cyclophosphamide (Cytoxan, Neosar, Procytox {Canadian}) [CPM, CTX, CYT, NSC 26271]
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Introduction
Tradename: Cytoxan.
Indications
- treatment of malignancy
- immunosuppression for severe autoimmune disease
- systemic lupus erythematosus (SLE):
- hematologic complications
- renal complications
- CNS complications
- rheumatoid arthritis
- dermatomyositis, polymyositis
- Wegener's granulomatosis
- vasculitis
- multiple sclerosis
- minimal change disease
- systemic lupus erythematosus (SLE):
- immunosuppression for organ transplantation
Contraindications
Dosage
- 500-1500 mg/m2 every 3-4 weeks (cancer chemotherapy)
- 400 mg/m2 for 4 days every 4-6 weeks
- 0.5-1 gram/m2 body surface every 4-6 weeks IV (SLE)
- 500-mg fixed-dose (IV) pulses, every 2-3 weeks (max 6 doses) in conjunction with glucocorticoids for elderly with systemic necrotizing vasculitis[9]
- dilute in 50 mL D5W, infuse over 1 hour
- give ondansetron (Zofran) 8 mg at beginning of infusion & 24 hours later
- 50-200 mg/m2 PO daily for 14 days every 28 days
- maintain high urinary output for 24 hours
Tabs: 50 mg.
Pharmacokinetics
- completely abdorbed from GI tract
- metabolized in the liver by cyt P450s CYP2B6 & CYP3A4 to active metabolite
- metabolites (85-90%) & parent compound (< 30%) eliminated in the urine
- elimination 1/2life is 3-12 hours
- elimination by dialysis 20-50%
elimination via liver
elimination via kidney
1/2life = 3-12 hours
elimination by hemodialysis = +
Monitor
clinical & laboratory monitoring every 4-8 weeks[10]
- complete blood count (CBC) with differential
- maintain WBC > 3000, neutrophils > 1500/mm3
- chemistry profile including liver function tests
- urinalysis & urine cytology
- cystoscopy if hematuria
Adverse effects
- alopecia
- generally occurs 3 weeks after therapy
- hair will regrow, perhaps with different color or texture
- cardiac toxicity
- congestive heart failure (CHF)[10]
- cardiac necrosis or hemorrhagic myocarditis
- gastrointestinal intolerance
- genitourinary
- hemorrhagic cystitis
- symptoms of UTI
- hematuria
- negative urine cultures
- bladder cancer
- hemorrhagic cystitis
- immunosuppression:
- gonadal suppression (ovarian failure)
- bone marrow suppression
- leukopenia (more common than b or c)
- anemia
- thrombocytopenia
- onset: 7 days; nadir: 10-14 days; recovery: 21 days
- increased risk of malignancy (overall RR=2)
- increased risk of lymphoma (RR=11)[10]
- increased risk of other hematologic malignancies
- increased risk of bladder cancer (RR=33)[10]
- 16% incidence of transitional cell carcinoma after 15 years[11]
- pulmonary fibrosis
- hyponatremia
- from increased ADH & water intoxication
- decreased water clearance
- predisposing factors
- pre-exisiting renal disease
- rapid rate of infusion
- other (< 1%)
- hypoglycemia, stomatitis, hemorrhagic colitis, darkening of skin & fingernails, hypokalemia, hyperuricemia, nasal stuffiness (large IV doses)
Drug interactions
- cyclophosphamide may decrease digoxin levels
- cyclophosphamide may potentiate effect of warfarin
- thiazide diuretics may increase the duration of leukopenia
- cardiotoxic drugs: doxorubicin
- drugs that effects cyt P450
- allopurinol
- imipramine
- phenothiazines
- succinylcholine
Laboratory
Mechanism of action
- alkylating agent
- blocks DNA synthesis & causes cell death Mechanism of drug resistance:
- increased drug inactivation via activation of aldehyde dehydrogenase
More general terms
- immunosuppressive agent
- alkylating agent nitrogen mustard
- disease-modifying antirheumatic agent (DMARD)
Additional terms
- aldehyde dehydrogenase
- cytochrome P450 2B6 (cytochrome P450 2B1, phenobarbital-inducible, CYP2B6)
- cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4)
Component of
- cyclophosphamide/dexamethasone/doxorubicin/vincristine; cyclophosphamide/vincristine/adriamycin/dexamethasone (CVAD)
- N-PEP-12 (MemoProve)
- rituximab/cyclophosphamide/vincristine (Oncocin)/prednisone (R-CVP)
- rituximab/cyclophosphamide/doxorubicin/vincristine (Oncocin)/dexamethasone (R-CVAD)
- rituximab/cyclophosphamide/doxorubicin/vincristine (Oncocin)/prednisone (R-CHOP)
- cyclophosphamide/methotrexate/5-fluorouracil (CMF)
- cyclophosphamide/doxorubicin (Adriamycin)/vincristine (VAC)
- cyclophosphamide/doxorubicin/vincristine (Oncocin)/prednisone (CHOP)
- cyclophosphamide/doxorubicin (Adriamycin)/5-fluorouracil (CAF)
- doxorubicin (Adriamycin) & cyclophosphamide (AC)
- cyclophosphamide/epirubicin/fluorouracil (CEF, FEC-100)
- cyclophosphamide/vincristine (Oncovin)/prednisone/procarbazine (C-MOPP)
- cyclophosphamide/vincristine (Oncocin)/prednisone (CVP, COP)
- cyclophosphamide/pentostatin/rituximab (PCR regimen)
References
- ↑ The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
- ↑ Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 792
- ↑ Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 856-57
- ↑ Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
- ↑ Kaiser Permanente Northern California Regional Drug Formulary, 1998
- ↑ Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 529, 533
- ↑ Geriatric Dosage Handbook, 6th edition, Selma et al eds, Lexi-Comp, Cleveland, 2001
- ↑ 8.0 8.1 Deprecated Reference
- ↑ 9.0 9.1 Pagnoux C, Quemeneur T, Ninet J et al Treatment of systemic necrotizing vasculitides in patients aged sixty-five years or older: Results of a multicenter, open-label, randomized controlled trial of corticosteroid and cyclophosphamide-based induction therapy. Arthritis & rheumatology 2015 Apr; 67:1117. PMID: https://www.ncbi.nlm.nih.gov/pubmed/25693055
- ↑ 10.0 10.1 10.2 10.3 10.4 10.5 Medical Knowledge Self Assessment Program (MKSAP) 17, American College of Physicians, Philadelphia 2015
- ↑ 11.0 11.1 Talar-Williams C, Hijazi YM, Walther MM et al Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis. Ann Intern Med. 1996 Mar 1;124(5):477-84. PMID: https://www.ncbi.nlm.nih.gov/pubmed/8602705
- ↑ Perez EA, Suman VJ, Davidson NE et al Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial. J Clin Oncol. 2008 Mar 10;26(8):1231-8 PMID: https://www.ncbi.nlm.nih.gov/pubmed/18250349