Drug products: Holoxan, Holoxan®
ATC code: L01AA06
Female sex is correlated with greater risk of ifosfamide side effects. No significant sex differences in the effect of ifosfamide have been observed. Use of ifosfamide during pregnancy may cause birth defects.
Worse outcome has been demonstrated in young male adults, compared to females, with Ewing sarcoma .
Pharmacokinetics and dosing
Studies have not been able to verify sex-related discrepancy in pharmacokinetics of ifosfamide .
Ifosfamide and cyclophosphamide were compared as single drugs in a randomized phase II study including 135 patients (15-70 years old) with advanced or metastatic soft-tissue sarcoma. Overall response rates considering both treatments together were four times higher in girls/women (20% vs. 5%). Sex difference was not significant taking ifosfamide alone (9 of 40 (23%) for girls/women vs 3 of 38 (8%) for boys/men) .
In a meta-analysis of three randomized clinical trials on sarcoma (897 boys/men and 631 girls/women, median age 12 (range 0-50) years), patients were treated with either cyclophosphamide or ifosfamide in combination with vincristine and dactinomycin. Analyses showed no significant heterogeneity of the treatment effect between sexes for both agents together .
Subgroup analysis of data from a randomized noninferiority study (EE99-R1)  comparing cyclophosphamide with ifosfamide, revealed higher risk of ifosfamide toxicity in girls/women than in boys/men (251 boys/men, 174 girls/women, median age 14 (range 0-50) years). The most significant sex-related differences were observed for nephrotoxicity (OR 2.98, 95% CI 1.43-6.2), infection (OR 2.5, 95% CI 1.68-3.73) and leukopenia/neutropenia (OR 1.58, 95% CI 1.01-2.47) . Two smaller clinical studies conducted earlier showed no significant different toxicity of ifosfamide between boys/men and girls/women [6, 7]. A meta-analysis in pediatric and adult sarcoma patients mentioned above  came to comparable conclusions as of the EE99-R1 study .
Sex-related difference in chemotherapy toxicity was evaluated in patients with non-metastatic osteosarcoma. Among those treated with regimens including ifosfamide, doxorubicin and cisplatin (501 boys/men, 255 girls/women, median age 17 (4-40) years), female patients experienced hematological toxicities more frequently than males. The frequency of grade four neutropenia and thrombocytopenia were significantly higher in the females than males (65 vs 50 %, and 51 vs 25 %) .
Reproductive health issues
Fetal defects and miscarriages have been reported. Women of childbearing potential and their partner should be advised against becoming pregnant and advised to use effective contraception during and 6 months after treatment with ifosfamide . Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).
Date of litterature search: 2022-02-25
- Vera Regitz-Zagrosek. Sex and Gender Differences in Pharmacology. Springer-Verlag Berlin Heidelberg; 2012.
- Freyer G, Tranchand B, Ligneau B, Ardiet C, Souquet PJ, Court-Fortune I et al. Population pharmacokinetics of doxorubicin, etoposide and ifosfamide in small cell lung cancer patients: results of a multicentre study. Br J Clin Pharmacol. 2000;50(4):315-24. PubMed
- Bramwell VH, Mouridsen HT, Santoro A, Blackledge G, Somers R, Verwey J et al. Cyclophosphamide versus ifosfamide: final report of a randomized phase II trial in adult soft tissue sarcomas. Eur J Cancer Clin Oncol. 1987;23(3):311-21. PubMed
- Fresneau B, Hackshaw A, Hawkins DS, Paulussen M, Anderson JR, Judson I et al. Investigating the heterogeneity of alkylating agents' efficacy and toxicity between sexes: A systematic review and meta-analysis of randomized trials comparing cyclophosphamide and ifosfamide (MAIAGE study). Pediatr Blood Cancer. 2017;64(8). PubMed
- Le Deley MC, Paulussen M, Lewis I, Brennan B, Ranft A, Whelan J et al. Cyclophosphamide compared with ifosfamide in consolidation treatment of standard-risk Ewing sarcoma: results of the randomized noninferiority Euro-EWING99-R1 trial. J Clin Oncol. 2014;32(23):2440-8. PubMed
- Paulussen M, Craft AW, Lewis I, Hackshaw A, Douglas C, Dunst J et al. Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol. 2008;26(27):4385-93. PubMed
- Crist WM, Anderson JR, Meza JL, Fryer C, Raney RB, Ruymann FB et al. Intergroup rhabdomyosarcoma study-IV: results for patients with nonmetastatic disease. J Clin Oncol. 2001;19(12):3091-102. PubMed
- Ferrari S, Palmerini E, Staals E, Abate ME, Longhi A, Cesari M et al. Sex- and age-related chemotherapy toxicity in patients with non-metastatic osteosarcoma. J Chemother. 2009;21(2):205-10. PubMed
- Holoxan (ifosfamide). Swedish Medical Products Agency [updated 2018-09-26, cited 2022-02-25]
- Conise (INSIKT). Kalmar: eHälsomyndigheten. 2018 [cited 2021-11-18.] länk
Reviewed by: Diana Rydberg, Pauline Raaschou
Approved by: Karin Schenck-Gustafsson