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Pronunciation:

(sye kloe FOS fa mide)

U.S. Brand Names:

Cytoxan®

Synonyms:

CPM; CTX; CYT; NSC-26271

Generic Available:

Yes: Tablet

Canadian Brand Names:

Cytoxan®; Procytox®

Use:

Oncologic: Treatment of Hodgkin's and non-Hodgkin's lymphoma, Burkitt's lymphoma, chronic lymphocytic leukemia (CLL), chronic myelocytic leukemia (CML), acute myelocytic leukemia (AML), acute lymphocytic leukemia (ALL), mycosis fungoides, multiple myeloma, neuroblastoma, retinoblastoma, rhabdomyosarcoma, Ewing's sarcoma; breast, testicular, endometrial, ovarian, and lung cancers, and in conditioning regimens for bone marrow transplantation

Nononcologic: Prophylaxis of rejection for kidney, heart, liver, and bone marrow transplants, severe rheumatoid disorders, nephrotic syndrome, Wegener's granulomatosis, idiopathic pulmonary hemosideroses, myasthenia gravis, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, autoimmune hemolytic anemia, idiopathic thrombocytic purpura (ITP), macroglobulinemia, and antibody-induced pure red cell aplasia

Pregnancy Risk Factor:

Lactation:

Enters breast milk/contraindicated

Contraindications:

Hypersensitivity to cyclophosphamide or any component of the formulation; pregnancy

Warnings/Precautions:

The U.S. Food and Drug Administration (FDA) currently recommends that procedures for proper handling and disposal of antineoplastic agents be considered. Dosage adjustment needed for renal or hepatic failure; use with caution in patients with bone marrow suppression.

Adverse Reactions:

>10%:

Dermatologic: Alopecia (40% to 60%) but hair will usually regrow although it may be a different color and/or texture. Hair loss usually begins 3-6 weeks after the start of therapy.

Endocrine & metabolic: Fertility: May cause sterility; interferes with oogenesis and spermatogenesis; may be irreversible in some patients; gonadal suppression (amenorrhea)

Gastrointestinal: Nausea and vomiting occur more frequently with larger doses, usually beginning 6-10 hours after administration; anorexia, diarrhea, mucositis, and stomatitis are also seen

Genitourinary: Severe, potentially fatal acute hemorrhagic cystitis or urinary fibrosis, believed to be a result of chemical irritation of the bladder by acrolein, a cyclophosphamide metabolite, occurs in 7% to 12% of patients and has been reported in up to 40% of patients in some series. Patients should be encouraged to drink plenty of fluids during therapy (most adults will require at least 2 L/day), void frequently, and avoid taking the drug at night. With large I.V. doses, I.V. hydration is usually recommended. The use of mesna and/or continuous bladder irrigation is rarely needed for doses <2 g/m².

Hematologic: Thrombocytopenia and anemia are less common than leukopenia

Onset: 7 days

Nadir: 10-14 days

Recovery: 21 days

1% to 10%:

Cardiovascular: Facial flushing

Central nervous system: Headache

Dermatologic: Skin rash

Renal: SIADH may occur, usually with doses >50 mg/kg (or 1 g/m²); renal tubular necrosis, which usually resolves with discontinuation of the drug, is also reported

Respiratory: Nasal congestion occurs when I.V. doses are administered too rapidly (large doses via 30-60 minute infusion); patients experience runny eyes, rhinorrhea, sinus congestion, and sneezing during or immediately after the infusion. If needed, a decongestant or decongestant/antihistamine (eg, pseudoephedrine or pseudoephedrine/triprolidine) can be used to prevent or relieve these symptoms.

<1%: High-dose therapy may cause cardiac dysfunction manifested as CHF; cardiac necrosis or hemorrhagic myocarditis has occurred rarely, but may be fatal. Cyclophosphamide may also potentiate the cardiac toxicity of anthracyclines. Other adverse reactions include anaphylactic reactions, dizziness, darkening of skin/fingernails, hypokalemia, hyperuricemia, hepatotoxicity, jaundice, neutrophilic eccrine hidradenitis, radiation recall, secondary malignancy (eg, bladder carcinoma), Stevens-Johnson syndrome, toxic epidermal necrolysis, hemorrhagic colitis, hemorrhagic ureteritis, renal tubular necrosis; interstitial pneumonitis and pulmonary fibrosis is occasionally seen with high doses.

Overdosage/Toxicology:

Symptoms of overdose include myelosuppression, alopecia, nausea, and vomiting. Treatment is supportive.

Drug Interactions:

Substrate of CYP2A6 (minor), 2B6 (major), 2C8/9 (minor), 2C19 (minor), 3A4 (major); Inhibits CYP3A4 (weak); Induces CYP2B6 (weak), 2C8/9 (weak)

Allopurinol may cause increase in bone marrow depression and may result in significant elevations of cyclophosphamide cytotoxic metabolites.

Anesthetic agents: Cyclophosphamide reduces serum pseudocholinesterase concentrations and may prolong the neuromuscular blocking activity of succinylcholine; use with caution with halothane, nitrous oxide, and succinylcholine.

Chloramphenicol results in prolonged cyclophosphamide half-life to increase toxicity.

CYP2B6 inducers: May increase the levels/effects of acrolein (the active metabolite of cyclophosphamide). Example inducers include carbamazepine, nevirapine, phenobarbital, phenytoin, and rifampin.

CYP2B6 inhibitors: May decrease the levels/effects of acrolein (the active metabolite of cyclophosphamide). Example inhibitors include desipramine, paroxetine, and sertraline.

CYP3A4 inducers: CYP3A4 inducers may increase the levels/effects of acrolein (the active metabolite of cyclophosphamide). Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

CYP3A4 inhibitors: May decrease the levels/effects of acrolein (the active metabolite of cyclophosphamide). Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil.

Digoxin: Cyclophosphamide may decrease digoxin serum levels.

Doxorubicin: Cyclophosphamide may enhance cardiac toxicity of anthracyclines.

Tetrahydrocannabinol results in enhanced immunosuppression in animal studies.

Thiazide diuretics: Leukopenia may be prolonged.

Ethanol/Nutrition/Herb Interactions:

Herb/Nutraceutical: Avoid black cohosh, dong quai in estrogen-dependent tumors.

Stability:

Store intact vials of powder at room temperature of 15°C to 30°C (59°F to 86°F). Reconstitute vials with sterile water, normal saline, or 5% dextrose to a concentration of 20 mg/mL. Reconstituted solutions are stable for 24 hours at room temperature and 6 days under refrigeration at 2°C to 8°C (36°F to 46°F). Further dilutions in D5W or NS are stable for 24 hours at room temperature and 6 days at refrigeration.

Compatibility:

Stable in D5LR, D5NS, D5W, LR, ¹/2NS, NS

Y-site administration: Compatible: Allopurinol, amifostine, amikacin, ampicillin, azlocillin, aztreonam, bleomycin, cefamandole, cefazolin, cefepime, cefoperazone, cefotaxime, cefoxitin, cefuroxime, chloramphenicol, chlorpromazine, cimetidine, cisplatin, cladribine, clindamycin, co-trimoxazole, dexamethasone sodium phosphate, diphenhydramine, doxorubicin, doxorubicin liposome, doxycycline, droperidol, erythromycin lactobionate, etoposide phosphate, famotidine, filgrastim, fludarabine, fluorouracil, furosemide, ganciclovir, gatifloxacin, gemcitabine, gentamicin, granisetron, heparin, hydromorphone, idarubicin, kanamycin, leucovorin, linezolid, lorazepam, melphalan, methotrexate, methylprednisolone sodium succinate, metoclopramide, metronidazole, minocycline, mitomycin, morphine, nafcillin, ondansetron, oxacillin, paclitaxel, penicillin G potassium, piperacillin, piperacillin/tazobactam, prochlorperazine edisylate, promethazine, propofol, ranitidine, sargramostim, sodium bicarbonate, teniposide, thiotepa, ticarcillin, ticarcillin/clavulanate, tobramycin, topotecan, vancomycin, vinblastine, vincristine, vinorelbine. Incompatible: Amphotericin B cholesteryl sulfate complex

Compatibility in syringe: Compatible: Bleomycin, cisplatin, doxapram, doxorubicin, droperidol, fluorouracil, furosemide, heparin, leucovorin, methotrexate, metoclopramide, mitomycin, vinblastine, vincristine

Compatibility when admixed: Compatible: Cisplatin with etoposide, dacarbazine, fluorouracil, hydroxyzine, mesna, methotrexate, methotrexate with fluorouracil, mitoxantrone, ondansetron

Mechanism of Action:

Cyclophosphamide is an alkylating agent that prevents cell division by cross-linking DNA strands and decreasing DNA synthesis. It is a cell cycle phase nonspecific agent. Cyclophosphamide also possesses potent immunosuppressive activity. Cyclophosphamide is a prodrug that must be metabolized to active metabolites in the liver.

Pharmacodynamics/Kinetics:

Absorption: Oral: Well absorbed

Distribution: Vd: 0.48-0.71 L/kg; crosses placenta; crosses into CSF (not in high enough concentrations to treat meningeal leukemia)

Protein binding: 10% to 56%

Metabolism: Hepatic to active metabolites acrolein, 4-aldophosphamide, 4-hydroperoxycyclophosphamide, and nor-nitrogen mustard

Bioavailability: >75%

Half-life elimination: 4-8 hours

Time to peak, serum: Oral: ~1 hour

Excretion: Urine (<30% as unchanged drug, 85% to 90% as metabolites)

Dosage:

Refer to individual protocols

Patients who are heavily pretreated with cytotoxic radiation or chemotherapy, or who have compromised bone marrow function may require a 33% to 50% reduction in initial dose.

Children:

SLE: I.V.: 500-750 mg/m² every month; maximum dose: 1 g/m²

JRA/vasculitis: I.V.: 10 mg/kg every 2 weeks

Children and Adults:

Oral: 50-100 mg/m²/day as continuous therapy or 400-1000 mg/m² in divided doses over 4-5 days as intermittent therapy

I.V.:

Single doses: 400-1800 mg/m² (30-50 mg/kg) per treatment course (1-5 days) which can be repeated at 2-4 week intervals

Continuous daily doses: 60-120 mg/m² (1-2.5 mg/kg) per day

Autologous BMT: IVPB: 50 mg/kg/dose x 4 days or 60 mg/kg/dose for 2 days; total dose is usually divided over 2-4 days

Nephrotic syndrome: Oral: 2-3 mg/kg/day every day for up to 12 weeks when corticosteroids are unsuccessful

Dosing adjustment in renal impairment: A large fraction of cyclophosphamide is eliminated by hepatic metabolism

Some authors recommend no dose adjustment unless severe renal insufficiency (Clcr<20 mL/minute)

Clcr >10 mL/minute: Administer 100% of normal dose

Clcr<10 mL/minute: Administer 75% of normal dose

Hemodialysis: Moderately dialyzable (20% to 50%); administer dose posthemodialysis

CAPD effects: Unknown

CAVH effects: Unknown

Dosing adjustment in hepatic impairment: The pharmacokinetics of cyclophosphamide are not significantly altered in the presence of hepatic insufficiency. No dosage adjustments are recommended.

Administration:

May be administered I.P., intrapleurally, IVPB, or continuous I.V. infusion; may also be administered slow IVP in doses 1 g.

I.V. infusions may be administered over 1-24 hours

Doses >500 mg to approximately 2 g may be administered over 20-30 minutes

To minimize bladder toxicity, increase normal fluid intake during and for 1-2 days after cyclophosphamide dose. Most adult patients will require a fluid intake of at least 2 L/day. High-dose regimens should be accompanied by vigorous hydration with or without mesna therapy.

Tablets are not scored and should not be cut or crushed; should be administered during or after meals.

Monitoring Parameters:

CBC with differential and platelet count, BUN, UA, serum electrolytes, serum creatinine

Dietary Considerations:

Tablets should be administered during or after meals.

Patient Education:

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Take exactly as directed, during or after meals; do not take at night. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake and void frequently to reduce incidence of bladder irritation. You will be more susceptible to infection (avoid crowds and exposure to infection and do not have any vaccinations without consulting prescriber). May cause loss of hair (reversible, although regrowth hair may be different color or texture); fertility or amenorrhea; nausea or vomiting (small, frequent meals, good mouth care, chewing gum, or sucking lozenges may help - if persistent consult prescriber for antiemetic); headache (consult prescriber for analgesic); nasal congestion or cold symptoms (consult prescriber for decongestant); or mouth sores (use soft toothbrush or cotton swab for oral care). Report any difficulty or pain with urination; chest pain, rapid heartbeat, or palpitations; easy bruising or bleeding; unusual rash; persistent nausea or vomiting; menstrual irregularities; swelling of extremities; respiratory difficulty; or unusual fatigue. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Do not get pregnant during therapy. Consult prescriber for instruction on appropriate contraceptive measures. This drug may cause severe fetal defects. Do not breast-feed.

Nursing Implications:

Encourage adequate hydration and frequent voiding to help prevent hemorrhagic cystitis

Additional Information:

May be used in combination with mesna to prevent hemorrhagic cystitis. Rarely required for doses <1.5-2 g/m².

Cardiovascular Considerations:

Rare but potentially life-threatening cardiovascular side effects may occur at higher doses (>200 mg/m²) including heart failure, cardiac necrosis, myocarditis, arrhythmias, tamponade, and pulmonary fibrosis. The dose should be based on indications, concomitant diseases (ie, renal dysfunction), and potential drug interactions.

Dental Health: Effects on Dental Treatment:

Key adverse event(s) related to dental treatment: Mucositis and stomatitis.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

No information available to require special precautions

Mental Health: Effects on Mental Status:

May cause dizziness

Mental Health: Effects on Psychiatric Treatment:

May cause myelosuppression; use caution with clozapine and carbamazepine

Oncology: Emetic Potential:

Very high (>90%): >1500 mg/m²

High (60% to 90%): >750 mg/m², 1500 mg/m²

Moderate (30% to 60%): 750 mg/m²

Oral: Moderate (30% to 60%)

Oncology: Vesicant:

Oncology: Bone Marrow Comments:

Approaches to reduction of hemorrhagic cystitis include infusion of 0.9% NaCl 3 L/m²/24 hours, infusion of 0.9% NaCl 3 L/m²/24 hours with continuous 0.9% NaCl bladder irrigation 300-1000 mL/hour, and infusion of 0.9% NaCl 1.5-3 L/m²/24 hours with intravenous mesna. Hydration should begin at least 4 hours before cyclophosphamide and continue at least 24 hours after completion of cyclophosphamide. The dose of daily mesna used should equal the daily dose of cyclophosphamide. Mesna can be administered as a continuous 24-hour intravenous infusion or be given in divided doses every 4 hours. Mesna should begin at the start of treatment, and continue at least 24 hours following the last dose of cyclophosphamide.

Enhanced bioactivation of cyclophosphamide may increase the risk of cardiotoxicity. A 30-minute infusion of thiotepa administered 1 hour before a 60-minute infusion of cyclophosphamide reduced bioactivation of cyclophosphamide to 4-hydroxycyclophosphamide in 20 patients. This effect did not occur with administration of thiotepa 1 hour following infusion of cyclophosphamide. Intravascular red blood cell hemolysis requiring transfusion support occurred during continuous flow plasmapheresis performed 12 hours following infusion of cyclophosphamide 60 mg/kg.

Oncology: Bone Marrow - High Dose:

I.V.:

60 mg/kg/day for 2 days (total dose: 120 mg/kg)

50 mg/kg/day for 4 days (total dose: 200 mg/kg)

1.8 g/m²/day for 4 days (total dose: 7.2 g/m²)

1875 mg/m²/24 hours for 72 hours (total dose: 5625 mg/m²)

Continuous I.V.: 1.5 g/m²/24 hours for 96 hours (total dose: 6 g/m²)

Duration of infusion is 1-24 hours; generally combined with other high-dose chemotherapeutic drugs, lymphocyte immune globulin, or total body irradiation (TBI).

Oncology: Bone Marrow - Unique Toxicity:

Cardiovascular: Heart failure, cardiac necrosis, pericardial tamponade, heart block

Endocrine & metabolic: Hyponatremia, acquired pseudocholinesterase deficiency, transient diabetes insipidus

Hematologic: Methemoglobinemia

Neuromuscular & skeletal: Rhabdomyolysis

Respiratory: Pleural effusion, interstitial pneumonitis

Dosage Forms:

Injection, powder for reconstitution:

Cytoxan®: 500 mg, 1 g, 2 g [contains mannitol 75 mg per cyclophosphamide 100 mg]

Tablet (Cytoxan®): 25 mg, 50 mg

Extemporaneously Prepared:

A 2 mg/mL oral elixir was stable for 14 days when refrigerated when made as follows: Reconstitute a 200 mg vial with aromatic elixir, withdraw the solution, and add sufficient aromatic elixir to make a final volume of 100 mL (store in amber glass container).

Brook D, Davis RE, and Bequette RJ, "Chemical Stability of Cyclophosphamide in Aromatic Elixir U.S.P.,"Am J Health Syst Pharm, 1973, 30:618-20.

International Brand Names:

Alkyloxan® (SG, TR); Carloxan® (DK); Ciclofosfamida® (CL, CO); Ciclofosfamida Dosa® (AR); Ciclofosfamida Filaxis® (AR); Ciclofosfamida L.CH.® (CL); Ciclofosfamid® (RO); Cycloblastin® (AU, NZ); Cycloblastine® (BE, LU); CycloGal® (YU); Cyclophosphamid A-Pharma® (DK); Cyclophosphamid-biosyn® (DE); Cyclophosphamide® (CZ, GB, RO); Cyclophosphan® (RO, RU); Cyclostin® (DE); Cycloxan® (IN); Cytophosphan® (IL); Cytoxan® (BG, CA, CZ, HU, ID, IL, NZ, YU); Endoxana® (GB); Endoxan-Asta® (AR, AT, AU, BD, CY, EG, IN, JO, KW, LB, PL, RO, SG, SY); Endoxan-Asta Lyophilisate® (ID); Endoxan® (AT, BE, CH, CL, CZ, DE, FR, HK, HR, HU, IL, LU, NL, PT, RO, RU, SI, TH, TR, ZA); Endoxan-Baxter® (IT); Genoxal® (ES, MX); Genuxal® (BR); Ledoxina® (MX, RO, RU); Neosar® (ID); Procytox® (CA); Sendoxan® (DK, FI, NO, SE); Sinfosfamida® (RO); Syklofosfamid® (FI); Syklofosfamid® [inj.] (TR)

References

Ahmed AR and Hombal SM, "Cyclophosphamide (Cytoxan®). A Review on Relevant Pharmacology and Clinical Uses,"J Am Acad Dermatol, 1984, 11(6):1115-26.

Brade W, Seeber S, and Herdrich K, "Comparative Activity of Ifosfamide and Cyclophosphamide,"Cancer Chemother Pharmacol, 1986, 18(Suppl 2):1-9.

Eder JP, Elias A, Shea TC, et al, "A Phase I-II Study of Cyclophosphamide, Thiotepa, and Carboplatin With Autologous Bone Marrow Transplantation in Solid Tumor Patients,"J Clin Oncol, 1990, 8(7):1239-45.

Fraiser LH, Kanekal S, and Kehrer JP, "Cyclophosphamide Toxicity. Characterizing and Avoiding the Problem,"Drugs, 1991, 42(5):781-95.

Giralt SA, LeMaistre CF, Vriesendorp HM, et al, "Etoposide, Cyclophosphamide, Total-Body Irradiation and Allogeneic Bone Marrow Transplantation for Hematologic Malignancies,"J Clin Oncol, 1994, 12(9):1923-30.

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