Cyclophosphamide

Class: Antineoplastic Agents
VA Class: AN100
CAS Number: 6055-19-2
Brands: Cytoxan

Introduction

Antineoplastic agent and immunosuppressant; nitrogen mustard-derivative alkylating agent.^a

Uses for Cyclophosphamide

Cyclophosphamide may be used alone in susceptible malignancies, but more often is used in combination or sequentially with other antineoplastic agents.¹⁶⁴

Hodgkin’s Disease

Treatment of Hodgkin’s disease as part of a combination regimen.^{153 164 171}

Non-Hodgkin’s Lymphoma

Treatment of various types of non-Hodgkin’s lymphoma, including high-grade (e.g., Burkitt’s, lymphoblastic) lymphomas and intermediate- or low-grade lymphomas, as part of a combination regimen.^{153 164}

Treatment of low-grade non-Hodgkin’s lymphomas as a single agent.¹⁵³

Multiple Myeloma

Treatment of multiple myeloma, with prednisone or as part of a combination regimen.^{153 164}

As effective as melphalan; combination of either agent with prednisone is considered treatment of choice.¹⁵³

Leukemias

Treatment of chronic lymphocytic (lymphoblastic) leukemia; considered a drug of choice.^{153 164}

Used with busulfan as a conditioning regimen prior to allogeneic hematopoietic progenitor (e.g., stem) cell transplantation in patients with chronic myelogenous leukemia.¹⁶⁶

Treatment of acute lymphoblastic leukemia, especially in children.^{153 164}

Treatment of acute myeloid (myelogenous, nonlymphocytic) leukemia (AML, ANLL) and as an additional drug for induction or post-induction therapy.^{153 164}

In meningeal leukemia, concentrations of cyclophosphamide and metabolites in brain and CSF probably are insufficient for adequate treatment.^a

Cutaneous T-cell Lymphoma

Treatment of advanced mycosis fungoides, a form of cutaneous T-cell lymphoma, alone or in combination regimens.^{a 164}

Neuroblastoma

Treatment of disseminated neuroblastoma; a treatment of choice when included in combination chemotherapy.¹⁵³

Ovarian Cancer

Treatment of ovarian germ cell tumors† as part of an alternative combination regimen (vincristine, dactinomycin, and cyclophosphamide [VAC]) .^{153 164}

Also has been used with a platinum-containing agent to treat advanced (stage III or IV) epithelial ovarian cancer,^{169 170} but randomized studies^{167 168} indicate that paclitaxel combined with a platinum-containing agent produces higher response rates and more prolonged overall survival and therefore is preferred.^{153 162 167 168}

Retinoblastoma

Treatment of retinoblastoma as part of a combination regimen.^{153 164}

Breast Cancer

Treatment of breast cancer as part of a combination regimen; some experts suggest that such regimens are the treatment of choice.^a

Adjunct to surgery in combination regimens; such regimens increase disease-free (i.e., decreased recurrence) and overall survival in premenopausal and postmenopausal women with node-negative or -positive early (TNM stage I or II) breast cancer.^{137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 156 158} Cyclophosphamide–methotrexate–fluorouracil regimen has been used extensively and is considered a regimen of choice.^{137 138 139 140 141 142 143 144 145 149 150 153 156 157 158}

Treatment of stage III (locally advanced) breast cancer (with or without hormonal therapy); drugs in combination regimens are administered sequentially following surgery and radiation therapy (for operable disease) or following biopsy and radiation therapy (for inoperable disease).¹³⁷ Commonly used effective combination regimens include cyclophosphamide, methotrexate, and fluorouracil; cyclophosphamide, doxorubicin, and fluorouracil; and cyclophosphamide, methotrexate, fluorouracil, and prednisone.¹³⁷

Regimens for stage III disease (and other regimens) also have been used to treat more advanced (stage IV) and recurrent breast cancer.¹³⁷

Small Cell Lung Cancer

Treatment of extensive-stage small cell lung cancer†; used in combination regimens (e.g., cyclophosphamide, doxorubicin, and vincristine [CAV]; cyclophosphamide, doxorubicin, and etoposide [CAE]).^{153 163}

Sarcomas

Treatment of rhabdomyosarcoma†; used in combination regimens (e.g., with dactinomycin and vincristine) and as an adjunct to surgery and radiation therapy.^{153 a}

Used in combination regimens for Ewing’s sarcoma† as an adjunct to surgery and radiation therapy; considered a treatment of choice.^{153 a}

Nephrotic Syndrome

Treatment of selected cases of biopsy-proven minimal change nephrotic syndrome in children.^a

Not for initial therapy; has induced remission in patients unresponsive to appropriate corticosteroid therapy or in whom intolerable adverse effects (e.g., growth failure) occur.^a

Renal, Hepatic, Cardiac, and Bone Marrow Transplantation

Used as an immunosuppressant to control rejection following renal, hepatic, cardiac, or bone marrow transplantation†.^a Considered by some experts to be as effective as azathioprine for maintenance of renal allografts and more effective than azathioprine for maintenance of hepatic allografts.^a

Because of the potential for serious adverse effects, some experts recommend reserving immunosuppressive use of cyclophosphamide for patients who become refractory to corticosteroids or other less toxic agents, or limiting such use to short-term treatment when feasible.^a

Cyclophosphamide Dosage and Administration

General

• 
  

  Consult specialized references for procedures for proper handling and disposal of antineoplastics.

  
  

Administration

Administer orally or by IV injection or infusion.¹⁶⁴

Has been administered IM and by intracavitary (e.g., intrapleural, intraperitoneal) injection and direct perfusion, but some experts believe the drug should not be administered via routes that bypass activation in the liver.^a

Oral Administration

May prepare extemporaneous oral liquid preparations of the drug by dissolving powder for injection in aromatic elixir.¹⁶⁴ (See Stability.)

IV Administration

Reconstitution

To reconstitute for direct IV injection, use 0.9% sodium chloride injection.¹⁶⁴ For IV infusion, reconstitute with sterile water for injection.¹⁶⁴

Powder for Injection Vial	Diluent Volume (to provide 20 mg/mL)
500 mg	25 mL
1 g	50 mL
2 g	100 mL

Shake vial after adding diluent; allow vial to stand a few minutes if powder fails to dissolve immediately and completely.¹⁶⁴

May directly inject solution constituted with 0.9% sodium chloride injection.¹⁶⁴

Solution constituted with sterile water for injection is hypotonic; do not inject directly.¹⁶⁴ Dilute with a compatible IV solution prior to IV infusion.¹⁶⁴ (See Solution Compatibility under Stability.)

Dosage

Dosage of cyclophosphamide expressed in terms of the anhydrous drug.¹⁶⁴

Use caution with high dosages; risk of toxicity (e.g., cardiotoxicity) and overdosage.^{159 160 161}

At higher than usual dosages (e.g., those used under protocol conditions), use particular care to verify dosage, administration schedule, and use of appropriate monitoring.^{159 160 161}

When used in combination with other cytotoxic agents, may need to reduce dosage of cyclophosphamide and other agents.¹⁶⁴

Consult published protocols for dosage, method of administration, and administration sequence of drugs in combination regimens.^a

Pediatric Patients

Cancer (General)

Oral

Usual induction or maintenance dosage is 1–5 mg/kg daily.^{164 c} Various other regimens have been reported.¹⁶⁴

Adjust dosage according to tumor response and/or leukopenia; use total leukocyte count to guide adjustment.¹⁶⁴

Transient decreases in total leukocyte count to 2000/mm³ (following short courses of therapy) or more persistent reduction to 3000/mm³ (with continuing therapy) may be tolerated without serious risk of infection if there is no marked granulocytopenia.¹⁶⁴

IV

As a single oncolytic agent in patients with no hematologic deficiencies: manufacturer states that usual initial dosage for induction therapy is 40–50 mg/kg given in divided doses over a period of 2–5 days.^{164 c}

Other IV regimens include 10–15 mg/kg every 7–10 days or 3–5 mg/kg twice weekly.¹⁶⁴ Various other regiments have been reported.¹⁶⁴

Adjust dosage according to tumor response and/or leukopenia; use total leukocyte count to guide adjustment.¹⁶⁴

Transient decreases in total leukocyte count to 2000/mm³ (following short courses of therapy) or more persistent reduction to 3000/mm³ (with continuing therapy) may be tolerated without serious risk of infection if there is no marked granulocytopenia.¹⁶⁴

Minimal Change Nephrotic Syndrome

Oral

2.5–3 mg/kg daily for 60–90 days has been recommended.¹⁶⁴

In males, >60 days of treatment increases oligospermia and azoospermia incidence; >90 days of treatment increases sterility risk.¹⁶⁴

May taper and discontinue corticosteroid therapy during the course of cyclophosphamide.¹⁶⁴

Adults

Cancer (General)

Oral

Usual induction or maintenance dosage is 1–5 mg/kg daily.^{164 c} Various other regimens have been reported.¹⁶⁴

Adjust dosage according to tumor response and/or leukopenia; use total leukocyte count to guide adjustment.¹⁶⁴

Transient decreases in total leukocyte count to 2000/mm³ (following short courses of therapy) or more persistent reduction to 3000/mm³ (with continuing therapy) may be tolerated without serious risk of infection if there is no marked granulocytopenia.¹⁶⁴

IV

As a single oncolytic agent in patients with no hematologic deficiencies: manufacturer states that usual initial dosage for induction therapy is 40–50 mg/kg given in divided doses over a period of 2–5 days.¹⁶⁴

Other IV regimens include 10–15 mg/kg every 7–10 days or 3–5 mg/kg twice weekly.¹⁶⁴ Various other regimens have been reported.¹⁶⁴

Adjust dosage according to tumor response and/or leukopenia, use total leukocyte count to guide adjustment.¹⁶⁴

Transient decreases in total leukocyte count to 2000/mm³ (following short courses of therapy) or more persistent reduction to 3000/mm³ (with continuing therapy) may be tolerated without serious risk of infection if there is no marked granulocytopenia.¹⁶⁴

Breast Cancer

Various cyclophosphamide-containing combination regimens have been used; consult published protocols.^{139 140 141 142 143 144 145 147 151 152 154 156 158}

Avoid arbitrary reductions in dosage of adjuvant combination chemotherapy; dose intensity appears to be an important factor influencing clinical outcome in early node-positive breast cancer (increasing response with increasing intensity).^{137 141 158}

Combination Regimen: Cyclophosphamide, Methotrexate, and Fluorouracil

Oral

Regimen containing oral cyclophosphamide in combination with IV fluorouracil and IV methotrexate is described in the table.^{139 140 158}

Drug	Dose	Administration Days per Cycle
Cyclophosphamide	100 mg/m2 orally 139 140 158	Days 1 through 14 139 140 158
Methotrexate	40 mg/m2 IV (≤60 yrs of age)139 140 158	Days 1 and 8 139 140 158
Fluorouracil	600 mg/m2 IV (≤60 yrs of age)139 140 158	Days 1 and 8139 140 158

Repeat monthly (i.e., allow a 2-week rest period between cycles).^{139 140 158}

Total of 6–12 cycles (i.e., 6–12 months of therapy); clinical superiority between 6- versus 12-month regimens not demonstrated.^{137 138 139 140 158}

Initial fluorouracil and methotrexate dosages have been reduced in patients >60 years of age.¹⁴⁰ (See Geriatric Patients under Dosage and Administration.)

Dosage also reduced if myelosuppression develops.^{139 140}

Sequential Regimen: Cyclophosphamide, Methotrexate, and Fluorouracil Plus Doxorubicin

In patients with early breast cancer and >3 positive axillary lymph nodes, addition of doxorubicin may improve outcome, and sequential regimens (i.e., administering several courses of doxorubicin first) may be more effective than alternating regimens; no additional benefit when <3 positive nodes are present.^{142 145}

IV

Initially, doxorubicin hydrochloride 75 mg/m² IV at 3-week intervals for 4 doses.^{142 156}

Subsequently, cyclophosphamide 600 mg/m² IV, methotrexate 40 mg/m² IV, and fluorouracil 600 mg/m² IV at 3-week intervals for 8 cycles.^{142 156}

Total of about 9 months of therapy.^{142 156}

Generally, patients with myelosuppression had next cycle delayed rather than reduction in dosage.^{142 156}

Prescribing Limits

Pediatric Patients

Minimal Change Nephrotic Syndrome

Oral

In males, treatment for >60 or >90 days increases incidence of oligospermia and azoospermia or risk of sterility, respectively. (See Minimal Change Nephrotic Syndrome under Dosage and Administration.)¹⁶⁴

Special Populations

Geriatric Patients

Breast Cancer

In patients >60 years of age receiving oral cyclophosphamide, IV methotrexate, and IV fluorouracil combination therapy, reduce initial methotrexate dosage to 30 mg/m² and fluorouracil dosage to 400 mg/m².¹⁴⁰

Cautions for Cyclophosphamide

Contraindications

• 
  

  Severely depressed bone marrow function.¹⁶⁴

  
  


• 
  

  Known hypersensitivity to cyclophosphamide or any ingredient in the formulation.¹⁶⁴

  
  

Warnings/Precautions

Warnings

Highly toxic, low therapeutic index; therapeutic response unlikely without some evidence of toxicity.^a

Use only under constant supervision by clinicians experienced in cytotoxic agent therapy.^a

Carcinogenesis

Secondary malignancies, most frequently urinary bladder, myeloproliferative, and lymphoproliferative, have occurred with monotherapy, combination therapy, or adjunctive therapy; may not be detected until several years after discontinuance.^a

Consider possibility of secondary malignancy when weighing possible benefits versus potential risks.^a

Fetal/Neonatal Morbidity and Mortality

May cause fetal toxicity when administered to pregnant women.^a

Inform pregnant women of the potential hazard to the fetus; advise women of childbearing potential to avoid becoming pregnant.^a (See Pregnancy under Cautions.)

Fertility

Dose- and duration-related gonadal suppression may occur;¹⁶⁴ large doses cause gonadal toxicity.^a

Interferes with oogenesis and spermatogenesis; amenorrhea, azoospermia, oligospermia, and ovarian fibrosis have been reported, and sterility may be irreversible in some men and women.¹⁶⁴

Full effect on prepubertal gonads not established, but ovarian failure and testicular atrophy have occurred.^a Male children, including prepubertal males receiving high-dose cyclophosphamide therapy, are at high risk for long-term, irreversible gonadal damage (e.g., infertility, subclinical Leydig cell insufficiency).¹⁷³

Inform patients of possible fertility impairment and counsel on fertility options prior to therapy whenever possible.¹⁷³

Long-term follow-up for evaluation of gonadal function advised.¹⁷³

Hemorrhagic Cystitis

Sterile hemorrhagic cystitis has been reported (especially in children) with long-term therapy; rarely can be severe or fatal.^a

Attributed to chemical irritation by accumulation of cyclophosphamide active metabolites in concentrated urine.^a

For prevention, instruct patients to increase fluid intake for 24 hours before, during, and for at least 24 hours following cyclophosphamide administration, and to void frequently for 24 hours after receiving the drug.^a

May use mesna (sodium 2-mercaptoethanesulphonate) to prevent or substantially decrease severity of urothelial toxicity (e.g., hemorrhagic cystitis).^{106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 130 131 132} Mesna is at least as effective as, and generally more effective than, hydration and forced diuresis, but not effective in all patients.^{105 120 121 122 124 127} Mesna also is uroprotective in patients with a history of bladder toxicity with cyclophosphamide or ifosfamide use.^{105 106}

Examine urine regularly for presence of red cells, which may precede hemorrhagic cystitis.^a

If hemorrhagic cystitis occurs, discontinue cyclophosphamide and, if possible, do not resume.^a

Hematuria usually resolves spontaneously within a few days after drug discontinuance, but may persist for several months.^a

May need blood transfusions in severe cases.^a

Protracted cases have been treated with 1–10% formaldehyde irrigations, electrocautery to the telangiectatic areas of the bladder, diversion of urine flow, and cryosurgery.^a

Other Genitourinary Effects

Bladder fibrosis (sometimes extensive), with or without cystitis.^a

Atypical epithelial cells in urine.^a

Cardiac Toxicity

Uncommon at usual dosages.^a Generally reported with high dosages (120–270 mg/kg over a few days or 60 mg/kg daily) in an intensive, multiple-drug antineoplastic regimen or in conjunction with transplantation procedures.^a

High-dose monotherapy or combination regimens have resulted in deaths from diffuse hemorrhagic myocardial necrosis and a syndrome of acute myopericarditis; rarely, severe (sometimes fatal) CHF has occurred within a few days after the first cyclophosphamide dose.^a

Potentially fatal cardiotoxicity has occurred with overdose (i.e., 4 g/m² daily for 4 doses rather than the intended total dosage of 4 g/m² [1 g/m² daily for 4 days]).^{159 160}

Hemopericardium secondary to hemorrhagic myocarditis and myocardial necrosis, and pericarditis without evidence of hemopericardium reported.^a

AMI has occurred with conventional doses of cyclophosphamide in conjunction with vincristine when there was no known history of cardiac disease.¹⁷²

Possible consequences of cardiotoxicity include debilitating heart failure, arrhythmias, potentially irreversible cardiomyopathy and/or pericarditis, and death.^{159 160 161}

Precise mechanism of cardiotoxicity not known; drug and/or metabolites may affect the endothelium directly (secondary extravasation of blood with high cyclophosphamide concentrations) or (with high doses) the antidiuretic effect may contribute.¹⁶¹

Clear risk factors not established; concomitant radiation therapy and/or other potentially cardiotoxic drugs (e.g., anthracyclines) appear to increase risk.¹⁶¹

Monitor for indicators of cardiotoxicity (e.g., sudden weight gain, ECG abnormalities, dyspnea, and/or other CHF signs)^{159 160 161} when higher than usual dosages are used.¹⁶¹

Immunosuppression

Increased infections (potentially fatal), possible hemorrhagic complications may occur because of immunosuppression; varicella-zoster infections appear to be particularly dangerous.^a

Instruct patients to notify clinician if fever, sore throat, or unusual bleeding or bruising occurs.^a

Carefully monitor hematologic status at least weekly for first few months of therapy or until maintenance dosage is determined, then every 2–3 weeks.^a

Use dose-related leukopenia as a guide to adjusting dosage; leukocyte count reduction to <2000/mm³ is common with initial loading dose, less frequent with smaller maintenance doses.^a

Transient reductions in leukocyte count to 2000/mm³ (during short courses of treatment) or more persistent reductions to 3000/mm³ (with continuing therapy) may be tolerated without serious risk of infection if marked granulocytopenia is not present.^a

Consider interruption or dosage reduction when bacterial, fungal, protozoan, helminthic, or viral infections occur, especially during or following recent corticosteroid therapy.^a

Sensitivity Reactions

Anaphylaxis

Anaphylactic reaction, including fatality, reported.¹⁶⁴

Possible cross-sensitivity with other alkylating agents.¹⁶⁴

Major Toxicities

Hematologic Effects

Dose-limiting, usually reversible after discontinuance.^a

Leukopenia is expected, may be severe; nadirs generally occur 8–15 days after a single dose of cyclophosphamide and recovery usually occurs within 17–28 days.^a

Thrombocytopenia is less common; nadir occurs 10–15 days after administration.^a

Anemia, particularly after large doses or prolonged therapy, has been reported; hemolytic anemia reported rarely.^a

Hypoprothrombinemia reported rarely.^a

Monitor hematologic profile (especially neutrophil and platelet counts) to determine degree of hematopoietic suppression.¹⁶⁴

Respiratory Effects

High dosages over prolonged periods may cause potentially fatal interstitial pulmonary fibrosis; cyclophosphamide discontinuance and administration of corticosteroids occasionally has failed to reverse the syndrome.^a

Interstitial pneumonitis also has been reported.¹⁶⁴

General Precautions

Monitor closely for possible toxicity and administer cautiously in presence of severe leukopenia, thrombocytopenia, tumor cell infiltration of bone marrow, impaired hepatic or renal function, or with history of previous radiation or other cytotoxic agent therapy.^a

Adrenalectomy

In adrenalectomized patients, adjustment of both replacement corticosteroid and cyclophosphamide dosages may be necessary.^{164 a}

Wound Healing

May interfere with normal wound healing.¹⁶⁴

Specific Populations

Pregnancy

Category D.¹⁶⁴ (See Fetal/Neonatal Morbidity and Mortality and see Fertility under Warnings.)

Lactation

Distributed into milk; discontinue nursing or the drug.^{164 a}

Pediatric Use

Manufacturers states that the safety profile in children is similar to that observed in adults.¹⁶⁴ Children receiving large doses of cyclophosphamide are at high risk for long-term gonadal damage and infertility.¹⁷³ (See Fertility under Warnings.)

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults, but some data suggest increased risk of cyclophosphamide toxicity in geriatric patients.¹⁶⁴

Titrate dosage with caution; initiate therapy at low end of dosage range.¹⁶⁴

Hepatic Impairment

Use with caution.^a Monitor closely for possible toxicity.¹⁶⁴

Renal Impairment

Use with caution.^a Monitor closely for possible toxicity.¹⁶⁴

Common Adverse Effects

Leukopenia, anorexia, nausea, vomiting, sterile hemorrhagic cystitis, alopecia.^a

Interactions for Cyclophosphamide

Converted to active metabolites in the liver by a mixed-function microsomal oxidase system; microsomal enzyme inducers (e.g., barbiturates) may result in increased conversion of cyclophosphamide to active metabolites and increased toxicity.^a

Clinical importance not assessed; monitor closely for toxicity.^a

Other drugs may inhibit microsomal enzyme activity and metabolism of cyclophosphamide.^a

Specific Drugs and Laboratory Tests

Drug or Test	Interaction	Comments
Allopurinol	Concomitant administration may increase the incidence of bone marrow depressiona	Mechanism and clinical importance not establisheda
Cardiotoxic drugs (e.g., doxorubicin)	Possible potentiation of cardiotoxic effectsa	Use caution with concomitant usea
Chloramphenicol	May inhibit microsomal enzyme activity and decrease cyclophosphamide metabolisma
Chloroquine	May inhibit microsomal enzyme activity and decrease cyclophosphamide metabolisma
Corticosteroids and sex hormones	May inhibit liver microsomal enzymes; discontinuance or reduction in steroid dosage may increase cyclophosphamide toxicitya	Clinical importance not establisheda
Imipramine	May inhibit microsomal enzyme activity and decrease cyclophosphamide metabolisma
Mesna	Interacts chemically with urotoxic cyclophosphamide metabolites (and/or their precursors) to prevent or decrease incidence and severity of bladder toxicity (e.g., hemorrhagic cystitis)106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 130 131 132 133 134 135 136	Used for uroprotection106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 130 131 132
Phenothiazines	May inhibit microsomal enzyme activity and decrease cyclophosphamide metabolisma
Potassium iodide	May inhibit microsomal enzyme activity and decrease cyclophosphamide metabolisma
Skin test antigens (e.g., tuberculin purified protein derivative, mumps, trichophyton, candida)	Frequent suppression of reactionsa
Succinylcholine	Cyclophosphamide may reduce serum pseudocholinesterase concentrations and prolong neuromuscular blocking activity of succinylcholine (especially in very ill patients receiving large IV cyclophosphamide doses)a	Clinical importance not established; use concomitantly with caution and avoid cyclophosphamide use with substantially depressed pseudocholinesterase concentrations. Inform anesthesiologist if cyclophosphamide has been used within 10 days before general anesthesiaa
Vitamin A	May inhibit microsomal enzyme activity and decrease cyclophosphamide metabolisma

Cyclophosphamide Pharmacokinetics

Absorption

Bioavailability

Oral: >75%.

Distribution

Extent

Distributed throughout the body.^a

Distributed into brain and CSF, but concentrations probably not sufficient to treat meningeal leukemia.^a

Assumed to cross the placenta; distributed into milk.^a

Plasma Protein Binding

Low (0–10%), but >60% for some alkylating metabolites.^a

Elimination

Metabolism

Metabolized to 4-hydroxycyclophosphamide (in equilibrium with acyclic tautomer aldophosphamide), then to 4-ketocyclophosphamide (may be inactive, toxicity controversial).^a

Aldophosphamide may be metabolized to carboxyphosphamide (inactive); also to phosphoramide mustard and acrolein (may account for cytotoxic effects).^a

Elimination Route

Excreted principally (36–99%) in urine within 48 hours, 5–30% as unchanged drug.^a

Half-life

3–12 hours (after IV administration).^a

Special Populations

In patients with renal impairment, metabolite levels are increased; no associated increased toxicity.¹⁶⁴

Stability

Storage

Oral

Tablets

Tight containers at 25°C (may be exposed briefly to temperatures up to 30°C); protect from >30°C.¹⁶⁴

Extemporaneous Oral Liquid Preparations

In glass containers; stable for 14 days under refrigeration.¹⁶⁴ (See Oral Administration under Dosage and Administration.)

Parenteral

Powder for Injection

25°C.¹⁶⁴

Temperature fluctuations during storage or transport may result in melting of the vial contents; visually inspect vials and discard any with signs of melting (clear or yellowish viscous liquid in droplets or as a connected phase).¹⁶⁴

Reconstituted Solutions

In 0.9% sodium chloride injection or sterile water for injection: stable for 24 hours at room temperature or 6 days at 2–8°C.¹⁶⁴

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility^HID

Compatible
Amino acids 4.25%, dextrose 25%
Dextrose 5% in Ringer’s164 injection
Dextrose 5% in sodium chloride 0.9%164
Dextrose 5% in water164
Ringer’s injection, lactated164
Sodium chloride 0.45 or 164 0.9%
(1/6) M sodium lactate164

Drug Compatibility

Admixture CompatibilityHID

Compatible
Cisplatin with etoposide
Fluorouracil
Hydroxyzine HCl
Methotrexate sodium
Methotrexate sodium with fluorouracil
Mitoxantrone HCl
Ondansetron HCl
Variable
Mesna

Y-site CompatibilityHID

Compatible
Allopurinol sodium
Amifostine
Amikacin sulfate
Ampicillin sodium
Aztreonam
Bleomycin sulfate
Cefazolin sodium
Cefepime HCl
Cefotaxime sodium
Cefoxitin sodium
Cefuroxime sodium
Chloramphenicol sodium succinate
Chlorpromazine HCl
Cimetidine HCl
Cisplatin
Cladribine
Clindamycin phosphate
Co-trimoxazole
Dexamethasone sodium phosphate
Diphenhydramine HCl
Doxorubicin HCl
Doxorubicin HCl liposome injection
Doxycycline hyclate
Droperidol
Erythromycin lactobionate
Etoposide phosphate
Famotidine
Filgrastim
Fludarabine phosphate
Fluorouracil
Furosemide
Gallium nitrate
Ganciclovir sodium
Gatifloxacin
Gemcitabine HCl
Gentamicin sulfate
Granisetron HCl
Heparin sodium
Hydromorphone HCl
Idarubicin HCl
Kanamycin sulfate
Leucovorin calcium
Linezolid
Lorazepam
Melphalan HCl
Methotrexate sodium
Methylprednisolone sodium succinate
Metoclopramide HCl
Metronidazole
Mitomycin
Morphine sulfate
Nafcillin sodium
Ondansetron HCl
Oxacillin sodium
Oxaliplatin
Paclitaxel
Pemetrexed disodium
Penicillin G potassium
Piperacillin sodium–tazobactam sodium
Prochlorperazine edisylate
Promethazine HCl
Propofol
Ranitidine HCl
Sargramostim
Sodium bicarbonate
Teniposide
Thiotepa
Ticarcillin disodium–clavulanate potassium
Tobramycin sulfate
Topotecan HCl
Vancomycin HCl
Vinblastine sulfate
Vincristine sulfate
Vinorelbine tartrate
Incompatible
Amphotericin B cholesteryl sulfate complex

ActionsActions

• 
  

  Active metabolites interfere with growth of rapidly proliferating malignant cells.¹⁶⁴

  
  


• 
  

  Polyfunctional alkylating agent, may cross-link DNA, interfering with DNA replication and transcription of RNA, disrupting nucleic acid function.^{164 a}

  
  


• 
  

  Also has potent immunosuppressive activity.^a

  
  


• 
  

  The drug exhibits phosphorylating properties that also enhance its cytotoxicity.^a

  
  

Advice to Patients

• 
  

  Importance of reporting vomiting occurring shortly after oral dose.^pdh

  
  


• 
  

  Importance of continuing cyclophosphamide therapy despite nausea and vomiting.^pdh

  
  


• 
  

  Advise that alopecia is likely, but usually reversible; new hair may be different color or texture.^{a pdh}

  
  


• 
  

  Importance of increasing fluid intake for 24 hours before, during, and for at least 24 hours after receiving cyclophosphamide, and voiding frequently for 24 hours after receiving the drug, to prevent hemorrhagic cystitis.^{a pdh}

  
  


• 
  

  Importance of promptly reporting unusual bleeding or bruising.^{a pdh}

  
  


• 
  

  Importance of avoiding individuals with infections and immediately informing clinician if fever, sore throat, chills, or signs of infection occur.^{a pdh}

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.