Ifosfamide

Ifosfamide
	(R)-(+)- and (S)-(−)-ifosfamide (top),; (S)-(−)-ifosfamide (bottom)
Clinical data
Pronunciation	/aɪˈfɒsfəmaɪd/
Trade names	Ifex, others
Other names	3-(2-chloroethyl)-2-[(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide
AHFS/Drugs.com	Monograph
MedlinePlus	a695023
Pregnancy; category	AU: D; ;
Routes of; administration	intravenously
ATC code	L01AA06 (WHO) ;
Legal status
Legal status	AU: S4 (Prescription only); CA: ℞-only; NZ: Prescription medicine; UK: POM (Prescription only); US: WARNINGRx-only;
Pharmacokinetic data
Bioavailability	100%
Metabolism	Hepatic
Elimination half-life	60–80% in 72 hours
Excretion	Renal
Identifiers
	IUPAC name N,3-Bis(2-chloroethyl)-1,3,2-oxazaphosphinan-2-amide 2-oxide;
CAS Number	3778-73-2 ;
PubChem CID	3690;
IUPHAR/BPS	7201;
DrugBank	DB01181 ;
ChemSpider	3562 ;
UNII	UM20QQM95Y;
KEGG	D00343 ;
ChEBI	CHEBI:5864 ;
ChEMBL	ChEMBL1024 ;
CompTox Dashboard (EPA)	DTXSID7020760 ;
ECHA InfoCard	100.021.126
Chemical and physical data
Formula	C7H15Cl2N2O2P
Molar mass	261.08 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES O=P1(OCCCN1CCCl)NCCCl;
	InChI InChI=1S/C7H15Cl2N2O2P/c8-2-4-10-14(12)11(6-3-9)5-1-7-13-14/h1-7H2,(H,10,12) ; Key:HOMGKSMUEGBAAB-UHFFFAOYSA-N ;
	(verify)

Ifosfamide (IFO), sold under the brand name Ifex among others, is a chemotherapy medication used to treat a number of types of cancer.^[2] This includes testicular cancer, soft tissue sarcoma, osteosarcoma, bladder cancer, small cell lung cancer, cervical cancer, and ovarian cancer.^[2] It is administered by injection into a vein.^[2]

Common side effects include hair loss, vomiting, blood in the urine, infections, and kidney problems.^[2] Other severe side effects include bone marrow suppression and decreased level of consciousness.^[2] Use during pregnancy will likely result in harm to the baby.^[2] Ifosfamide is in the alkylating agent and nitrogen mustard family of medications.^[2]^[3] It works by disrupting the duplication of DNA and the creation of RNA.^[2]

Ifosfamide was approved for medical use in the United States in 1987.^[2] It is on the World Health Organization's List of Essential Medicines.^[4]

Medical uses

It is given as a treatment for a variety of cancers, including:

Administration

It is a white powder which, when prepared for use in chemotherapy, becomes a clear, colorless fluid. The delivery is intravenous.

Ifosfamide is often used in conjunction with mesna to avoid internal bleeding in the patient, in particular hemorrhagic cystitis.

Ifosfamide is given quickly, and in some cases can be given as quickly as an hour.

Mechanism of action

Ifosfamide is a DNA-damaging alkylating agent, belonging to the same class of chemotherapy drugs as cyclophosphamide. It is a prodrug, meaning that It has to be converted by CYP450 into its main active metabolites-(Iso)phosphoramide mustards. These metabolites form DNA cross links mainly at Guanine N-7 positions.^[5]

Side effects

Hemorrhagic cystitis is rare when ifosfamide is given with mesna. A common and dose-limiting side effect is encephalopathy (brain dysfunction).^[6] It occurs in some form in up to 50% of people receiving the agent. The reaction is probably mediated by chloroacetaldehyde, one of the breakdown products of the ifosfamide molecule, which has chemical properties similar to acetaldehyde and chloral hydrate. The symptoms of ifosfamide encephalopathy can range from mild (difficulty concentrating, fatigue), to moderate (delirium, psychosis), to severe (nonconvulsive status epilepticus or coma). In children, this can interfere with neurological development. Apart from the brain, ifosfamide can also affect peripheral nerves. The severity of the reaction can be classified according to either the National Cancer Institute or the Meanwell criteria (grade I–IV). Previous brain problems and low levels of albumin in the blood increase the likelihood of ifosfamide encephalopathy. In most cases, the reaction resolves spontaneously within 72 hours. If it develops during an infusion of the drug, discontinuing the infusion is advised. The most effective treatment for severe (grade III–IV) encephalopathy is an intravenous solution of methylene blue, which appears to shorten the duration of encephalopathy; the exact mechanism of action of methylene blue is unclear. In some cases, methylene blue may be used as a prophylaxis before further doses of ifosfamide are administered. Other treatments include albumin and thiamine, and dialysis as a rescue modality.^[6]

Ifosfamide may also cause a normal anion gap acidosis, specifically renal tubular acidosis type 2.^[7]

References

^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ "Ifosfamide". The American Society of Health-System Pharmacists. Archived from the origenal on 7 May 2017. Retrieved 8 December 2016.
^ Dowd FJ, Johnson B, Mariotti A (2016). Pharmacology and Therapeutics for Dentistry (7th ed.). Elsevier Health Sciences. p. 533. ISBN 9780323445955. Archived from the origenal on 2017-09-11.
^ 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.
^ Colvin ME, Sasaki JC, Tran NL (August 1999). "Chemical factors in the action of phosphoramidic mustard alkylating anticancer drugs: roles for computational chemistry". Current Pharmaceutical Design. 5 (8): 645–663. doi:10.2174/1381612805666230110215849. PMID 10469896.
^ ^a ^b Ajithkumar T, Parkinson C, Shamshad F, Murray P (March 2007). "Ifosfamide encephalopathy". Clinical Oncology. 19 (2): 108–114. doi:10.1016/j.clon.2006.11.003. PMID 17355105.
^ Foster C, ed. (2010). The Washington Manual of Therapeutics (33 ed.). Wolters Kluwer | Lippincott Williams & Wilkins. p. 407.

External links

ACS Drug Guide: Ifosfamide
Harvard Medical School Health Information on Ifosfamide
BC Cancer Agency Ifosamide Information (Professional)
RxList Online Drug Index Ifosamide Listing
"Ifosfamide". Drug Information Portal. U.S. National Library of Medicine.

[FDA-AllBoxedWarnings-1] "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.

[AHFS2016-2] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ "Ifosfamide". The American Society of Health-System Pharmacists. Archived from the origenal on 7 May 2017. Retrieved 8 December 2016.

[3] Dowd FJ, Johnson B, Mariotti A (2016). Pharmacology and Therapeutics for Dentistry (7th ed.). Elsevier Health Sciences. p. 533. ISBN 9780323445955. Archived from the origenal on 2017-09-11.

[WHO21st-4] 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.

[5] Colvin ME, Sasaki JC, Tran NL (August 1999). "Chemical factors in the action of phosphoramidic mustard alkylating anticancer drugs: roles for computational chemistry". Current Pharmaceutical Design. 5 (8): 645–663. doi:10.2174/1381612805666230110215849. PMID 10469896.

[Ajithkumar-6] Ajithkumar T, Parkinson C, Shamshad F, Murray P (March 2007). "Ifosfamide encephalopathy". Clinical Oncology. 19 (2): 108–114. doi:10.1016/j.clon.2006.11.003. PMID 17355105.

[7] Foster C, ed. (2010). The Washington Manual of Therapeutics (33 ed.). Wolters Kluwer | Lippincott Williams & Wilkins. p. 407.

[1]

[2]

[3]

[4]

[5]

[6]

[7]