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cyclophosphamide (Cytoxan, Neosar, Procytox {Canadian}) [CPM, CTX, CYT, NSC 26271]

Tradename: Cytoxan. Indications: - treatment of malignancy - Hodgkin's disease, non-Hodgkin's lymphoma - leukemias - breast cancer - ovarian cancer - multiple myeloma - head & neck cancer - bladder cancer - gastric cancer - hepatocellular carcinoma - lung cancer - osteogenic sarcoma - soft tissue sarcoma - neuroblastoma - retinoblastoma - Wilm's tumor - 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 - immunosuppression for organ transplantation - organ transplantation rejection - stem cell transplantation [8] Contraindications: - not recommended during pregnancy [10] Dosage: 1) 500-1500 mg/m2 every 3-4 weeks (cancer chemotherapy) - 400 mg/m2 for 4 days every 4-6 weeks 2) 0.5-1 gram/m2 body surface every 4-6 weeks IV (SLE) 3) 500-mg fixed-dose (IV) pulses, every 2-3 weeks (max 6 doses) in conjunction with glucocorticoids for elderly with systemic necrotizing vasculitis [9] 4) dilute in 50 mL D5W, infuse over 1 hour 5) give ondansetron (Zofran) 8 mg at beginning of infusion & 24 hours later 6) 50-200 mg/m2 PO daily for 14 days every 28 days 7) maintain high urinary output for 24 hours Tabs: 50 mg. Pharmacokinetics: 1) completely abdorbed from GI tract 2) metabolized in the liver by cyt P450s CYP2B6 & CYP3A4 to active metabolite 3) metabolites (85-90%) & parent compound (< 30%) eliminated in the urine 4) elimination 1/2life is 3-12 hours 5) elimination by dialysis 20-50% Monitor: clinical & laboratory monitoring every 4-8 weeks [10] 1) complete blood count (CBC) with differential - maintain WBC > 3000, neutrophils > 1500/mm3 2) chemistry profile including liver function tests 3) urinalysis & urine cytology 4) cystoscopy if hematuria Adverse effects: 1) alopecia a) generally occurs 3 weeks after therapy b) hair will regrow, perhaps with different color or texture 2) cardiac toxicity a) congestive heart failure (CHF) [10] b) cardiac necrosis or hemorrhagic myocarditis 3) gastrointestinal intolerance a) nausea/vomiting more frequent with larger doses b) anorexia, diarrhea, stomatitis, mucositis, jaundice 4) genitourinary a) hemorrhagic cystitis 1] symptoms of UTI 2] hematuria 3] negative urine cultures b) bladder cancer 5) immunosuppression: a) opportunistic infections b) hypogammaglobulinemia 6) gonadal suppression (ovarian failure) 7) bone marrow suppression a) leukopenia (more common than b or c) b) anemia c) thrombocytopenia d) onset: 7 days; nadir: 10-14 days; recovery: 21 days 8) increased risk of malignancy (overall RR=2) - increased risk of lymphoma (RR=11) [10] - increased risk of other hematologic malignancies - myelodysplasia - increased risk of bladder cancer (RR=33) [10] - 16% incidence of transitional cell carcinoma after 15 years [11] 9) pulmonary fibrosis 10) hyponatremia a) from increased ADH & water intoxication b) decreased water clearance c) predisposing factors 1] pre-exisiting renal disease 2] rapid rate of infusion 11) other (< 1%) - hypoglycemia, stomatitis, hemorrhagic colitis, darkening of skin & fingernails, hypokalemia, hyperuricemia, nasal stuffiness (large IV doses) Drug interactions: 1) cyclophosphamide may decrease digoxin levels 2) cyclophosphamide may potentiate effect of warfarin 3) thiazide diuretics may increase the duration of leukopenia 4) cardiotoxic drugs: doxorubicin 5) drugs that effects cyt P450 a) phenobarbital b) phenytoin c) chloramphenicol 6) allopurinol 7) imipramine 8) phenothiazines 9) succinylcholine Laboratory: - cyclophosphamide in serum/plasma - cyclophosphamide in urine Mechanism of action: - alkylating agent - blocks DNA synthesis & causes cell death Mechanism of drug resistance: - increased drug inactivation via activation of aldehyde dehydrogenase

Interactions

drug interactions drug adverse effects (more general classes) monitor with immunosuppressive agents

Related

aldehyde dehydrogenase cytochrome P450 2B6 (cytochrome P450 2B1, phenobarbital-inducible, CYP2B6) cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4)

General

alkylating agent nitrogen mustard disease-modifying antirheumatic agent (DMARD) immunosuppressive agent

Properties

MISC-INFO: elimination route LIVER KIDNEY pregnancy-category D 1/2life 3-12 HOURS elimination by hemodialysis + <20-50%>

Database Correlations

PUBCHEM correlations

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
  2. Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 792
  3. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 856-57
  4. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  5. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  6. Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 529, 533
  7. Geriatric Dosage Handbook, 6th edition, Selma et al eds, Lexi-Comp, Cleveland, 2001
  8. Deprecated Reference
  9. 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: 25693055
  10. Medical Knowledge Self Assessment Program (MKSAP) 17, American College of Physicians, Philadelphia 2015
  11. 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: 8602705
  12. 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: 18250349

Component-of

cyclophosphamide/dexamethasone/doxorubicin/vincristine; cyclophosphamide/vincristine/adriamycin/dexamethasone (CVAD) cyclophosphamide/doxorubicin (Adriamycin)/5-fluorouracil (CAF) cyclophosphamide/doxorubicin (Adriamycin)/vincristine (VAC) cyclophosphamide/doxorubicin/vincristine (Oncocin)/prednisone (CHOP) cyclophosphamide/epirubicin/fluorouracil (CEF, FEC-100) cyclophosphamide/methotrexate/5-fluorouracil (CMF) cyclophosphamide/pentostatin/rituximab (PCR regimen) cyclophosphamide/vincristine (Oncocin)/prednisone (CVP, COP) cyclophosphamide/vincristine (Oncovin)/prednisone/procarbazine (C-MOPP) doxorubicin (Adriamycin) & cyclophosphamide (AC) N-PEP-12 (MemoProve) rituximab/cyclophosphamide/doxorubicin/vincristine (Oncocin)/dexamethasone (R-CVAD) rituximab/cyclophosphamide/doxorubicin/vincristine (Oncocin)/prednisone (R-CHOP) rituximab/cyclophosphamide/vincristine (Oncocin)/prednisone (R-CVP)