Cyclophosphamide

(BAN, rINN)
Cyclophosphamide Chemical formula
Synonyms: B-518; Ciclofosfamida; Ciklofosfamidas; Ciklofoszfamid; Cyclophosphamidum; Cyclophosphamidum Monohydricum; Cyclophosphanum; Cyklofosfamid; Cyklofosfamid monohydrát; NSC26271; Siklofosfamid; Syklofosfamidi; WR-138719. 2-[Bis(2-chloroethyl)amino]perhydro-1,3,2-oxazaphosphorinan 2-oxide monohydrate.
Cyrillic synonym: Циклофосфамид.

💊 Chemical information

Chemical formula: C7H15Cl2N2O2P, H2O = 279.1.
CAS — 6055-19-2 (cyclophosphamide monohydrate); 5018-0 (anhydrous cyclophosphamide).
ATC — L01AA01.
ATC Vet — QL01AA01.

Pharmacopoeias.

In Chin., Eur., Int., Jpn, and US.

Ph. Eur. 6.2

(Cyclophosphamide). A white or almost white, crystalline powder. Soluble in water; freely soluble in alcohol. A freshly prepared 2% solution in water has a pH of 4.0 to 6.0.

USP 31

(Cyclophosphamide). A white, crystalline powder. It liquefies upon loss of its water of crystallisation. Soluble in water and in alcohol. A 1% solution in water has a pH of 3.9 to 7.1 when determined 30 minutes after preparation. Store in airtight containers at 2° to 30°.

💊 Adverse Effects and Treatment

The major dose-limiting effect is myelosuppression. After single doses the nadir of the white cell count may occur in around 1 to 2 weeks with full recovery usually in 3 to 4 weeks. Thrombocytopenia and anaemia may occur but tend to be less common and less severe. Haemorrhagic cystitis may develop after high or prolonged dosage, and can be life-threatening. Adequate hydration to maintain urine output at 100 mL/hour and use of mesna are generally recommended in an attempt to reduce urotoxicity. If mesna is used, frequent emptying of the bladder should be avoided. Doses of cyclophosphamide should be given early in the day. Alopecia occurs in about 20% of patients given low doses and in practically all patients given high doses. Hair loss starts after 3 weeks of treatment but regrowth is usually evident after 3 months, even with continued treatment. Hyperpigmentation of skin, especially that of the palms and soles, and of the nails, has been reported. Nausea and vomiting commonly occur, and may be reduced by prophylactic antiemetics. Mucositis may also occur. Other adverse effects include a syndrome resembling inappropriate secretion of antidiuretic hormone (which may require diuretic therapy), disturbances of carbohydrate metabolism, gonadal suppression (common and occasionally resulting in sterility), interstitial pulmonary fibrosis, and, especially at high doses, cardiotoxicity.

Effects on the bladder.

Sterile haemorrhagic cystitis can occur after high-dose infusions of cyclophosphamide or after prolonged low-dose oral use.1,2 It is believed to be secondary to renal excretion of alkylating metabolites, particularly the acrolein metabolite, that cause sloughing, thinning, and inflammation of the bladder wall. Damage ranges from minor bleeding to diffuse necrotic ulceration, and can lead to anaemia, constriction of the bladder, bladder perforation, and death.2 Symptoms may be delayed, and have been reported to occur up to 6 months after stopping the drug.3 An increased incidence of cystitis when patients on a high-dose cyclophosphamide regimen were transferred from one brand to another has been reported,4 apparently because one was labelled in terms of the anhydrous substance and one as the monohydrate, resulting in a 6.4% difference in the content of active substance.5 Measures used to prevent haemorrhagic cystitis include intravenous hydration with diuresis, frequent voiding, or bladder catheterisation with irrigation, to increase urine output and dilute the excreted metabolites. Mesna may be used as a uroprotectant to reduce exposure to the metabolites.2 If bleeding occurs, various drugs have been instilled intravesically, including sodium chloride 0.9%, alum, or prostaglandins.2,6-9 Silver nitrate, formaldehyde, or phenol instillations have been used but are painful and patients require anaesthesia.2 There is limited information to suggest that conjugated oestrogens given orally or intravenously may be effective.2,10 Nonpharmacological techniques are reserved for refractory cases and include arterial embolisation or surgery.2 In addition to the shorter term effects, cyclophosphamide has been reported to be associated with the development of bladder carcinoma.1,11-14 A history of cyclophosphamide-induced cystitis may be associated with an increased risk of bladder carcinoma1,11 but some studies have not found a link,13 and bladder malignancies can develop in patients who have not experienced cystitis while receiving cyclophosphamide.12 For a discussion of the carcinogenic effects of antineoplastics, including cyclophosphamide.
1. Talar-Williams C, et al. Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis. Ann Intern Med 1996; 124: 477–84
2. West NJ. Prevention and treatment of hemorrhagic cystitis. Pharmacotherapy 1997; 17: 696–706
3. Armstrong B, et al. Delayed cystitis due to cyclophosphamide. N Engl J Med 1979; 300: 45
4. Shaw IC, et al. Difference in bioactivity between two preparations of cyclophosphamide. Lancet 1983; i: 709
5. Hilgard P, et al. Bioactivity of cyclophosphamide preparations. Lancet 1983; i: 1436
6. Mohiuddin J, et al. Treatment of cyclophosphamide-induced cystitis with prostaglandin E . Ann Intern Med 1984; 101: 142
7. Miller LJ, et al. Treatment of cyclophosphamide-induced hemorrhagic cystitis with prostaglandins. Ann Pharmacother 1994; 28: 590–4
8. Ippoliti C, et al. Intravesicular carboprost for the treatment of hemorrhagic cystitis after marrow transplantation. Urology 1995; 46: 811–15
9. Laszlo D, et al. Prostaglandin E2 bladder instillation for the treatment of hemorrhagic cystitis after allogeneic bone marrow transplantation. Haematologica 1995; 80: 421–5
10. Ordemann R, et al. Encouraging results in the treatment of haemorrhagic cystitis with estrogen – report of 10 cases and review of the literature. Bone Marrow Transplant 2000; 25: 981–5
11. Wall RL, Clausen KP. Carcinoma of the urinary bladder in patients receiving cyclophosphamide. N Engl J Med 1975; 293: 271–3
12. Plotz PH, et al. Bladder complications in patients receiving cyclophosphamide for systemic lupus erythematosus or rheumatoid arthritis. Ann Intern Med 1979; 91: 221–3
13. Pedersen-Bjergaard J, et al. Carcinoma of the urinary bladder after treatment with cyclophosphamide for non-Hodgkin’s lymphoma. N Engl J Med 1988; 318: 1028–32
14. Travis LB, et al. Bladder cancer after chemotherapy for nonHodgkin’s lymphoma. N Engl J Med 1989; 321: 544–5.

Effects on the blood.

Amifostine has been reported to protect against the myelosuppressive effects of cyclophosphamide, and may be used to reduce neutropenia-related infection associated with the combination of cyclophosphamide and cisplatin.

Effects on carbohyd

rate metabolism. Acute onset type 1 diabetes occurred in a patient treated with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP), and was thought to be due to the cyclophosphamide.1
1. Atlan-Gepner C, et al. A cyclophosphamide-induced autoimmune diabetes. Lancet 1998; 352: 373–4.

Effects on electrolytes.

Water intoxication has been reported with cyclophosphamide,1-4 usually in high doses (30 to 50 mg/kg or more) although symptoms have been reported after a dose of 20 mg/kg in a patient with renal disease,3 and in another patient with SLE but apparently normal renal function who received 10 mg/kg.4 One case of severe hyponatraemia leading to convulsions and death has been reported.5 Symptoms resemble the syndrome of inappropriate antidiuretic hormone secretion (SIADH)5 but plasma concentrations of antidiuretic hormone do not appear to be raised in these patients.3
1. DeFronzo RA, et al. Water intoxication in man after cyclophosphamide therapy: time course and relation to drug activation. Ann Intern Med 1973; 78: 861–9
2. Green TP, Mirkin BL. Prevention of cyclophosphamide-induced antidiuresis by furosemide infusion. Clin Pharmacol Ther 1981; 29: 634–42
3. Bressler RB, Huston DP. Water intoxication following moderatedose intravenous cyclophosphamide. Arch Intern Med 1985; 145: 548–9
4. McCarron MO, et al. Water intoxication after low dose cyclophosphamide. BMJ 1995; 311: 292
5. Harlow PJ, et al. A fatal case of inappropriate ADH secretion induced by cyclophosphamide therapy. Cancer 1979; 44: 896–8.

Effects on the eyes.

Recurrent transient myopia, apparently due to increased hydration of the lens of the eye, was induced by an intravenous bolus of cyclophosphamide in an adolescent with SLE.1 CMV retinitis has occurred in patients during or after cyclophosphamide therapy; presenting symptoms included floaters and blurred or decreased vision.2
1. Arranz JA, et al. Cyclophosphamide-induced myopia. Ann Intern Med 1992; 116: 92–3
2. Agrawal A, et al. Visual symptoms in patients on cyclophosphamide may herald sight threatening disease. Br J Ophthalmol 2003; 87: 122–3.

Effects on reproductive potential.

Severe gonadal failure with transient or permanent azoospermia is common in men treated with cyclophosphamide. Suppression of germ-cell function with intramuscular testosterone in 5 men during cyclophosphamide therapy for nephrotic syndrome was associated with a more rapid return of spermatogenesis compared with 10 patients who did not receive the androgen.1
1. Masala A, et al. Use of testosterone to prevent cyclophosphamide-induced azoospermia. Ann Intern Med 1997; 126: 292–5.

Effects on the skin.

An erythematous pruritic rash, similar to the palmar-plantar erythrodysesthesia syndrome but oc curring on the dorsal surfaces of the hands and feet, occurred 6 days after the first high dose of cyclophosphamide in a patient being prepared for bone marrow transplantation.1 Previous cyclophosphamide-containing chemotherapy did not produce this reaction. The symptoms improved somewhat on treatment with triamcinolone ointment, and subsequently desquamation of the hands occurred with decreased purplish discoloration and oedema of the feet. There has also been a report of 2 patients who developed Stevens-Johnson syndrome, with some features suggestive of overlapping toxic epidermal necrolysis.2
1. Matsuyama JR, Kwok KK. A variant of the chemotherapy-associated erythrodysesthesia syndrome related to high-dose cyclophosphamide. DICP Ann Pharmacother 1989; 23: 776–9
2. Vasculitic syndromes. Treatment of the systemic vasculitides has revolved around the use of corticosteroids and cyclophosphamide. The benefits are uncertain in polyarteritis nodosa and Takayasu’s arteritis, but the benefits of combined therapy are generally accepted in Churg-Strauss syndrome and microscopic polyangiitis, and cyclophosphamide is the mainstay of effective treatment of Wegener’s granulomatosis. A number of regimens are in use; in particular intermittent high-dose intravenous (‘pulsed’) use is being evaluated in comparison with continuous therapy.
1. Richmond R, et al. Optimisation of cyclophosphamide therapy in systemic vasculitis. Clin Pharmacokinet 1998; 34: 79–90.

💊 Preparations

BP 2008: Cyclophosphamide Injection; Cyclophosphamide Tablets; USP 31: Cyclophosphamide for Injection; Cyclophosphamide Tablets.

Proprietary Preparations

Arg.: Ciclokebir; Endoxan†; Genoxal†; Austral.: Cycloblastin; Endoxan; Austria: Endoxan; Belg.: Endoxan; Braz.: Ciclodrax†; Cyclan†; Fosfaseron†; Genuxal; Canad.: Cytoxan; Procytox; Chile: Endoxan; Ledoxina; Cz.: Cytoxan†; Endoxan; Denm.: Carloxan†; Sendoxan; Fin.: Sendoxan; Fr.: Endoxan; Ger.: Cyclostin†; Endoxan; Gr.: Endoxan; Hong Kong: Endoxan; Hung.: Cytoxan; Endoxan; India: Cycloxan; Endoxan; Oncophos; Indon.: Endoxan; Irl.: Endoxana; Israel: Cytophosphan; Cytoxan†; Endoxan; Ital.: Endoxan; Jpn: Endoxan†; Malaysia: Endoxan†; Mex.: Genoxal†; Hidrofosmin; Ledoxina; Neth.: Endoxan; Norw.: Sendoxan; NZ: Cycloblastin; Cytoxan; Endoxan; Philipp.: Cytoxan; Endoxan; Ledoxan; Xyclomed; Pol.: Endoxan; Port.: Endoxan; S.Afr.: Cycloblastin; Endoxan; Singapore: Alkyloxan†; Endoxan; Spain: Genoxal; Swed.: Sendoxan; Switz.: Endoxan; Thai.: Endoxan; Ledoxan; Turk.: Alkyloxan; Endoxan; UK: Endoxana†; USA: Cytoxan†; Neosar; Venez.: Biodoxan.
Published December 14, 2018.