Bendamustine

Bendamustine, sold under the brand name Treanda among others, is a chemotherapy medication used in the treatment of chronic lymphocytic leukemia (CLL), multiple myeloma, and non-Hodgkin's lymphoma.^[3][4] It is given by injection into a vein.^[3]

Bendamustine

Clinical data
Trade names	Treanda, others
Other names	SDX-105
AHFS/Drugs.com	Monograph
MedlinePlus	a608034
License data	US DailyMed: Treanda
Routes of administration	Intravenous infusion
ATC code	L01AA09 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)[1] US: ℞-only
Pharmacokinetic data
Bioavailability	NA (intravenous only)
Protein binding	94–96%
Metabolism	Hydrolyzed to inactive metabolites. Two minor metabolites (M3 and M4) formed by CYP1A2
Elimination half-life	40 min (bendamustine), 3 h (M3), 30 min (M4)
Excretion	~50% urinary, ~25% fecal [2]
Identifiers
IUPAC name 4-[5-[Bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]butanoic acid
CAS Number	16506-27-7 Y
PubChem CID	65628
IUPHAR/BPS	7478
DrugBank	DB06769 Y
ChemSpider	59069 Y
UNII	9266D9P3PQ
ChEMBL	ChEMBL487253 Y
CompTox Dashboard (EPA)	DTXSID2046888
ECHA InfoCard	100.205.789
Chemical and physical data
Formula	C16H21Cl2N3O2
Molar mass	358.26 g·mol−1
3D model (JSmol)	Interactive image
SMILES ClCCN(c2ccc1c(nc(n1C)CCCC(=O)O)c2)CCCl
InChI InChI=1S/C16H21Cl2N3O2/c1-20-14-6-5-12(21(9-7-17)10-8-18)11-13(14)19-15(20)3-2-4-16(22)23/h5-6,11H,2-4,7-10H2,1H3,(H,22,23) Y Key:YTKUWDBFDASYHO-UHFFFAOYSA-N Y
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Common side effects include low blood cell counts, fever, nausea, diarrhea, loss of appetite, cough, and rash.^[3] Other severe side effects include allergic reactions and increased risk of infection.^[3] Use in pregnancy is known to harm the baby.^[3] Bendamustine is in the alkylating agents family of medication.^[3] It works by interfering with the function of DNA and RNA.^[3]

Bendamustine was approved for medical use in the United States in 2008.^[3] It is on the World Health Organization's List of Essential Medicines.^[5][6] It was originally made from nitrogen mustard.^[3]

Medical uses

Adult Atypical Sporadic Burkitt Lymphoma successfully treated with Bendamustine and Rituximab

One combination for stage III/IV relapsed or refractory indolent lymphomas and mantle cell lymphoma (MCL), with or without prior rituximab-containing chemoimmunotherapy treatment, is bendamustine with mitoxantrone and rituximab.^[7] In Germany in 2012 it has become the first line treatment of choice for indolent lymphoma.^[8] After trial results released in June 2012 showed that it more than doubled disease progression-free survival when given along with rituximab. The combination also left patients with fewer side effects than the older R-CHOP treatment.^[9]

Adverse effects

Common adverse reactions are typical for the class of nitrogen mustards, and include nausea, fatigue, vomiting, diarrhea, fever, constipation, loss of appetite, cough, headache, unintentional weight loss, difficulty breathing, rashes, and stomatitis, as well as immunosuppression, anemia, and low platelet counts. Notably, this drug has a low incidence of hair loss (alopecia) unlike most other chemotherapy drugs.^[10]

Warning

Bendamustine solution is not compatible with Closed System Transfer Devices (CSTD) Situation: *Most CSTD vendors have adapted their system to become compatible.

• FDA issued a warning on March 11, 2015, not to use bendamustine solution with CSTDs, adapters and syringes which contain either polycarbonate or acrylonitrile-butadiene-styrene (ABS) due to the incompatibility with N,N-dimethylacetamide (DMA).

Background:

• PhaSealR & SpirosR CSTDs contain either polycarbonate or ABS can dissolve when coming into contact with bendamustine (which contains DMA).

Assessment:

• This can lead to device failure, possible product contamination, and potential serious adverse health consequences, including skin reactions in health care professionals preparing and administering this product and the risk of small blood vessel blockage in patients.

Recommendations:

• Immediately, stop using all PhaSealR &/or SpirosR products including adapters when preparing & administering bendamustine.
• Only use polypropylene syringes with bendamustine. These syringes are translucent in appearance.
• Continue to use all universal PPE & safety precautions for hazardous drugs when preparing & administering bendamustine.

Pharmacology

Bendamustine is a white, water-soluble microcrystalline powder with amphoteric properties. It acts as an alkylating agent causing intra-strand and inter-strand cross-links between DNA bases.

After intravenous infusion it is extensively metabolised in the liver by cytochrome p450. More than 95% of the drug is bound to protein – primarily albumin. Only free bendamustine is active. Elimination is biphasic with a half-life of 6–10 minutes and a terminal half-life of approximately 30 minutes. It is eliminated primarily through the kidneys.

History

Bendamustine was first made in 1963 by Ozegowski and Krebs in East Germany (the former German Democratic Republic).^[11] Until 1990 it was available only in East Germany. East German researchers found that it was useful for treating chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma and lung cancer.

Bendamustine received its first marketing approval in Germany, where it is marketed under the tradename Ribomustin, by Astellas Pharma GmbH's licensee, Mundipharma International Corporation Limited. It is indicated as a single-agent or in combination with other anti-cancer agents for indolent non-Hodgkin's lymphoma, multiple myeloma, and chronic lymphocytic leukemia. SymBio Pharmaceuticals Ltd. holds exclusive rights to develop and market bendamustine HCl in Japan and selected Asia Pacific Rim countries.

In March 2008, Cephalon received approval from the United States Food and Drug Administration to market bendamustine in the US, where it is sold under the tradename Treanda, for treatment of chronic lymphocytic leukemia.^[12]

In October 2008, the FDA granted further approval to market Treanda for the treatment of indolent B-cell non-Hodgkin's lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.^[13]

Research

It is also being studied for the treatment of sarcoma.^[14] It is also being investigated in phase II trials for the non-cancer treatment of AL amyloidosis.^[15]

References

1. "Prescription medicines: registration of new chemical entities in Australia, 2014". Therapeutic Goods Administration (TGA). 21 June 2022. Archived from the original on 10 April 2023. Retrieved 10 April 2023.
2. Dubbelman AC, Rosing H, Darwish M, D'Andrea D, Bond M, Hellriegel E, et al. (March 2013). "Pharmacokinetics and excretion of 14C-bendamustine in patients with relapsed or refractory malignancy". Drugs in R&D. 13 (1): 17–28. doi:10.1007/s40268-012-0001-5. PMC 3627029. PMID 23322528.
3. "Bendamustine Hydrochloride". The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
4. British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. p. 579. ISBN 9780857111562.
5. World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
6. World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
7. Weide R, Hess G, Köppler H, Heymanns J, Thomalla J, Aldaoud A, et al. (July 2007). "High anti-lymphoma activity of bendamustine/mitoxantrone/rituximab in rituximab pretreated relapsed or refractory indolent lymphomas and mantle cell lymphomas. A multicenter phase II study of the German Low Grade Lymphoma Study Group (GLSG)". Leukemia & Lymphoma. 48 (7): 1299–1306. doi:10.1080/10428190701361828. PMID 17613757. S2CID 2381354.
8. Susman E (December 2012). Zaleznik DF (ed.). "New Combo Replaces CHOP for Lymphoma". MedPageToday. Archived from the original on 2014-09-11.
9. Mundell EJ (June 3, 2012). "'Rediscovered' Lymphoma Drug Helps Double Survival: Study". U.S. News & World Report. Archived from the original on July 12, 2012.
10. Tageja N, Nagi J (August 2010). "Bendamustine: something old, something new" (PDF). Cancer Chemotherapy and Pharmacology. 66 (3): 413–423. doi:10.1007/s00280-010-1317-x. PMID 20376452. S2CID 25605764.
11. Ozegowski W, Krebs D (June 1963). "Aminosäureantagonisten. III. ω-[Bis-(β-chloräthyl)-amino-benzimidazolyl-(2)]-propion- bzw. -buttersäuren als potentielle Cytostatika". Advanced Synthesis and Catalysis. 20 (3–4): 178–186. doi:10.1002/prac.19630200310.
12. "Cephalon Receives FDA Approval for TREANDA, a Novel Chemotherapy for Chronic Lymphocytic Leukemia". Cephalon press release. Archived from the original on 2008-04-21. Retrieved 2008-03-23.
13. "Cephalon Receives FDA Approval for TREANDA to Treat Patients with Relapsed Indolent Non-Hodgkin's Lymphoma". Cephalon press release. Archived from the original on 2008-12-07. Retrieved 2008-11-03.
14. Bagchi S (August 2007). "Bendamustine for advanced sarcoma". The Lancet. Oncology. 8 (8): 674. doi:10.1016/S1470-2045(07)70225-5. PMID 17726779.
15. Lagos GG, Lentzsch S, Comenzo RL, Zonder JA, Osman K, Gould J, et al. (8 December 2017). "Long Term Follow up of Patients with Relapsed/Refractory Systemic Light Chain (AL) Amyloidosis Treated with Bendamustine and Dexamethasone in a Phase 2 Study". Blood. 130 (supplement 1): 1838.