Professional Drug Information > Cyclophosphamide

Cyclophosphamide (Systemic)

VA CLASSIFICATION
Primary: AN100
Secondary: DE801; IM403; MS103

Commonly used brand name(s): Cytoxan; Neosar; Procytox.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antineoplastic—

immunosuppressant—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Leukemia, acute lymphocytic (treatment) or
Leukemia, acute nonlymphocytic (treatment)—Cyclophosphamide is indicated for treatment of acute lymphoblastic (stem-cell) leukemia in children (including during remission to prolong the duration), and for treatment of acute nonlymphocytic leukemia.^{01}{06}

Leukemia, chronic myelocytic (treatment) or
Leukemia, chronic lymphocytic (treatment)—Cyclophosphamide is indicated for treatment of chronic granulocytic leukemia (it is usually ineffective in acute blastic crisis) and chronic lymphocytic leukemia.^{01}{06}

Carcinoma, ovarian, epithelial (treatment)
Carcinoma, breast (treatment)
Neuroblastoma (treatment)
Retinoblastoma (treatment)
[Carcinoma, lung, non–small cell (treatment) ]
[Carcinoma, lung, small cell (treatment)]
[Carcinoma, cervical (treatment)]¹
[Carcinoma, endometrial (treatment) ]¹
[Carcinoma, bladder (treatment)]¹
[Carcinoma, prostatic (treatment) ]¹
[Carcinoma, testicular (treatment) ]¹
[Wilms' tumor (treatment)]¹or
[Carcinoma, adrenocortical (treatment)]¹—Cyclophosphamide is indicated for treatment of adenocarcinoma of the ovary^{01}{06}, breast carcinoma^{01}{06}, neuroblastoma^{01}{06} [in patients with disseminated disease] , retinoblastoma^{01}{06}, small cell ^{08} and non–small cell^{07} lung carcinoma, cervical carcinoma^{04}, and for endometrial carcinoma, bladder carcinoma, prostatic carcinoma, testicular carcinoma^{04}, Wilms' tumor^{04}, and adrenocortical carcinoma^{24}{25}{26} (Evidence rating: IIID).

Lymphomas, Hodgkin's (treatment) ^{{01} {06}} or
Lymphomas, non-Hodgkin's (treatment) ^{{01} {06}}—Cyclophosphamide is indicated for treatment of Stage III and IV (Ann Arbor or Peter's Staging System) Hodgkin's disease and non-Hodgkin's lymphomas including nodular or diffuse lymphocytic lymphoma, mixed-cell type lymphoma, histiocytic lymphoma, Burkitt's lymphoma, and [lymphoblastic lymphosarcoma] .

Multiple myeloma (treatment)—Cyclophosphamide is indicated for treatment of multiple myeloma^{01}{06}.

Mycosis fungoides (treatment)—Cyclophosphamide is indicated for treatment of advanced mycosis fungoides^{01}{06}.

Nephrotic syndrome (treatment)¹—Cyclophosphamide is indicated as an immunosuppressant in the treatment of steroid-resistant or frequently relapsing steroid-sensitive biopsy-proven minimal-change nephrotic syndrome in children^{01} [ and adults] .

[Ewing's sarcoma (treatment)]¹
[Osteosarcoma, (treatment)]¹or
[Sarcomas, soft tissue (treatment) ]¹—Cyclophosphamide is indicated for treatment of various sarcomas, including Ewing's sarcoma, osteosarcoma^{04}, and soft-tissue sarcomas.

[Tumors, germ cell, ovarian (treatment) ]¹
[Tumors, brain, primary (treatment) ]¹ or
[Tumors, trophoblastic, gestational (treatment)]¹—Cyclophosphamide is indicated for treatment of germ cell ovarian^{12}, primary brain^{11}, and gestational trophoblastic^{09} tumors.

[Thymoma (treatment)]¹—Cyclophosphamide is indicated for treatment of thymoma^{10}.

[Histiocytosis X (treatment)]¹—Cyclophosphamide is indicated as first-line therapy, as a single agent or in combination with other chemotherapeutic agents, for treatment of Histiocytosis X (Letterer-Siwe disease)^{{14}{15}{16}{17}{18}{19}{20}{21}{22}{23}} (Evidence rating: IIID).

[Waldenström's macroglobulinemia ]¹—Cyclophosphamide is indicated for treatment of Waldenström's macroglobulinemia^{13}.

[Transplant rejection, organ (prophylaxis) ]¹—Cyclophosphamide is used for its immunosuppressant activity, for prevention of rejection in homotransplantation.

[Arthritis, rheumatoid (treatment) ]¹
[Wegener's granulomatosis (treatment) ]¹
[Lupus erythematosus, systemic]¹
[Dermatomyositis, systemic (treatment) ]¹ or
[Multiple sclerosis (treatment)]¹—Cyclophosphamide is used as an immunosuppressant in the treatment of rheumatoid arthritis and other autoimmune diseases such as polymyositis (systemic dermatomyositis), multiple sclerosis, Wegener's granulomatosis, systemic lupus erythematosus (SLE), and other types of vasculitis.

—Extreme caution is recommended in use of cyclophosphamide for non-neoplastic conditions because of potential carcinogenicity with long-term use of this agent.

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    279.1

Mechanism of action/Effect:

Cyclophosphamide is classed as an alkylating agent of the nitrogen mustard type. An activated form of cyclophosphamide, phosphoramide mustard, alkylates or binds with many intracellular molecular structures, including nucleic acids. Its cytotoxic action is primarily due to cross-linking of strands of DNA^{01} and RNA, as well as to inhibition of protein synthesis.


Other actions/effects:

Cyclophosphamide is a potent immunosuppressant^{01}. It also causes marked and persistent inhibition of cholinesterase activity^{01}.

Absorption:

Well absorbed after oral administration (bioavailability greater than 75%)^{01}.

Distribution:

Crosses blood-brain barrier to limited extent.

Protein binding:

Very low (some active metabolites—greater than 60%^{01}).

Biotransformation:

Hepatic (including initial activation and subsequent degradation).

Half-life:

Unchanged drug—3 to 12 hours^{01}.

Time to peak concentration:

Plasma—Metabolites: 2 to 3 hours after intravenous administration^{01}.

Elimination:
    Renal, 5 to 25% unchanged^{01}.
    In dialysis—Cyclophosphamide is dialyzable^{01}.


Precautions to Consider

Carcinogenicity/Mutagenicity

Secondary malignancies are potential delayed effects of many antineoplastic agents, although it is not clear whether the effect is related to their mutagenic or immunosuppressive action. The effect of dose and duration of therapy is also unknown, although risk seems to increase with long-term use. Although information is limited, available data seem to indicate that the carcinogenic risk is greatest with the alkylating agents.

Cyclophosphamide is a potent carcinogen in animals. In humans, it has been associated with development of myeloproliferative and lymphoproliferative carcinomas as well as urinary bladder carcinoma (especially in patients who developed hemorrhagic cystitis while receiving cyclophosphamide)^{01} up to several years after administration. One case of carcinoma of the renal pelvis occurred in a patient who received long-term treatment with cyclophosphamide for cerebral vasculitis.^{01}

Pregnancy/Reproduction
Fertility—
Gonadal suppression, resulting in amenorrhea or azoospermia, may occur in patients taking antineoplastic therapy, especially with the alkylating agents. In general, these effects appear to be related to dose and length of therapy and may be irreversible. Prediction of the degree of testicular or ovarian function impairment is complicated by the common use of combinations of several antineoplastics, which makes it difficult to assess the effects of individual agents.

However, there have been numerous reports of gonadal suppression with use of cyclophosphamide, which seems to depend on dose, duration, and state of gonadal function at the time of therapy; sterility may be irreversible in some patients^{01}.

Paternal use of cyclophosphamide prior to conception has been associated with cardiac and limb abnormalities in an infant.

Pregnancy—
Cyclophosphamide crosses the placenta. Use in humans has resulted in both normal and malformed (missing fingers and/or toes, cardiac anomalies, hernias) newborns; risk seems to be less in the second and third trimesters. Low birth weight is also a risk with exposure of the fetus to antineoplastics.

First trimester: It is usually recommended that use of antineoplastics, especially combination chemotherapy, be avoided whenever possible, especially during the first trimester. Although information is limited because of the relatively few instances of antineoplastic administration during pregnancy, the mutagenic, teratogenic, and carcinogenic potential of these medications must be considered.

Other hazards to the fetus include adverse reactions seen in adults.

In general, use of a contraceptive is recommended during cytotoxic drug therapy.

Studies in animals have shown that cyclophosphamide is teratogenic in mice, rats, rabbits, and monkeys given 0.02, 0.08, 0.5, and 0.07 times the human dose, respectively.

FDA Pregnancy Category D.

Breast-feeding

Cyclophosphamide is distributed into breast milk^{01}. Breast-feeding is not recommended during chemotherapy because of the risks to the infant (adverse effects, mutagenicity, carcinogenicity).

Pediatrics

Appropriate studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of cyclophosphamide in children.

Prepubescent girls treated with cyclophosphamide usually develop secondary sexual characteristics normally, have regular menses, and subsequently conceive; however, ovarian fibrosis and apparent complete loss of germ cells after prolonged treatment in late prepubescence have been reported^{01}. Prepubescent boys treated with cyclophosphamide develop secondary sexual characteristics normally, but may have oligospermia or azoospermia, increased gonadotropin secretion, and some degree of testicular atrophy; azoospermia may be reversible, although possibly not for several years after the end of cyclophosphamide therapy^{01}.


Geriatrics


Although appropriate studies on the relationship of age to the effects of cyclophosphamide have not been performed in the geriatric population, geriatrics-specific problems are not expected to limit the usefulness of this medication in the elderly. However, elderly patients are more likely to have age-related renal function impairment, which may require caution in patients receiving cyclophosphamide.


Dental

The bone marrow depressant effects of cyclophosphamide may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. Dental work, whenever possible, should be completed prior to initiation of therapy or deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene during treatment, including caution in use of regular toothbrushes, dental floss, and toothpicks.

Cyclophosphamide may also rarely cause stomatitis associated with considerable discomfort.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Allopurinol or
Colchicine or
» Probenecid or
» Sulfinpyrazone    (cyclophosphamide may raise the concentration of blood uric acid; dosage adjustment of antigout agents may be necessary to control hyperuricemia and gout; uricosuric antigout agents may increase risk of uric acid nephropathy )

    (concurrent use with allopurinol may enhance the bone marrow toxicity of cyclophosphamide; if concurrent use is required, close observation for toxic effects should be considered)


Anticoagulants, oral    (cyclophosphamide may increase anticoagulant activity as a result of decreased hepatic synthesis of procoagulant factors and interference with platelet formation, but may also decrease anticoagulant activity by an unknown mechanism)


Blood dyscrasia–causing medications (see Appendix II)    (leukopenic and/or thrombocytopenic effects of cyclophosphamide may be increased with concurrent or recent therapy if these medications cause the same effects; dosage adjustment of cyclophosphamide, if necessary, should be based on blood counts)


» Bone marrow depressants, other (see Appendix II ) or
» Radiation therapy    (additive bone marrow depression may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively)


» Cocaine    (inhibition of cholinesterase activity by cyclophosphamide reduces or slows cocaine metabolism, thereby increasing and/or prolonging its effects and increasing the risk of toxicity^{03})


» Cytarabine    (concurrent use of high-dose cytarabine with cyclophosphamide for bone marrow transplant preparation has been reported to result in an increase in cardiomyopathy with subsequent death)


Daunorubicin or
Doxorubicin    (concurrent use with cyclophosphamide may result in increased cardiotoxicity; it is recommended that the total dose of daunorubicin or doxorubicin not exceed 400 mg per square meter of body surface area)


Hepatic enzyme inducers (see Appendix II)     (these agents may induce microsomal metabolism to increase formation of alkylating metabolites of cyclophosphamide, thereby reducing the half-life and increasing the activity of cyclophosphamide)


» Immunosuppressants, other, such as:
Azathioprine
Chlorambucil
Corticosteroids, glucocorticoid
Cyclosporine
Mercaptopurine
Muromonab-CD3    (concurrent use with cyclophosphamide may increase the risk of infection and development of neoplasms)


Lovastatin    (concurrent use in cardiac transplant patients may be associated with an increased risk of rhabdomyolysis and acute renal failure)


Succinylcholine ^{01}    (cyclophosphamide may decrease plasma concentrations or activity of pseudocholinesterase, the enzyme that metabolizes succinylcholine, thereby enhancing the neuromuscular blockade of succinylcholine. Increased or prolonged respiratory depression or paralysis [apnea] may occur but is of minor clinical significance while the patient is being mechanically ventilated; however, caution and careful monitoring of the patient are recommended during and following concurrent or sequential use, especially if there is a possibility of incomplete reversal of neuromuscular blockade postoperatively)


Vaccines, killed virus    (because normal defense mechanisms may be suppressed by cyclophosphamide therapy, the patient's antibody response to the vaccine may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year )


» Vaccines, live virus    (because normal defense mechanisms may be suppressed by cyclophosphamide therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematologic status and only with the knowledge and consent of the physician managing the cyclophosphamide therapy. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. Patients with leukemia in remission should not receive live virus vaccine until at least 3 months after their last chemotherapy. In addition, immunization with oral poliovirus vaccine should be postponed in persons in close contact with the patient, especially family members)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Candida skin test and
Mumps skin test and
Trichophyton skin test and
Tuberculin PPD skin test    (positive reactions may be suppressed)


Papanicolaou (PAP) test    (false-positive results may be produced)

With physiology/laboratory test values
Pseudocholinesterase    (serum concentrations may be decreased)


Uric acid    (blood and urine concentrations may be increased)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Adrenalectomy    (toxic effects of cyclophosphamide may be increased; dosage adjustment of both replacement steroids and cyclophosphamide may be necessary^{01})


» Bone marrow depression ^{01}
» Chickenpox, existing or recent (including recent exposure) or
» Herpes zoster    (risk of severe generalized disease)


Gout, history of or
Urate renal stones, history of    (risk of hyperuricemia)


» Hepatic function impairment ^{01}    (effect of cyclophosphamide may be reduced because of its dependence on hepatic microsomal enzyme activation)


» Infection ^{01}
» Renal function impairment    (reduced elimination; dosage reduction usually not necessary^{01})


Sensitivity to cyclophosphamide ^{01}
» Tumor cell infiltration of bone marrow ^{01}    (a reduction by one-third to one-half in cyclophosphamide dosage for induction is recommended for patients with bone marrow depression due to tumor cell infiltration)


» Caution should be used also in patients who have had previous cytotoxic drug therapy or radiation therapy ^{01} ; a reduction by one-third to one-half in cyclophosphamide dosage for induction is recommended for patients with bone marrow depression due to cytotoxic or radiation therapy.

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Alanine aminotransferase (ALT [SGPT]) values, serum and
Aspartate aminotransferase (AST [SGOT]) values, serum and
Bilirubin values, serum and
Lactate dehydrogenase (LDH) values, serum    (determinations recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)


Blood urea nitrogen (BUN) concentrations and
Creatinine concentrations, serum    (determinations recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)


» Examination of urine for microscopic hematuria ^{01}    (recommended at periodic intervals during therapy, as well as for several hours following a large intravenous dose)


» Hematocrit or hemoglobin and
» Leukocyte count, total and, if appropriate, differential and
» Platelet count    (determinations recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)


Uric acid concentrations, serum    (determinations recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)


Urinary output and
Urinary specific gravity    (determinations recommended following high-dose intravenous administration to detect possible syndrome of inappropriate antidiuretic hormone [SIADH] )






Side/Adverse Effects

Note: Many “side effects” of antineoplastic therapy are unavoidable and represent the medication"s pharmacologic action. Some of these (for example, leukopenia and thrombocytopenia) are actually used as parameters to aid in individual dosage titration.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Amenorrhea ^{01} (missing menstrual periods)
    
leukopenia or infection ^{01} (less frequently, fever or chills; cough or hoarseness ; lower back or side pain; painful or difficult urination)—usually asymptomatic

Note: With amenorrhea, regular menses usually resume within a few months after the end of cyclophosphamide therapy^{01}.
A marked leukopenia usually occurs, with the nadir of the leukocyte count occurring 7 to 12 days after administration and recovery after 17 to 21 days.


With high-dose and/or long-term therapy
    
Cardiotoxicity, including acute myopericarditis ^{01} (fast heartbeat; fever or chills; shortness of breath)
    
condition resembling syndrome of inappropriate antidiuretic hormone (SIADH) ^{01} (dizziness, confusion, or agitation; unusual tiredness or weakness)
    
hemorrhagic cystitis ^{01} (blood in urine; painful urination )
    
hyperuricemia, uric acid nephropathy, nonhemorrhagic cystitis, or nephrotoxicity (joint pain ; lower back or side pain; swelling of feet or lower legs)
    
pneumonitis or interstitial pulmonary fibrosis ^{01} (cough, shortness of breath)

Note: Cardiotoxicity is most severe with use of doses of 180 to 270 mg per kg of body weight (mg/kg) within 4 to 6 days.
A few cases of severe and sometimes fatal congestive heart failure have occurred within a few days after the first dose of a high-dose course of cyclophosphamide; histopathologic examination primarily revealed hemorrhagic myocarditis^{01}. Hemopericardium has occurred secondary to hemorrhagic myocarditis and myocardial necrosis^{01}. Pericarditis has been reported independent of any hemopericardium^{01}.
Hemorrhagic cystitis may occur within a few hours or be delayed several weeks; thought to be caused by metabolites of cyclophosphamide (chloroacetic acid, acrolein^{02}) excreted in the urine^{01}. Usually resolves a few days after withdrawal of cyclophosphamide, but may persist; may be fatal. Fibrosis of the urinary bladder, with or without cystitis, may also occur and may be extensive^{01}. Atypical urinary bladder epithelial cells may be found in urine^{01}. Hemorrhagic ureteritis and renal tubular necrosis, which usually resolve after withdrawal of cyclophosphamide, have also been reported^{01}.
Hyperuricemia with uric acid nephropathy occurs most commonly during initial treatment of patients with leukemia or lymphoma, as a result of rapid cell breakdown which leads to elevated serum uric acid concentrations.


Incidence less frequent
    
Anemia ^{01}
    
thrombocytopenia ^{01} (unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)—usually asymptomatic

Incidence rare
    
Anaphylactic reaction ^{01} (sudden shortness of breath)
    
hemorrhagic colitis ^{{01} {01}} (black, tarry stools)
    
hepatitis (yellow eyes or skin ^{01})
    
hyperglycemia (frequent urination; unusual thirst)
    
redness, swelling, or pain at site of injection
    
stomatitis ^{01} (sores in mouth and on lips)

Note: Anaphylaxis has resulted in death^{01}.




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Darkening of skin and fingernails ^{01}
    
loss of appetite ^{01}
    
nausea or vomiting ^{01} — especially with high oral doses

Incidence less frequent
    
Diarrhea or stomach pain ^{01}
    
flushing or redness of face
    
headache
    
increased sweating
    
myxedema ( swollen lips)
    
skin rash, hives, or itching ^{01}



Those not indicating need for medical attention
Incidence more frequent
    
Loss of hair ^{01}

Note: Normal hair growth usually returns after treatment has ended, although it may be slightly different in color or texture^{01}.




Those indicating the need for medical attention if they occur after medication is discontinued
    
Hemorrhagic cystitis (blood in urine)




Overdose
For more information on the management of overdose, contact a Poison Control Center (see Poison Control Center Listing).

Treatment of overdose
There is no specific antidote to cyclophosphamide. Supportive therapy is recommended^{01}.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Cyclophosphamide (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to cyclophosphamide

Pregnancy—Use not recommended because of mutagenic, teratogenic, and carcinogenic potential; advisability of using contraception; telling physician immediately if pregnancy is suspected





Breast-feeding—Not recommended because of risk of serious side effects
Other medications, especially cytotoxic drugs, cocaine, cytarabine, other bone marrow suppressants, other immunosuppressants, probenecid, radiation therapy, or sulfinpyrazone
Other medical problems, especially chickenpox, herpes zoster, hepatic function impairment, other infections, renal function impairment, or tumor cell infiltration of bone marrow

Proper use of this medication
» Importance of not taking more or less medication than the amount prescribed

Caution in taking combination therapy; taking each medication at the right time

» Importance of ample fluid intake and subsequent increase in urine output, as well as frequent voiding (including at least once during night), to prevent hemorrhagic cystitis and aid in excretion of uric acid; following physician instructions for recommended fluid intake; some patients may require up to 3000 mL (3 quarts) per day

Usually best if taken in the morning to reduce risk of hemorrhagic cystitis; however, physician may recommend taking in small doses throughout day to lessen stomach upset; following physician's instructions for timing of doses

» Probability of nausea, vomiting, and loss of appetite; importance of continuing medication despite stomach upset; checking with physician before discontinuing medication

Checking with physician if vomiting occurs shortly after dose is taken

» Proper dosing
Not taking at all; not doubling doses; checking with physician

» Proper storage

Precautions while using this medication
» Importance of close monitoring by physician

» Avoiding immunizations unless approved by physician; other persons in patient's household should avoid immunizations with oral poliovirus vaccine; avoiding persons who have taken oral poliovirus vaccine or wearing a protective mask that covers nose and mouth

Caution if any kind of surgery, including dental surgery, or emergency treatment with general anesthesia is required within 10 days of treatment^{01}

Caution if bone marrow depression occurs
» Avoiding exposure to persons with infections, especially during periods of low blood counts; checking with physician immediately if fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination occurs

» Checking with physician immediately if unusual bleeding or bruising; black, tarry stools; blood in urine; or pinpoint red spots on skin occur

Caution in use of regular toothbrush, dental floss, or toothpick; physician, dentist, or nurse may suggest alternatives; checking with physician before having dental work done

Not touching eyes or inside of nose unless hands washed immediately before

Using caution to avoid accidental cuts with use of sharp objects such as safety razor or fingernail or toenail cutters

Avoiding contact sports or other situations where bruising or injury could occur
Caution if any laboratory tests required; possible interference with test results


Side/adverse effects
Signs of potential side effects, especially, amenorrhea, leukopenia, infection, cardiotoxicity, SIADH, hemorrhagic cystitis, hyperuricemia, uric acid nephropathy, nonhemorrhagic cystitis, nephrotoxicity, pneumonitis, interstitial pulmonary fibrosis, anemia, thrombocytopenia, anaphylactic reaction, hemorrhagic colitis, hepatitis, hyperglycemia, redness or swelling or pain at site of injection, and stomatitis

Physician or nurse can help in dealing with side effects

Possibility of hair loss; normal hair growth should return after treatment has ended; new hair may be slightly different in color or texture


General Dosing Information
Patients receiving cyclophosphamide should be under supervision of a physician experienced in cancer chemotherapy or immunosuppressive therapy.

A variety of dosage schedules and regimens of cyclophosphamide, alone or in combination with other antitumor agents, are used. The prescriber may consult the medical literature as well as the manufacturer's literature in choosing a specific dosage.

Dosage must be adjusted to meet the individual requirements of each patient, based on clinical response and appearance or severity of toxicity.

Development of uric acid nephropathy in patients with leukemia or lymphoma may be prevented by adequate oral hydration and, in some cases, administration of allopurinol. Alkalinization of urine may be necessary if serum uric acid concentrations are elevated.

To reduce the risk of hemorrhagic cystitis, adequate hydration is recommended prior to cyclophosphamide treatment and for at least 72 hours following treatment to ensure ample urine output. In addition, the patient should be encouraged to take cyclophosphamide in the morning so that the majority of the metabolites have been excreted by bedtime and to void frequently, to prevent prolonged contact of irritating metabolites with bladder mucosa.

Cyclophosphamide should be discontinued at the first sign of hemorrhagic cystitis. In severe cases, blood replacement may be necessary. Electrocautery diversion of urine flow, cryosurgery, and formaldehyde bladder instillations have been used. Resumption of therapy should be undertaken with caution since recurrence is common.

Initiation of planned maintenance antineoplastic therapy is recommended as soon as the leukocyte count returns to adequate levels following induction.

If marked leukopenia (particularly granulocytopenia) or thrombocytopenia occurs, cyclophosphamide therapy should be withdrawn until leukocyte and platelet counts return to satisfactory levels. Then therapy may be reinstituted, possibly at a lower dose.

In acute leukemia, cyclophosphamide may be administered despite the presence of thrombocytopenia and bleeding; cessation of bleeding and increase in platelet count have occurred in some cases during treatment and platelet transfusions are useful in others.

Special precautions are recommended in patients who develop thrombocytopenia as a result of administration of cyclophosphamide. These may include extreme care in performing invasive procedures; regular inspection of intravenous sites, skin (including perirectal area), and mucous membrane surfaces for signs of bleeding or bruising; limiting frequency of venipuncture and avoiding intramuscular injections; testing urine, emesis, stool, and secretions for occult blood; care in use of regular toothbrushes, dental floss, toothpicks, safety razors, and fingernail and toenail cutters; avoiding constipation; and using caution to prevent falls and other injuries. Such patients should avoid alcohol and aspirin intake because of the risk of gastrointestinal bleeding. Platelet transfusions may be required.

Patients who develop leukopenia should be observed carefully for signs of infection. Antibiotic support may be required. In neutropenic patients who develop fever, broad-spectrum antibiotic coverage should be initiated empirically, pending bacterial cultures and appropriate diagnostic tests.

For parenteral dosage forms only
Cyclophosphamide may be administered by intravenous push or infusion, intramuscularly, intraperitoneally, or intrapleurally^{01}.

Diet/Nutrition
Oral cyclophosphamide should usually be taken on an empty stomach; however, if stomach upset occurs, doses may be divided and given with meals.

Safety considerations for handling this medication
There is limited but increasing evidence and concern that personnel involved in preparation and administration of parenteral antineoplastics may be at some risk because of the potential mutagenicity, teratogenicity, and/or carcinogenicity of these agents, although the actual risk is unknown. USP advisory panels recommend cautious handling both in preparation and disposal of antineoplastic agents. Precautions that have been suggested include:   • Use of a biological containment cabinet during reconstitution and dilution of parenteral medications and wearing of disposable surgical gloves and masks.
   • Use of proper technique to prevent contamination of the medication, work area, and operator during transfer between containers (including proper training of personnel in this technique).
   • Cautious and proper disposal of needles, syringes, vials, ampuls, and unused medication.
A number of medical centers have developed detailed guidelines for handling of antineoplastic agents.


Combination chemotherapy
Cyclophosphamide may be used in combination with other agents in various regimens. As a result, incidence and/or severity of side effects may be altered and different dosages (usually reduced) may be used. For example, cyclophosphamide is part of the following chemotherapeutic combinations (some commonly used acronyms are in parentheses):   —carmustine, cyclophosphamide, vinblastine, procarbazine, and prednisone (BCVPP).
   —cyclophosphamide, doxorubicin, and fluorouracil (CAF).
   —cyclophosphamide, doxorubicin, methotrexate, and procarbazine (CAMP).
   —cyclophosphamide, doxorubicin, and cisplatin (CAP).
   —cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).
   —cyclophosphamide, doxorubicin, and cisplatin (CISCA).
   —cyclophosphamide, methotrexate, and lomustine (CMC).
   —cyclophosphamide, methotrexate, and fluorouracil (CMF).
   —cyclophosphamide, methotrexate, fluorouracil, vincristine, and prednisone (CMFVP).
   —cyclophosphamide, vincristine, and prednisone (COP or CVP).
   —cyclophosphamide, vincristine, doxorubicin, and dacarbazine (CyVADIC).
   —vincristine, dactinomycin, and cyclophosphamide (VAC).
For specific dosages and schedules, consult the literature. For information regarding each agent, consult the individual monographs.


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

CYCLOPHOSPHAMIDE ORAL SOLUTION

Note: In the U.S. and Canada, Cyclophosphamide Injection USP [Cytoxan; Neosar; Procytox] is the dosage form being used to prepare the oral solution dosage form.


Usual adult dose
Leukemia, acute lymphocytic or
Leukemia, acute nonlymphocytic or
Leukemia, chronic myelocytic or
Leukemia, chronic lymphocytic or
Carcinoma, ovarian, epithelial or
Carcinoma, breast or
Neuroblastoma or
Retinoblastoma or
[Carcinoma, lung, non–small cell] or
[Carcinoma, lung, small cell] or
[Carcinoma, endometrial]¹or
[Carcinoma, bladder]¹ or
[Carcinoma, prostatic]¹or
Lymphomas, Hodgkin's or
Lymphomas, non-Hodgkin's or
Multiple myeloma or
Mycosis fungoides or
[Ewing's sarcoma]¹or
[Sarcomas, soft tissue]¹ or
[Tumors, germ cell, ovarian]¹
Oral, 1 to 5 mg per kg of body weight per day.

[Carcinoma, adrenocortical]¹
Consult medical literature or manufacturer's literature for specific dosage.

[Rheumatoid arthritis]¹
Oral, 1.5 to 2 mg per kg of body weight per day, the dosage being increased up to a maximum of 3 mg per kg of body weight per day.

[Wegener's granulomatosis]¹
Oral, 1 to 2 mg per kg of body weight per day, administered in combination with prednisone.


Usual pediatric dose
Leukemia, acute lymphocytic or
Leukemia, acute nonlymphocytic or
Leukemia, chronic myelocytic or
Leukemia, chronic lymphocytic or
Neuroblastoma or
Retinoblastoma or
Lymphomas, Hodgkin's; or
Lymphomas, non-Hodgkin's
Induction: Oral, 2 to 8 mg per kg of body weight or 60 to 250 mg per square meter of body surface area a day in divided doses for six or more days.

Maintenance: Oral, 2 to 5 mg per kg of body weight or 50 to 150 mg per square meter of body surface area twice a week.

Nephrotic syndrome
Oral, 2.5 to 3 mg per kg of body weight per day.

[Histiocytosis X]¹
Consult medical literature or manufacturer's literature for specific dosage.


Strength(s) usually available
U.S.—
Dosage form not commercially available. Compounding required for prescriptions.

Canada—
Dosage form not commercially available. Compounding required for prescriptions.

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F). Protect from freezing. Store in a tight container.

Preparation of dosage form:
Cyclophosphamide oral solution may be prepared by dissolving Cyclophosphamide for Injection USP in Aromatic Elixir NF^{01} to a concentration of 1 to 5 mg of cyclophosphamide per mL.

Stability:
Stable for up to 14 days when stored in a glass container in the refrigerator^{01}.

Auxiliary labeling:
   • For oral use.
   • Take on an empty stomach.
   • Drink plenty of water with this medicine.


CYCLOPHOSPHAMIDE TABLETS USP

Usual adult dose
Leukemia, acute lymphocytic or
Leukemia, acute nonlymphocytic or
Leukemia, chronic myelocytic or
Leukemia, chronic lymphocytic or
Carcinoma, ovarian, epithelial or
Carcinoma, breast or
Neuroblastoma or
Retinoblastoma or
[Carcinoma, lung, non–small cell] or
[Carcinoma, lung, small cell] or
[Carcinoma, endometrial]¹or
[Carcinoma, bladder]¹ or
[Carcinoma, prostatic]¹or
Lymphomas, Hodgkin's or
Lymphomas, non-Hodgkin's or
Multiple myeloma or
Mycosis fungoides or
[Ewing's sarcoma]¹or
[Sarcomas, soft tissue]¹ or
[Tumors, germ cell, ovarian]¹
Oral, 1 to 5 mg per kg of body weight per day.

[Carcinoma, adrenocortical]¹
Consult medical literature or manufacturer's literature for specific dosage.

[Rheumatoid arthritis]¹
Oral, 1 to 2 mg per kg of body weight per day, the dose being adjusted on the basis of leukocyte counts.

[Wegener's granulomatosis]¹
Oral, 1.5 to 2 mg per kg of body weight per day, the dosage being increased up to a maximum of 3 mg per kg of body weight per day.


Usual pediatric dose
Leukemia, acute lymphocytic or
Leukemia, acute nonlymphocytic or
Leukemia, chronic myelocytic or
Leukemia, chronic lymphocytic or
Neuroblastoma or
Retinoblastoma or
Lymphomas, Hodgkin's or
Lymphomas, non-Hodgkin's
Induction: Oral, 2 to 8 mg per kg of body weight or 60 to 250 mg per square meter of body surface area a day in divided doses for six or more days.

Maintenance: Oral, 2 to 5 mg per kg of body weight or 50 to 150 mg per square meter of body surface area twice a week.

Nephrotic syndrome¹
Oral, 2.5 to 3 mg per kg of body weight per day^{01}.

[Histiocytosis X]¹
Consult medical literature or manufacturer's literature for specific dosage.


Strength(s) usually available
U.S.—


25 mg (Rx) [Cytoxan (lactose)]


50 mg (Rx) [Cytoxan (lactose)]

Canada—


25 mg (Rx) [Cytoxan] [Procytox]


50 mg (Rx) [Cytoxan] [Procytox]

Packaging and storage:
Store between 2 and 25 °C (36 and 77 °F). Store in a tight container.

Auxiliary labeling:
   • Take on an empty stomach.
   • Drink plenty of water with this medicine.



Parenteral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

CYCLOPHOSPHAMIDE FOR INJECTION USP

Usual adult dose
Leukemia, acute lymphocytic or
Leukemia, acute nonlymphocytic or
Leukemia, chronic myelocytic or
Leukemia, chronic lymphocytic or
Carcinoma, ovarian, epithelial or
Carcinoma, breast or
Neuroblastoma or
Retinoblastoma or
[Carcinoma, lung, non–small cell] or
[Carcinoma, lung, small cell] or
[Carcinoma, endometrial]¹or
[Carcinoma, bladder]¹ or
[Carcinoma, prostatic]¹or
Lymphomas, Hodgkin's or
Lymphomas, non-Hodgkin's or
Multiple myeloma or
Mycosis fungoides or
[Ewing's sarcoma]¹or
[Sarcomas, soft tissue]¹ or
[Tumors, germ cell, ovarian]¹
Initial: Intravenous, 40 to 50 mg per kg of body weight in divided doses over a period of two to five days, or 10 to 15 mg per kg of body weight every seven to ten days, or 3 to 5 mg per kg of body weight two times a week,^{01} or 1.5 to 3 mg per kg of body weight a day.

[Carcinoma, adrenocortical]¹
Consult medical literature or manufacturer's literature for specific dosage.


Usual adult prescribing limits
Much higher dosages have been used, depending on the condition being treated. Physicians should consult the medical literature in choosing a specific dosage.

Usual pediatric dose
Leukemia, acute lymphocytic or
Leukemia, acute nonlymphocytic or
Leukemia, chronic myelocytic or
Leukemia, chronic lymphocytic or
Neuroblastoma or
Retinoblastoma or
Lymphomas, Hodgkin's or
Lymphomas, non-Hodgkin's
Induction: Intravenous, 2 to 8 mg per kg of body weight or 60 to 250 mg per square meter of body surface area a day in divided doses for six or more days (or total dose for seven days once a week).

Maintenance: Intravenous, 10 to 15 mg per kg of body weight every seven to ten days, or 30 mg per kg of body weight at three- to four-week intervals or when bone marrow recovery occurs.

[Histiocytosis X]¹
Consult medical literature or manufacturer's literature for specific dosage.


Strength(s) usually available
U.S.—



Lyophilized


100 mg (Rx) [Cytoxan (mannitol 75 mg)]


200 mg (Rx) [Cytoxan (mannitol 150 mg)]


500 mg (Rx) [Cytoxan (mannitol 375 mg)]


1 gram (Rx) [Cytoxan (mannitol 750 mg)]


2 grams (Rx) [Cytoxan (mannitol 1.5 grams)]



Nonlyophilized


100 mg (Rx) [Neosar (sodium chloride 45 mg [1.9 mmol])]


200 mg (Rx) [Neosar (sodium chloride 90 mg [3.9 mmol])]


500 mg (Rx) [Neosar (sodium chloride 225 mg [9.7 mmol])]


1 gram (Rx) [Neosar (sodium chloride 450 mg [19.5 mmol])]


2 grams (Rx) [Neosar (sodium chloride 900 mg [39 mmol])]

Canada—



Lyophilized


1 gram (Rx) [Cytoxan (mannitol 750 mg)]


2 grams (Rx) [Cytoxan (mannitol 1.5 grams)]



Nonlyophilized


200 mg (Rx) [Procytox (sodium chloride 90 mg [3.9 mmol])]


500 mg (Rx) [Procytox (sodium chloride 225 mg [9.7 mmol])]


1 gram (Rx) [Procytox (sodium chloride 450 mg [19.5 mmol])]


2 gram (Rx) [Procytox (sodium chloride 900 mg [39 mmol])]

Packaging and storage:
Store at a temperature not exceeding 25 °C (77 °F)^{01}.

Preparation of dosage form:
Nonlyophilized cyclophosphamide for injection may be prepared for parenteral use by adding 5 mL (100-mg vial), 10 mL (200-mg vial), 25 mL (500-mg vial), 50 mL (1-gram vial), or 100 mL (2-gram vial) of sterile water for injection or bacteriostatic water for injection (paraben-preserved only) to the vial and shaking to dissolve (may be difficult and take up to 6 minutes) to provide a solution containing 20 mg of cyclophosphamide per mL. The resulting solution may be added to 5% dextrose injection, 5% dextrose and 0.9% sodium chloride injection, 5% dextrose and Ringer's injection, lactated Ringer's injection, 0.45% sodium chloride injection, or sodium lactate injection for administration by intravenous infusion.

Lyophilized cyclophosphamide for injection may be prepared for parenteral use by adding 5 mL (100-mg vial), 10 mL (200-mg vial), 20 to 25 mL (500-mg vial), 50 mL (1-gram vial), or 80 to 100 mL (2-gram vial) of sterile water for injection or bacteriostatic water for injection (paraben-preserved only) to the vial and shaking to dissolve (takes about 45 seconds) to provide a solution containing 20 mg of cyclophosphamide per mL. The resulting solution may be added to 5% dextrose injection, 5% dextrose and 0.9% sodium chloride injection, 5% dextrose and Ringer's injection, lactated Ringer's injection, 0.45% sodium chloride injection, or sodium lactate injection for administration by intravenous infusion^{01}.

Caution: Use of diluents containing benzyl alcohol is not recommended for preparation of medications for use in neonates. A fatal toxic syndrome consisting of metabolic acidosis, central nervous system (CNS) depression, respiratory problems, renal failure, hypotension, and possibly seizures and intracranial hemorrhages has been associated with this use.

Stability:
Reconstituted solutions of cyclophosphamide are stable for 24 hours at room temperature, or for 6 days if refrigerated^{01}. If bacteriostatic water for injection is not used for reconstitution, it is recommended that the solution be used promptly (preferably within 6 hours).

Note: Because cyclophosphamide for injection contains no preservative, caution in preparing and storing solutions is required to ensure sterility.

Revised: 05/22/2002

References

1. Cytoxan package insert (Mead Johnson—US), Rev 1/90; Rev 7/96.
   

2. Reviewers" comments, 1985 revision.
   

3. Cocaine (Mucosal-Local) monograph, 1989 USP DI.
   

4. Hematology-Oncology Advisory Panel (1985-1990), Memorandum No. 26, 8/28/89.
   

5. Neosar package insert (Adria—US), Rev 7/19/88.
   

6. Cytoxan product monograph (Bristol—Canada), Rev 7/92.
   

7. Non-small cell lung cancer [9/97]. National Cancer Institute. Available from: URL: http://cancernet.nci.nih.gov
   

8. Small cell lung cancer [5/96]. National Cancer Institute. Available from: URL: http://cancernet.nci.nih.gov
   

9. Gestational trophoblastic tumor [5/96]. National Cancer Institute. Available from: URL: http://cancernet.nci.nih.gov
   

10. Blossom GV, Stieger Z, Stephenson LW. Neoplasms of the mediastinum. In: DeVita VT, Hellman S, Rosenberg SA. Cancer principles and practice of oncology. 5th ed. Lippincott-Raven Publishers; 1997. p. 951-69.
    

11. Reviewers" responses to Hematologic-Oncologic Disease Advisory Panel Memo #9 of 1/30/97.
    

12. Ovarian germ cell tumor [9/97]. National Cancer Institute. Available from: URL: http://cancernet.nci.nih.gov
    

13. Plasma cell neoplasm [8/97]. National Cancer Institute. Available from: URL: http://cancernet.nci.nih.gov
    

14. Ceci A, de Terlizzi M, Colella R, et al. Langerhans cell histiocytosis in childhood: Results from the Italian Cooperative AIEOP-CNR-H.X "83 study. Med Pediatr Oncol 1993; 21: 259-64.
    

15. Lahey ME, Heyn RM, Newton WA, et al. Histiocytosis X: clinical trial of chlorambucil: A report from Childrens Cancer Study Group. Med Pediatr Oncol 1979; 7: 197-203.
    

16. Komp DM, Silva-Sosa M, Miale T, et al. Evaluation of a MOPP-type regimen in histiocytosis X: A Southwest Oncology Group study. Cancer Treat Rep 1977; 61: 855-9.
    

17. Komp DM, Vietti TJ, Berry DH, et al. Combination chemotherapy in histiocytosis X. Med Pediatr Oncol 1977; 3: 267-73.
    

18. Starling KA, Donaldson MH, Haggard ME, et al. Therapy of histiocytosis X with vincristine, vinblastine, and cyclophosphamide . The Southwe stern Cancer Chemotherapy Study group. Amer J Dis Child 1972; 123: 105-10.
    

19. Gaines P, Chan JC, Cockram CS. Histiocytosis X involving the thyroid and hypothalamus. Postgrad Med J 1991; 67: 680-2.
    

20. Chantler C, Milner AD, Winterborn MH. Treatment of Letterer-Siwe disease. Arch Dis Child 1971; 46: 552-4.
    

21. Mauger DC. Letterer-Siwe disease (acute disseminated histiocytosis X): a case complicated by disseminated intravascular coagulation and responding to heparin therapy. Pediatrics 1971; 47: 435-7.
    

22. Al-Rashid RA. Successful treatment of an infant with Letterer-Siwe disease with vinblastine sulfate. Clin Pediatr 1970; 9: 494-6.
    

23. Esterly NB, Swick HM. Cutaneous Letterer-Siwe disease. Amer J Dis Child 1969; 117: 236-8.
    

24. Arico M, Bossi G, Livieri C, et al. Partial response after intensive chemotherapy for adrenal cortical carcinoma in a child. Med Pediatr Oncol 1992; 20: 246-8.
    

25. van Slooten H, van Oosterom AT. CAP (cyclophosphamide, doxorubicin, and cisplatin) regimen in adrenal cortical carcinoma. Cancer Treat Rep 1983; 67: 377-9.
    

26. Visconti EB, Peters RW, Cangir A, et al. Unusual case of adrenal cortical carcinoma in a female infant. Arch Dis Child 1978; 53: 342-44.
    

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