Cytoxan

Yes

Cyclophosphamide is the generic name of the prescription drug Cytoxan, a chemotherapy drug for people with certain cancers.

It’s prescribed for non-Hodgkin lymphoma, Hodgkin lymphoma, multiple myeloma, small-cell lung cancer (SCLC), leukemia, ovarian cancer, retinoblastoma, neuroblastoma, and breast cancer.

Cyclophosphamide is sometimes used to treat kidney damage.

Doctors may also prescribe cyclophosphamide off-label to treat some kidney infections; systemic sclerosis or scleroderma (hardening of the organs and body tissues); and juvenile arthritis.

The Food and Drug Administration (FDA) approved cyclophosphamide as Cytoxan in 1959, and Baxter International, Inc. manufactures it.

Cyclophosphamide Warnings

You shouldn’t take cyclophosphamide if any of the following situations apply to you:

• You are allergic to cyclophosphamide or any other component in the drug.
• You have had radiation treatment in the past.
• Your absolute neutrophil count (ANC) is less than 1,500.
• Your platelet count (PLT) is less than 50,000.

Talk to your doctor before taking cyclophosphamide if you are 65 years old or older and have:

• Kidney or liver disease
• Heart disease
• Severe infection
• An open wound that’s currently healing
• Have previously taken a drug that can damage your heart or are taking one now

Pregnancy and Cyclophosphamide

Cyclophosphamide can affect a developing fetus.

You and your doctor need to decide whether the benefits of taking the drug during pregnancy outweigh the risk.

Cyclophosphamide is found in breast milk and isn’t considered safe to use while breastfeeding.

Tell your doctor if you’re pregnant, planning a pregnancy, or are breastfeeding before you take cyclophosphamide.

• Store tablets at or below 77°F (25°C).
• Store capsules at 20°C to 25°C (68°F to 77°F).
• Keep this and all medicines out of the reach of children.
• Keep all doctor and laboratory appointments.

• Breast Cancer
• Granulomatosis with Polyangiitis (GPA or Wegener's Granulomatosis)
• Leukemia
• Lupus (Systemic Lupus Erythematosus or SLE)
• Multiple Myeloma
• Ovarian Cancer
• Rheumatoid Arthritis (RA)
• Sjogren's Syndrome

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 studies167 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

In the U.S.

• Cytoxan
• Cytoxan Lyophilized

Available Dosage Forms:

• Powder for Solution
• Tablet
• Capsule

Therapeutic Class: Antineoplastic Agent

Pharmacologic Class: Alkylating Agent

Chemical Class: Nitrogen Mustard

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Cough or hoarseness
• fever or chills
• lower back or side pain
• missing menstrual periods
• painful or difficult urination

• Blood in the urine
• dizziness, confusion, or agitation
• fast heartbeat
• joint pain
• shortness of breath
• swelling of the feet or lower legs
• unusual tiredness or weakness

• Black, tarry stools
• pinpoint red spots on the skin
• unusual bleeding or bruising

• Frequent urination
• redness, swelling, or pain at the injection site
• sores in the mouth and on the lips
• sudden shortness of breath
• unusual thirst
• yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Darkening of the skin and fingernails
• loss of appetite
• nausea or vomiting

• Diarrhea
• flushing or redness of the face
• headache
• increased sweating
• skin rash, hives, or itching
• stomach pain
• swollen lips

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

General

Special attention to the possible development of toxicity should be exercised in patients being treated with cyclophosphamide if any of the following conditions are present.

1. Leukopenia
2. Thrombocytopenia
3. Tumor cell infiltration of bone marrow
4. Previous X-ray therapy
5. Previous therapy with other cytotoxic agents
6. Impaired hepatic function
7. Impaired renal function

Laboratory Tests

During treatment, the patient’s hematologic profile (particularly neutrophils and platelets) should be monitored regularly to determine the degree of hematopoietic suppression. Urine should also be examined regularly for red cells which may precede hemorrhagic cystitis.

Drug Interactions

The rate of metabolism and the leukopenic activity of cyclophosphamide reportedly are increased by chronic administration of high doses of phenobarbital.

The physician should be alert for possible combined drug actions, desirable or undesirable, involving cyclophosphamide even though cyclophosphamide has been used successfully concurrently with other drugs, including other cytotoxic drugs.

Cyclophosphamide treatment, which causes a marked and persistent inhibition of cholinesterase activity, potentiates the effect of succinylcholine chloride.

If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, the anesthesiologist should be alerted.

Adrenalectomy

Since cyclophosphamide has been reported to be more toxic in adrenalectomized dogs, adjustment of the doses of both replacement steroids and cyclophosphamide may be necessary for the adrenalectomized patient.

Wound Healing

Cyclophosphamide may interfere with normal wound healing.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

See WARNINGS for information on carcinogenesis, mutagenesis, and impairment of fertility.

Pregnancy

Pregnancy Category DSee WARNINGS.

Nursing Mothers

Cyclophosphamide is excreted in breast milk. Because of the potential for serious adverse reactions and the potential for tumorigenicity shown for cyclophosphamide in humans, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety profile of Cytoxan in pediatric patients is similar to that of the adult population (see ADVERSE REACTIONS).

Geriatric Use

Insufficient data from clinical studies of Cytoxan for malignant lymphoma, multiple myeloma, leukemia, mycosis fungoides, neuroblastoma, retinoblastoma, and breast carcinoma are available for patients 65 years of age and older to determine whether they respond differently than younger patients. In two clinical trials in which cyclophosphamide was compared with paclitaxel, each in combination with cisplatin, for the treatment of advanced ovarian carcinoma, 154 (28%) of 552 patients who received cyclophosphamide plus cisplatin were 65 years or older. Subset analyses (<65 versus >65 years) from these trials, published reports of clinical trials of cyclophosphamide-containing regimens in breast cancer and non-Hodgkin’s lymphoma, and postmarketing experience suggest that elderly patients may be more susceptible to cyclophosphamide toxicities. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range and adjusting as necessary based on patient response (see DOSAGE AND ADMINISTRATION: Treatment of Malignant Diseases).

Information on adverse reactions associated with the use of Cytoxan (cyclophosphamide) is arranged according to body system affected or type of reaction. The adverse reactions are listed in order of decreasing incidence. The most serious adverse reactions are described in the WARNINGS section.

Reproductive System

See WARNINGS for information on impairment of fertility.

Digestive System

Nausea and vomiting commonly occur with cyclophosphamide therapy. Anorexia and, less frequently, abdominal discomfort or pain and diarrhea may occur. There are isolated reports of hemorrhagic colitis, oral mucosal ulceration and jaundice occurring during therapy. These adverse drug effects generally remit when cyclophosphamide treatment is stopped.

Skin and Its Structures

Alopecia occurs commonly in patients treated with cyclophosphamide. The hair can be expected to grow back after treatment with the drug or even during continued drug treatment, though it may be different in texture or color. Skin rash occurs occasionally in patients receiving the drug. Pigmentation of the skin and changes in nails can occur. Very rare reports of Stevens-Johnson syndrome and toxic epidermal necrolysis have been received during postmarketing surveillance; due to the nature of spontaneous adverse event reporting, a definitive causal relationship to cyclophosphamide has not been established.

Hematopoietic System

Leukopenia occurs in patients treated with cyclophosphamide, is related to the dose of drug, and can be used as a dosage guide. Leukopenia of less than 2000 cells/mm3 develops commonly in patients treated with an initial loading dose of the drug, and less frequently in patients maintained on smaller doses. The degree of neutropenia is particularly important because it correlates with a reduction in resistance to infections. Fever without documented infection has been reported in neutropenic patients.

Thrombocytopenia or anemia develop occasionally in patients treated with Cytoxan. These hematologic effects usually can be reversed by reducing the drug dose or by interrupting treatment. Recovery from leukopenia usually begins in 7 to 10 days after cessation of therapy.

Urinary System

See WARNINGS for information on cystitis and urinary bladder fibrosis.

Hemorrhagic ureteritis and renal tubular necrosis have been reported to occur in patients treated with cyclophosphamide. Such lesions usually resolve following cessation of therapy.

Infections

See WARNINGS for information on reduced host resistance to infections.

Carcinogenesis

See WARNINGS for information on carcinogenesis.

Respiratory System

Interstitial pneumonitis has been reported as part of the postmarketing experience. Interstitial pulmonary fibrosis has been reported in patients receiving high doses of cyclophosphamide over a prolonged period.

Other

Anaphylactic reactions have been reported; death has also been reported in association with this event. Possible cross-sensitivity with other alkylating agents has been reported. SIADH (syndrome of inappropriate ADH secretion) has been reported with the use of cyclophosphamide. Malaise and asthenia have been reported as part of the postmarketing experience.

Cytoxan® contains cyclophosphamide monohydrate and is supplied in vials for single dose use.

Cytoxan (cyclophosphamide for injection, USP).

Store vials at or below 77° F (25° C). During transport or storage of Cytoxan vials, temperature influences can lead to melting of the active ingredient, cyclophosphamide. Vials containing melted substance can be visually differentiated. Melted cyclophosphamide is a clear or yellowish viscous liquid usually found as a connected phase or in droplets in the affected vials. Do not use Cytoxan vials if there are signs of melting.

Cytoxan® Tablets, 25 mg and Cytoxan Tablets, 50 mg, are white tablets with blue flecks containing 25 mg and 50 mg cyclophosphamide (anhydrous), respectively.

Cytoxan Tablets (cyclophosphamide tablets, USP).

Store tablets at or below 77° F (25° C); tablets will withstand brief exposure to temperatures up to 86° F (30° C) but should be protected from temperatures above 86° F (30° C).

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing Cytoxan sterile powder for injection, or bottles containing Cytoxan tablets. This includes all handling activities in clinical settings, pharmacies, storerooms, and home healthcare settings, including during unpacking and inspection, transport within a facility, and dose preparation and administration.