[4] Other severe side effects include an increased future risk of cancer, infertility, allergic reactions, and pulmonary fibrosis.

Regular and frequent laboratory evaluations are required to monitor kidney function, avoid drug-induced bladder complications and screen for bone marrow toxicity.

[citation needed] The main use of cyclophosphamide is with other chemotherapy agents in the treatment of lymphomas, some forms of brain cancer, neuroblastoma, leukemia and some solid tumors.

Cyclophosphamide is also used to treat minimal change disease,[8] severe rheumatoid arthritis, granulomatosis with polyangiitis,[5] Goodpasture syndrome[9] and multiple sclerosis.

[10] Because of its potential side effects such as amenorrhea or ovarian failure, cyclophosphamide is used for early phases of treatment and later substituted by other medications, such as mycophenolic acid or azathioprine.

[15][16] Like other alkylating agents, cyclophosphamide is teratogenic and contraindicated in pregnant women (pregnancy category D) except for life-threatening circumstances in the mother.

[20] Pulmonary injury appears rare,[21] but can present with two clinical patterns: an early, acute pneumonitis and a chronic, progressive fibrosis.

[26] Risks of hemorrhagic cystitis can be minimized with adequate fluid intake, avoidance of nighttime dosage and mesna (sodium 2-mercaptoethane sulfonate), a sulfhydryl donor which binds and detoxifies acrolein.

[28] Neutropenia or lymphopenia arising secondary to cyclophosphamide usage can predispose people to a variety of bacterial, fungal and opportunistic infections.

[32] The use of leuprorelin in women of reproductive age before administration of intermittently dosed cyclophosphamide may diminish the risks of premature menopause and infertility.

[33] Cyclophosphamide is carcinogenic and may increase the risk of developing lymphomas, leukemia, skin cancer, transitional cell carcinoma of the bladder or other malignancies.

[citation needed] Oral cyclophosphamide is rapidly absorbed and then converted by mixed-function oxidase enzymes (cytochrome P450 system) in the liver to active metabolites.

[39] The active metabolites of cyclophosphamide are highly protein bound and distributed to all tissues, are assumed to cross the placenta and are known to be present in breast milk.

[41] Cyclophosphamide metabolites are primarily excreted in the urine unchanged, and drug dosing should be appropriately adjusted in the setting of renal dysfunction.

This is because carboxycyclophosphamide cannot undergo β-elimination (the carboxylate acts as an electron-donating group, nullifying the potential for transformation), preventing nitrogen mustard activation and subsequent alkylation.

As reported by O. M. Colvin in his study of the development of cyclophosphamide and its clinical applications, Phosphoramide mustard, one of the principal toxic metabolites of cyclophosphamide, was synthesized and reported by Friedman and Seligman in 1954[50] ...It was postulated that the presence of the phosphate bond to the nitrogen atom could inactivate the nitrogen mustard moiety, but the phosphate bond would be cleaved in gastric cancers and other tumors which had a high phosphamidase content.

However, in studies carried out after the clinical efficacy of cyclophosphamide was demonstrated, phosphoramide mustard proved to be cytotoxic in vitro (footnote omitted), but to have a low therapeutic index in vivo.