inc. Announces FDA Approval of Hepzato Kit for the Treatment of Adult Patients with Unresectable Hepatic-Dominant Metastatic Uveal Melanoma | publisher=Delcath Systems | via=PR Newswire | date=14 August 2023 | url=https://www.prnewswire.com/news-releases/delcath-systems-inc-announces-fda-approval-of-hepzato-kit-for-the-treatment-of-adult-patients-with-unresectable-hepatic-dominant-metastatic-uveal-melanoma-301900346.html | access-date=7 September 2023}}
Side effects
- Nausea
- Bone marrow suppression, including
- Decreased white blood cell count causing increased risk of infection
- Decreased platelet count causing increased risk of bleeding
Less common side effects include:
- Severe allergic reactions
- Pulmonary fibrosis (scarring of lung tissue) including fatal outcomes (usually only with prolonged use)
- Hair loss
- Interstitial pneumonitis
- Rash
- Itching
- Irreversible bone marrow failure due to melphalan not being withdrawn early enough
- Cardiac arrest
Mechanism of action
Melphalan chemically alters the DNA nucleotide guanine through alkylation, and causes linkages between strands of DNA. This chemical alteration inhibits DNA synthesis and RNA synthesis, functions necessary for cells to survive. These changes cause cytotoxicity in both dividing and non-dividing tumor cells.{{cite web|title=Melphalan|url=http://www.cancer.gov/drugdictionary?cdrid=42973|publisher=National Cancer Institute|access-date=4 August 2014}}
Synthesis
File:Melphalan synthesis.svg).]]
4-Nitro-L-phenylalanine (1) was converted to its phthalimide by heating with phthalic anhydride, and this was converted to its ethyl ester (2). Catalytic hydrogenation produced the corresponding aniline. Heating in acid with oxirane, followed by treatment with phosphorus oxychloride provided the bischloride, and removal of the protecting groups by heating in hydrochloric acid gave melphalan (3).
Society and culture
= Legal status =
On 17 September 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for melphalan.{{cite web | title=Phelinun: Pending EC decision | website=European Medicines Agency (EMA) | date=18 September 2020 | url=https://www.ema.europa.eu/en/medicines/human/summaries-opinion/phelinun | access-date=21 September 2020}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. The applicant for this medicinal product is Adienne S.r.l. S.U. Melphalan was approved for medical use in the European Union in November 2020.{{cite web | title=Phelinun EPAR | website=European Medicines Agency (EMA) | date=15 September 2020 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/phelinun | access-date=23 April 2022}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
References
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{{Chemotherapeutic agents}}
{{Nitrogen mustards}}
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Category:Chloroethyl compounds
Category:IARC Group 1 carcinogens
Category:World Health Organization essential medicines