Cyclophosphamide

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Cyclophosphamide
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2]; Sree Teja Yelamanchili, MBBS [3]

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Overview

Cyclophosphamide is a antineoplastic, immunosuppressive agent that is FDA approved for the treatment of malignant diseases, minimal change nephrotic syndrome in pediatric patients. Common adverse reactions include neutropenia, febrile neutropenia, fever, alopecia, nausea, vomiting, and diarrhea.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Acute myeloid leukemia

  • Dosing Information
  • Single agent: 40 to 50 mg/kg IV in divided doses over 2 to 5 days OR 10 to 15 mg/kg IV every 7 to 10 days OR 3 to 5 mg/kg IV twice weekly.
  • Single agent: oral cyclophosphamide is usually administered at dosages in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.

Breast cancer

  • Dosing Information
  • Single agent: 40 to 50 mg/kg IV in divided doses over 2 to 5 days OR 10 to 15 mg/kg IV every 7 to 10 days OR 3 to 5 mg/kg IV twice weekly.
  • Single agent: 1 to 5 mg/kg/day ORALLY, for both initial and maintenance dosing.

Burkitt's lymphoma

  • Dosing Information
  • Single agent: 40 to 50 mg/kg IV in divided doses over 2 to 5 days OR 10 to 15 mg/kg IV every 7 to 10 days OR 3 to 5 mg/kg IV twice weekly.
  • Single agent: oral cyclophosphamide is usually administered at dosages in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.

Chronic lymphoid leukemia

  • Dosing Information
  • Chronic lymphoid leukemia: (single agent) 40 to 50 mg/kg IV in divided doses over 2 to 5 days OR 10 to 15 mg/kg IV every 7 to 10 days OR 3 to 5 mg/kg IV twice weekly.
  • Chronic lymphoid leukemia: (single agent) oral cyclophosphamide is usually administered at dosages in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.

Chronic myeloid leukemia

  • Dosing Information
  • Chronic myeloid leukemia: (single agent) 40 to 50 mg/kg IV in divided doses over 2 to 5 days OR 10 to 15 mg/kg IV every 7 to 10 days OR 3 to 5 mg/kg IV twice weekly.
  • Chronic myeloid leukemia: (single agent) oral cyclophosphamide is usually administered at dosages in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.

Hodgkin's disease, Stages III and IV (Ann Arbor staging system)

  • Dosing Information
  • Hodgkin's disease, Stages III and IV (Ann Arbor staging system): (single agent) 40 to 50 mg/kg IV in divided doses over 2 to 5 days OR 10 to 15 mg/kg IV every 7 to 10 days OR 3 to 5 mg/kg IV twice weekly.
  • Hodgkin's disease, Stages III and IV (Ann Arbor staging system): (single agent) oral cyclophosphamide is usually administered at dosages in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.

Malignant histiocytosis (clinical)

  • Dosing Information
  • Malignant histiocytosis (clinical): (single agent) 40 to 50 mg/kg IV in divided doses over 2 to 5 days OR 10 to 15 mg/kg IV every 7 to 10 days OR 3 to 5 mg/kg IV twice weekly.
  • Malignant histiocytosis (clinical): (single agent) oral cyclophosphamide is usually administered at dosages in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.

Malignant lymphoma - mixed small and large cell

  • Dosing Information
  • Malignant lymphoma - mixed small and large cell: (single agent) 40 to 50 mg/kg IV in divided doses over 2 to 5 days OR 10 to 15 mg/kg IV every 7 to 10 days OR 3 to 5 mg/kg IV twice weekly.
  • Malignant lymphoma - mixed small and large cell: (single agent) oral cyclophosphamide is usually administered at dosages in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.

Malignant lymphoma - small lymphocytic, Nodular or diffuse

  • Dosing Information
  • Malignant lymphoma - small lymphocytic, Nodular or diffuse: (single agent) 40 to 50 mg/kg IV in divided doses over 2 to 5 days OR 10 to 15 mg/kg IV every 7 to 10 days OR 3 to 5 mg/kg IV twice weekly.
  • Malignant lymphoma - small lymphocytic, Nodular or diffuse: (single agent) oral cyclophosphamide is usually administered at dosages in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.

Mantle cell lymphoma, Stages III and IV (Ann Arbor staging system)

  • Dosing Information

Multiple myeloma

  • Dosing Information
  • Multiple myeloma: (single agent) 40 to 50 mg/kg IV in divided doses over 2 to 5 days OR 10 to 15 mg/kg IV every 7 to 10 days OR 3 to 5 mg/kg IV twice weekly.
  • Multiple myeloma: (single agent) oral cyclophosphamide is usually administered at dosages in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.

Mycosis fungoides, Advanced

  • Dosing Information
  • Mycosis fungoides, Advanced: (single agent) 40 to 50 mg/kg IV in divided doses over 2 to 5 days OR 10 to 15 mg/kg IV every 7 to 10 days OR 3 to 5 mg/kg IV twice weekly.
  • Mycosis fungoides, Advanced: (single agent) oral cyclophosphamide is usually administered at dosages in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.

Neuroblastoma, Disseminated disease

  • Dosing Information
  • Neuroblastoma, Disseminated disease: (single agent) 40 to 50 mg/kg IV in divided doses over 2 to 5 days OR 10 to 15 mg/kg IV every 7 to 10 days OR 3 to 5 mg/kg IV twice weekly.
  • Neuroblastoma, Disseminated disease: (single agent) oral cyclophosphamide is usually administered at dosages in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.

Non-Hodgkin's lymphoma

  • Dosing Information
  • Non-Hodgkin's lymphoma: (single agent) 40 to 50 mg/kg IV in divided doses over 2 to 5 days OR 10 to 15 mg/kg IV every 7 to 10 days OR 3 to 5 mg/kg IV twice weekly.
  • Non-Hodgkin's lymphoma: (single agent) oral cyclophosphamide is usually administered at dosages in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.

Ovarian carcinoma

  • Dosing Information
  • Ovarian carcinoma: (single agent) 40 to 50 mg/kg IV in divided doses over 2 to 5 days OR 10 to 15 mg/kg IV every 7 to 10 days OR 3 to 5 mg/kg IV twice weekly.
  • Ovarian carcinoma: (single agent) oral cyclophosphamide is usually administered at dosages in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.

Retinoblastoma

  • Dosing Information
  • Retinoblastoma: (single agent) 40 to 50 mg/kg IV in divided doses over 2 to 5 days OR 10 to 15 mg/kg IV every 7 to 10 days OR 3 to 5 mg/kg IV twice weekly.
  • Retinoblastoma: (single agent) oral cyclophosphamide is usually administered at dosages in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

  • There is limited information regarding Off-Label Guideline-Supported Use of Cyclophosphamide in adult patients.

Non–Guideline-Supported Use

  • Bone marrow transplant
  • Pheochromocytoma, Malignant
  • Wegener's granulomatosis

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Acute lymphoid leukemia

  • Dosing Information
  • Acute lymphoid leukemia: (single agent) 40 to 50 mg/kg IV in divided doses over 2 to 5 days OR 10 to 15 mg/kg IV every 7 to 10 days OR 3 to 5 mg/kg IV twice weekly.
  • Acute lymphoid leukemia: (single agent) oral cyclophosphamide is usually administered at dosages in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.
Acute myeloid leukemia
  • Dosing Information
  • Acute myeloid leukemia: (single agent) 40 to 50 mg/kg IV in divided doses over 2 to 5 days OR 10 to 15 mg/kg IV every 7 to 10 days OR 3 to 5 mg/kg IV twice weekly.
  • Acute myeloid leukemia: (single agent) oral cyclophosphamide is usually administered at dosages in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.

Burkitt's lymphoma

  • Dosing Information
  • Burkitt's lymphoma: (single agent) 40 to 50 mg/kg IV in divided doses over 2 to 5 days OR 10 to 15 mg/kg IV every 7 to 10 days OR 3 to 5 mg/kg IV twice weekly.
  • Burkitt's lymphoma: (single agent) oral cyclophosphamide is usually administered at dosages in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.

Chronic lymphoid leukemia

  • Dosing Information
  • Chronic lymphoid leukemia: (single agent) 40 to 50 mg/kg IV in divided doses over 2 to 5 days OR 10 to 15 mg/kg IV every 7 to 10 days OR 3 to 5 mg/kg IV twice weekly.
  • Chronic lymphoid leukemia: (single agent) oral cyclophosphamide is usually administered at dosages in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.

Chronic myeloid leukemia

  • Dosing Information
  • Chronic myeloid leukemia: (single agent) 40 to 50 mg/kg IV in divided doses over 2 to 5 days OR 10 to 15 mg/kg IV every 7 to 10 days OR 3 to 5 mg/kg IV twice weekly.
  • Chronic myeloid leukemia: (single agent) oral cyclophosphamide is usually administered at dosages in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.

Hodgkin's disease, Stages III and IV (Ann Arbor staging system)

  • Dosing Information
  • Hodgkin's disease, Stages III and IV (Ann Arbor staging system): (single agent) 40 to 50 mg/kg IV in divided doses over 2 to 5 days OR 10 to 15 mg/kg IV every 7 to 10 days OR 3 to 5 mg/kg IV twice weekly.
  • Hodgkin's disease, Stages III and IV (Ann Arbor staging system): (single agent) oral cyclophosphamide is usually administered at dosages in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.

Malignant histiocytosis (clinical)

  • Dosing Information
  • Malignant histiocytosis (clinical): (single agent) 40 to 50 mg/kg IV in divided doses over 2 to 5 days OR 10 to 15 mg/kg IV every 7 to 10 days OR 3 to 5 mg/kg IV twice weekly.
  • Malignant histiocytosis (clinical): (single agent) oral cyclophosphamide is usually administered at dosages in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.

Malignant lymphoma - mixed small and large cell

  • Dosing Information
  • Malignant lymphoma - mixed small and large cell: (single agent) 40 to 50 mg/kg IV in divided doses over 2 to 5 days OR 10 to 15 mg/kg IV every 7 to 10 days OR 3 to 5 mg/kg IV twice weekly.
  • Malignant lymphoma - mixed small and large cell: (single agent) oral cyclophosphamide is usually administered at dosages in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.

Malignant lymphoma - small lymphocytic, Nodular or diffuse

  • Dosing Information
  • Malignant lymphoma - small lymphocytic, Nodular or diffuse: (single agent) 40 to 50 mg/kg IV in divided doses over 2 to 5 days OR 10 to 15 mg/kg IV every 7 to 10 days OR 3 to 5 mg/kg IV twice weekly.
  • Malignant lymphoma - small lymphocytic, Nodular or diffuse: (single agent) oral cyclophosphamide is usually administered at dosages in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.

Mantle cell lymphoma, Stages III and IV (Ann Arbor staging system)

  • Dosing Information

Minimal change disease, In patients who fail to respond to or are unable to tolerate adrenocorticosteroid therapy

  • Cyclophosphamide is indicated for the treatment of biopsy proven minimal change nephrotic syndrome in pediatrics patients who failed to adequately respond to or are unable to tolerate adrenocorticosteroid therapy.
  • Dosing Information
  • Minimal change disease, In patients who fail to respond to or are unable to tolerate adrenocorticosteroid therapy: 2 mg/kg ORALLY every day for 8 to 12 weeks; MAX cumulative dose 168 mg/kg; treatment beyond 90 days in males increases probability of sterility.
  • Limitations of Use:
  • The safety and effectiveness for the treatment of nephrotic syndrome in adults or other renal disease has not been established.

Multiple myeloma

  • Dosing Information
  • Multiple myeloma: (single agent) 40 to 50 mg/kg IV in divided doses over 2 to 5 days OR 10 to 15 mg/kg IV every 7 to 10 days OR 3 to 5 mg/kg IV twice weekly.
  • Multiple myeloma: (single agent) oral cyclophosphamide is usually administered at dosages in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.

Mycosis fungoides, Advanced

  • Dosing Information
  • Mycosis fungoides, Advanced: (single agent) 40 to 50 mg/kg IV in divided doses over 2 to 5 days OR 10 to 15 mg/kg IV every 7 to 10 days OR 3 to 5 mg/kg IV twice weekly.
  • Mycosis fungoides, Advanced: (single agent) oral cyclophosphamide is usually administered at dosages in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.

Neuroblastoma, Disseminated disease

  • Dosing Information
  • Neuroblastoma, Disseminated disease: (single agent) 40 to 50 mg/kg IV in divided doses over 2 to 5 days OR 10 to 15 mg/kg IV every 7 to 10 days OR 3 to 5 mg/kg IV twice weekly.
  • Neuroblastoma, Disseminated disease: (single agent) oral cyclophosphamide is usually administered at dosages in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.

Non-Hodgkin's lymphoma

  • Dosing Information
  • Non-Hodgkin's lymphoma: (single agent) 40 to 50 mg/kg IV in divided doses over 2 to 5 days OR 10 to 15 mg/kg IV every 7 to 10 days OR 3 to 5 mg/kg IV twice weekly.
  • Non-Hodgkin's lymphoma: (single agent) oral cyclophosphamide is usually administered at dosages in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.

Ovarian carcinoma

  • Dosing Information
  • Ovarian carcinoma: (single agent) 40 to 50 mg/kg IV in divided doses over 2 to 5 days OR 10 to 15 mg/kg IV every 7 to 10 days OR 3 to 5 mg/kg IV twice weekly.
  • Ovarian carcinoma: (single agent) oral cyclophosphamide is usually administered at dosages in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.

Retinoblastoma

  • Dosing Information
  • Retinoblastoma: (single agent) 40 to 50 mg/kg IV in divided doses over 2 to 5 days OR 10 to 15 mg/kg IV every 7 to 10 days OR 3 to 5 mg/kg IV twice weekly.
  • Retinoblastoma: (single agent) oral cyclophosphamide is usually administered at dosages in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

  • There is limited information regarding Off-Label Guideline-Supported Use of Cyclophosphamide in pediatric patients.

Non–Guideline-Supported Use

  • There is limited information regarding Off-Label Non–Guideline-Supported Use of Cyclophosphamide in pediatric patients.

Contraindications

Hypersensitivity

  • Cyclophosphamide is contraindicated in patients who have a history of severe hypersensitivity reactions to it, any of its metabolites, or to other components of the product. Anaphylactic reactions including death have been reported with cyclophosphamide. Possible cross-sensitivity with other alkylating agents can occur.

Urinary Outflow Obstruction

Warnings

Myelosuppression, Immunosuppression, Bone Marrow Failure and Infections

  • Antimicrobial prophylaxis may be indicated in certain cases of neutropenia at the discretion of the managing physician. In case of neutropenic fever, antibiotic therapy is indicated. Antimycotics and/or antivirals may also be indicated.
  • Monitoring of complete blood counts is essential during cyclophosphamide treatment so that the dose can be adjusted, if needed. Cyclophosphamide should not be administered to patients with neutrophils ≤1,500/mm3 and platelets <50,000/mm3. Cyclophosphamide treatment may not be indicated, or should be interrupted, or the dose reduced, in patients who have or who develop a serious infection. G-CSF may be administered to reduce the risks of neutropenia complications associated with cyclophosphamide use. Primary and secondary prophylaxis with G-CSF should be considered in all patients considered to be at increased risk for neutropenia complications. The nadirs of the reduction in leukocyte count and thrombocyte count are usually reached in weeks 1 and 2 of treatment. Peripheral blood cell counts are expected to normalize after approximately 20 days. Bone marrow failure has been reported. Severe myelosuppression may be expected particularly in patients pretreated with and/or receiving concomitant chemotherapy and/or radiation therapy.

Urinary Tract and Renal Toxicity

  • Hemorrhagic cystitis, pyelitis, ureteritis, and hematuria have been reported with cyclophosphamide. Medical and/ or surgical supportive treatment may be required to treat protracted cases of severe hemorrhagic cystitis. Discontinue cyclophosphamide therapy in case of severe hemorrhagic cystitis. Urotoxicity (bladder ulceration, necrosis, fibrosis, contracture and secondary cancer) may require interruption of cyclophosphamide treatment or cystectomy. Urotoxicity can be fatal. Urotoxicity can occur with short-term or long-term use of cyclophosphamide.
  • Before starting treatment, exclude or correct any urinary tract obstructions. Urinary sediment should be checked regularly for the presence of erythrocytes and other signs of urotoxicity and/or nephrotoxicity. Cyclophosphamide should be used with caution, if at all, in patients with active urinary tract infections. Aggressive hydration with forced diuresis and frequent bladder emptying can reduce the frequency and severity of bladder toxicity. Mesna has been used to prevent severe bladder toxicity.

Cardiotoxicity

  • The risk of cardiotoxicity may be increased with high doses of cyclophosphamide, in patients with advanced age, and in patients with previous radiation treatment to the cardiac region and/or previous or concomitant treatment with other cardiotoxic agents.
  • Particular caution is necessary in patients with risk factors for cardiotoxicity and in patients with pre-existing cardiac disease.
  • Monitor patients with risk factors for cardiotoxicity and with pre-existing cardiac disease.

Pulmonary Toxicity

  • Pneumonitis, pulmonary fibrosis, pulmonary veno-occlusive disease and other forms of pulmonary toxicity leading to respiratory failure have been reported during and following treatment with cyclophosphamide. Late onset pneumonitis (greater than 6 months after start of cyclophosphamide) appears to be associated with increased mortality. Pneumonitis may develop years after treatment with cyclophosphamide.
  • Monitor patients for signs and symptoms of pulmonary toxicity.

Secondary Malignancies

Veno-occlusive Liver Disease

  • Veno-occlusive liver disease (VOD) including fatal outcome has been reported in patients receiving cyclophosphamide­- containing regimens. A cytoreductive regimen in preparation for bone marrow transplantation that consists of cyclophosphamide in combination with whole-body irradiation, busulfan, or other agents has been identified as a major risk factor. VOD has also been reported to develop gradually in patients receiving long-term low-dose immunosuppressive doses of cyclophosphamide. Other risk factors predisposing to the development of VOD include preexisting disturbances of hepatic function, previous radiation therapy of the abdomen, and a low performance status.

Embryo-Fetal Toxicity

  • Cyclophosphamide can cause fetal harm when administered to a pregnant woman. Exposure to cyclophosphamide during pregnancy may cause birth defects, miscarriage, fetal growth retardation, and fetotoxic effects in the newborn. Cyclophosphamide is teratogenic and embryo-fetal toxic in mice, rats, rabbits and monkeys.
  • Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception during treatment and for up to 1 year after completion of therapy.

Infertility

  • Male and female reproductive function and fertility may be impaired in patients being treated with cyclophosphamide. Cyclophosphamide interferes with oogenesis and spermatogenesis. It may cause sterility in both sexes. Development of sterility appears to depend on the dose of cyclophosphamide, duration of therapy, and the state of gonadal function at the time of treatment. Cyclophosphamide-induced sterility may be irreversible in some patients. Advise patients on the potential risks for infertility [see Use in Specific Populations (8.4 and 8.6)].

Impairment of Wound Healing

  • Cyclophosphamide may interfere with normal wound healing.

Hyponatremia

  • Hyponatremia associated with increased total body water, acute water intoxication, and a syndrome resembling SIADH (syndrome of inappropriate secretion of antidiuretic hormone), which may be fatal, has been reported.

Adverse Reactions

Clinical Trials Experience

  • The following adverse reactions are discussed in more detail in other sections of the labeling.

Common Adverse Reactions

Hematopoietic system:

  • Neutropenia occurs in patients treated with cyclophosphamide. 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.

Gastrointestinal system:

Skin and its structures:

  • Alopecia occurs in patients treated with cyclophosphamide. Skin rash occurs occasionally in patients receiving the drug. Pigmentation of the skin and changes in nails can occur.

Postmarketing Experience

  • The following adverse reactions have been identified from clinical trials or post-marketing surveillance. Because they are reported from a population from unknown size, precise estimates of frequency cannot be made.
  • Psychiatric: confusional state.

Drug Interactions

  • An increase of the concentration of cytotoxic metabolites may occur with:
  • Protease inhibitors: Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen.
  • Combined or sequential use of cyclophosphamide and other agents with similar toxicities can potentiate toxicities.
  • Increased hematotoxicity and/or immunosuppression may result from a combined effect of cyclophosphamide and, for example:
  • Increased cardiotoxicity may result from a combined effect of cyclophosphamide and, for example:
  • Increased pulmonary toxicity may result from a combined effect of cyclophosphamide and, for example:
  • Amiodarone
  • G-CSF, GM-CSF (granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor): Reports suggest an increased risk of :*pulmonary toxicity in patients treated with cytotoxic chemotherapy that includes cyclophosphamide and G-CSF or GMCSF.
  • Increased nephrotoxicity may result from a combined effect of cyclophosphamide and, for example:
  • Increase in other toxicities:
  • Increased risk of hemorrhagic cystitis may result from a combined effect of cyclophosphamide and past or concomitant radiation treatment.
  • Etanercept: In patients with Wegener's granulomatosis, the addition of etanercept to standard treatment, including cyclophosphamide, was associated with a higher incidence of non-cutaneous malignant solid tumors.
  • Metronidazole: Acute encephalopathy has been reported in a patient receiving cyclophosphamide and metronidazole. Causal association is unclear. In an animal study, the combination of cyclophosphamide with metronidazole was associated with increased cyclophosphamide toxicity.
  • Tamoxifen: Concomitant use of tamoxifen and chemotherapy may increase the risk of thromboembolic complications.
  • Coumarins: Both increased and decreased warfarin effect have been reported in patients receiving warfarin and cyclophosphamide.
  • Cyclosporine: Lower serum concentrations of cyclosporine have been observed in patients receiving a combination of cyclophosphamide and cyclosporine than in patients receiving only cyclosporine. This interaction may result in an increased incidence of graft-versus-host disease.
  • Depolarizing muscle relaxants: Cyclophosphamide treatment causes a marked and persistent inhibition of cholinesterase activity. Prolonged apnea may occur with concurrent depolarizing muscle relaxants (e.g., succinylcholine). If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, alert the anesthesiologist.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): D Pregnancy Category D

Risk Summary

  • Cyclophosphamide can cause fetal harm when administered to a pregnant woman based on its mechanism of action and published reports of effects in pregnant patients or animals. Exposure to cyclophosphamide during pregnancy may cause fetal malformations, miscarriage, fetal growth retardation, and toxic effects in the newborn. Cyclophosphamide is teratogenic and embryo-fetal toxic in mice, rats, rabbits and monkeys. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

Human Data

  • Malformations of the skeleton, palate, limbs and eyes as well as miscarriage have been reported after exposure to cyclophosphamide in the first trimester. Fetal growth retardation and toxic effects manifesting in the newborn, including leukopenia, anemia, pancytopenia, severe bone marrow hypoplasia, and gastroenteritis have been reported after exposure to cyclophosphamide.

Animal Data

  • Administration of cyclophosphamide to pregnant mice, rats, rabbits and monkeys during the period of organogenesis at doses at or below the dose in patients based on body surface area resulted in various malformations, which included neural tube defects, limb and digit defects and other skeletal anomalies, cleft lip and palate, and reduced skeletal ossification.


Pregnancy Category (AUS):

  • Australian Drug Evaluation Committee (ADEC) Pregnancy Category
  • There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cyclophosphamide in women who are pregnant.

Labor and Delivery

  • There is no FDA guidance on use of Cyclophosphamide during labor and delivery.

Nursing Mothers

  • Cyclophosphamide is present in breast milk. Neutropenia, thrombocytopenia, low hemoglobin, and diarrhea have been reported in infants breast fed by women treated with cyclophosphamide. Because of the potential for serious adverse reactions in nursing infants from cyclophosphamide, 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

  • Pre-pubescent girls treated with cyclophosphamide generally develop secondary sexual characteristics normally and have regular menses. Ovarian fibrosis with apparently complete loss of germ cells after prolonged cyclophosphamide treatment in late pre-pubescence has been reported. Girls treated with cyclophosphamide who have retained ovarian function after completing treatment are at increased risk of developing premature menopause.
  • Pre-pubescent boys treated with cyclophosphamide develop secondary sexual characteristics normally, but may have oligospermia or azoospermia and increased gonadotropin secretion. Some degree of testicular atrophy may occur.
  • Cyclophosphamide-induced azoospermia is reversible in some patients, though the reversibility may not occur for several years after cessation of therapy.

Geriatic Use

  • There is insufficient data from clinical studies of cyclophosphamide available for patients 65 years of age and older to determine whether they respond differently than younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac functioning, and of concomitant disease or other drug therapy.

Gender

  • There is no FDA guidance on the use of Cyclophosphamide with respect to specific gender populations.

Race

  • There is no FDA guidance on the use of Cyclophosphamide with respect to specific racial populations.

Renal Impairment

  • In patients with severe renal impairment, decreased renal excretion may result in increased plasma levels of cyclophosphamide and its metabolites. This may result in increased toxicity. Monitor patients with severe renal impairment (CrCl =10 mL/min to 24 mL/min) for signs and symptoms of toxicity.
  • Cyclophosphamide and its metabolites are dialyzable although there are probably quantitative differences depending upon the dialysis system being used. In patients requiring dialysis, use of a consistent interval between cyclophosphamide administration and dialysis should be considered.

Hepatic Impairment

  • Patients with severe hepatic impairment have reduced conversion of cyclophosphamide to the active 4-hydroxyl metabolite, potentially reducing efficacy.

Females of Reproductive Potential and Males

Contraception

  • Pregnancy should be avoided during treatment with cyclophosphamide because of the risk of fetal harm.
  • Female patients of reproductive potential should use highly effective contraception during and for up to 1 year after completion of treatment.
  • Male patients who are sexually active with female partners who are or may become pregnant should use a condom during and for at least 4 months after treatment.

Infertility

Females

  • Amenorrhea, transient or permanent, associated with decreased estrogen and increased gonadotropin secretion develops in a proportion of women treated with cyclophosphamide. Affected patients generally resume regular menses within a few months after cessation of therapy. The risk of premature menopause with cyclophosphamide increases with age. Oligomenorrhea has also been reported in association with cyclophosphamide treatment.
  • Animal data suggest an increased risk of failed pregnancy and malformations may persist after discontinuation of cyclophosphamide as long as oocytes/follicles exist that were exposed to cyclophosphamide during any of their maturation phases. The exact duration of follicular development in humans is not known, but may be longer than 12 months.

Males

  • Men treated with cyclophosphamide may develop oligospermia or azoospermia which are normally associated with increased gonadotropin but normal testosterone secretion.

Immunocompromised Patients

There is no FDA guidance one the use of Cyclophosphamide in patients who are immunocompromised.

Administration and Monitoring

Administration

  • During or immediately after the administration, adequate amounts of fluid should be ingested or infused to force diuresis in order to reduce the risk of urinary tract toxicity. Therefore, cyclophosphamide should be administered in the morning.

Dosing for Malignant Diseases

Adults and Pediatric Patients

Intravenous

  • When used as the only oncolytic drug therapy, the initial course of cyclophosphamide for patients with no hematologic deficiency usually consists of 40 mg per kg to 50 mg per kg given intravenously in divided doses over a period of 2 to 5 days. Other intravenous regimens include 10 mg per kg to 15 mg per kg given every 7 to 10 days or 3 mg per kg to 5 mg per kg twice weekly.

Oral

  • Oral cyclophosphamide dosing is usually in the range of 1 mg per kg per day to 5 mg per kg per day for both initial and maintenance dosing.
  • Many other regimens of intravenous and oral cyclophosphamide have been reported. Dosages must be adjusted in accord with evidence of antitumor activity and/ or leukopenia. The total leukocyte count is a good, objective guide for regulating dosage.
  • When cyclophosphamide is included in combined cytotoxic regimens, it may be necessary to reduce the dose of cyclophosphamide as well as that of the other drugs.

Dosing for Minimal Change Nephrotic Syndrome in Pediatric Patients

  • An oral dose of 2 mg per kg daily for 8 to 12 weeks (maximum cumulative dose 168 mg per kg) is recommended. Treatment beyond 90 days increases the probability of sterility in males.

Preparation, Handling and Administration

  • Handle and dispose of cyclophosphamide in a manner consistent with other cytotoxic drugs.1 Caution should be exercised when handling and preparing Cyclophosphamide for Injection, USP. To minimize the risk of dermal exposure, always wear gloves when handling vials containing Cyclophosphamide for Injection, USP.

Cyclophosphamide for Injection, USP

Intravenous Administration

  • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use cyclophosphamide vials if there are signs of melting. Melted cyclophosphamide is a clear or yellowish viscous liquid usually found as a connected phase or in droplets in the affected vials.
  • Cyclophosphamide does not contain any antimicrobial preservative and thus care must be taken to assure the sterility of prepared solutions. Use aseptic technique.

For Direct Intravenous Injection

  • Reconstitute Cyclophosphamide with 0.9% Sodium Chloride Injection, USP only, using the volumes listed below in Table 1. Gently swirl the vial to dissolve the drug completely. Do not use Sterile Water for Injection, USP because it results in a hypotonic solution and should not be injected directly.
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For Intravenous Infusion

  • Reconstitution of Cyclophosphamide:
  • Reconstitute Cyclophosphamide using 0.9% Sodium Chloride Injection, USP or Sterile Water for Injection, USP with the volume of diluent listed below in Table 2. Add the diluent to the vial and gently swirl to dissolve the drug completely.
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  • Dilution of Reconstituted Cyclophosphamide:
  • Further dilute the reconstituted Cyclophosphamide solution to a minimum concentration of 2 mg per mL with any of the following diluents:
  • 5% Dextrose Injection, USP
  • 5% Dextrose and 0.9% Sodium Chloride Injection, USP
  • 0.45% Sodium Chloride Injection, USP
  • To reduce the likelihood of adverse reactions that appear to be administration rate-dependent (e.g., facial swelling, headache, nasal congestion, scalp burning), cyclophosphamide should be injected or infused very slowly. Duration of the infusion also should be appropriate for the volume and type of carrier fluid to be infused.
  • Storage of Reconstituted and Diluted Cyclophosphamide Solution:
  • If not used immediately, for microbiological integrity, cyclophosphamide solutions should be stored as described in Table 3.
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Use of Reconstituted Solution for Oral Administration

  • Liquid preparations of cyclophosphamide for oral administration may be prepared by dissolving cyclophosphamide for injection in Aromatic Elixir, National Formulary (NF). Such preparations should be stored under refrigeration in glass containers and used within 14 days.

DOSAGE FORMS AND STRENGTHS

  • Cyclophosphamide for Injection, USP is a sterile white powder available in
  • 500 mg
  • 1 g
  • 2 g

Monitoring

  • There is limited information regarding Monitoring of Cyclophosphamide in the drug label.
  • Description

IV Compatibility

  • There is limited information regarding IV Compatibility of Cyclophosphamide in the drug label.

Overdosage

  • No specific antidote for cyclophosphamide is known.
  • Overdosage should be managed with supportive measures, including appropriate treatment for any concurrent infection, myelosuppression, or cardiac toxicity should it occur.
  • Serious consequences of overdosage include manifestations of dose dependent toxicities such as myelosuppression, urotoxicity, cardiotoxicity (including cardiac failure), veno-occlusive hepatic disease, and stomatitis.
  • Patients who received an overdose should be closely monitored for the development of toxicities, and hematologic toxicity in particular.
  • Cyclophosphamide and its metabolites are dialyzable. Therefore, rapid hemodialysis is indicated when treating any suicidal or accidental overdose or intoxication.
  • Cystitis prophylaxis with mesna may be helpful in preventing or limiting urotoxic effects with cyclophosphamide overdose.

Pharmacology

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Mechanism of Action

  • The mechanism of action is thought to involve cross-linking of tumor cell DNA.

Structure

  • Cyclophosphamide is a synthetic antineoplastic drug chemically related to the nitrogen mustards. The chemical name for cyclophosphamide is 2-[bis(2-chloroethyl)amino] tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide monohydrate, and has the following structural formula:
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  • Cyclophosphamide is a white crystalline powder with the molecular formula C7H15Cl2N2O2P•H2O and a molecular weight of 279.1. Cyclophosphamide is soluble in water, saline, or ethanol.
  • Cyclophosphamide for Injection, USP is for intravenous or oral use, it has no inactive ingredients. When reconstituted in water Cyclophosphamide for Injection, USP has a pH range of 3.0 to 9.0.
  • Cyclophosphamide for Injection, USP is a sterile white powder available as 500 mg, 1 g, and 2 g strength vials.
  • 500 mg vial contains 534.5 mg cyclophosphamide monohydrate equivalent to 500 mg cyclophosphamide
  • 1 g vial contains 1069.0 mg cyclophosphamide monohydrate equivalent to 1 g cyclophosphamide
  • 2 g vial contains 2138.0 mg cyclophosphamide monohydrate equivalent to 2 g cyclophosphamide

Pharmacodynamics

  • Cyclophosphamide is biotransformed principally in the liver to active alkylating metabolites by a mixed function microsomal oxidase system. These metabolites interfere with the growth of susceptible rapidly proliferating malignant cells.

Pharmacokinetics

  • Following IV administration, elimination half-life (t1/2) ranges from 3 to 12 hours with total body clearance (CL) values of 4 to 5.6 L/h. Pharmacokinetics are linear over the dose range used clinically. When cyclophosphamide was administered at 4.0 g/m2 over a 90 minutes infusion, saturable elimination in parallel with first-order renal elimination describe the kinetics of the drug.

Absorption

  • After oral administration, peak concentrations of cyclophosphamide occurred at one hour. Area under the curve ratio for the drug after oral and IV administration (AUCpo : AUCiv) ranged from 0.87 to 0.96.

Distribution

  • Approximately 20% of cyclophosphamide is protein bound, with no dose dependent changes. Some metabolites are protein bound to an extent greater than 60%. Volume of distribution approximates total body water (30 to 50 L).

Metabolism

  • The liver is the major site of cyclophosphamide activation. Approximately 75% of the administered dose of cyclophosphamide is activated by hepatic microsomal cytochrome P450s including CYP2A6, 2B6, 3A4, 3A5, 2C9, 2C18 and 2C19, with 2B6 displaying the highest 4-hydroxylase activity. Cyclophosphamide is activated to form 4-hydroxycyclophosphamide, which is in equilibrium with its ring-open tautomer aldophosphamide. 4-hydroxycyclophosphamide and aldophosphamide can undergo oxidation by aldehyde dehydrogenases to form the inactive metabolites 4-ketocyclophosphamide and carboxyphosphamide, respectively. Aldophosphamide can undergo B-elimination to form active metabolites phosphoramide mustard and acrolein. This spontaneous conversion can be catalyzed by albumin and other proteins.
  • Less than 5% of cyclophosphamide may be directly detoxified by side chain oxidation, leading to the formation of inactive metabolites 2-dechloroethylcyclophosphamide. At high doses, the fraction of parent compound cleared by 4-hydroxylation is reduced resulting in non-linear elimination of cyclophosphamide in patients. Cyclophosphamide appears to induce its own metabolism. Auto-induction results in an increase in the total clearance, increased formation of 4-hydroxyl metabolites and shortened t1/2 values following repeated administration at 12- to 24-hour interval.

Elimination

  • Cyclophosphamide is primarily excreted as metabolites. 10 to 20% is excreted unchanged in the urine and 4% is excreted in the bile following IV administration.

Special Populations

Renal Impairment

  • The pharmacokinetics of cyclophosphamide were determined following one-hour intravenous infusion to renally impaired patients. The results demonstrated that the systemic exposure to cyclophosphamide increased as the renal function decreased. Mean dose-corrected AUC increased by 38% in the moderate renal group,(Creatinine clearance (CrCl of 25 to 50 mL/min), by 64% in the severe renal group (CrCl of 10 to 24 mL/min) and by 23% in the hemodialysis group (CrCl of <10 mL/min) compared to the control group. The increase in exposure was significant in the severe group (p>0.05); thus, patients with severe renal impairment should be closely monitored for toxicity [see Use in Specific Populations (8.7)].
  • The dialyzability of cyclophosphamide was investigated in four patients on long-term hemodialysis. Dialysis clearance calculated by arterial-venous difference and actual drug recovery in dialysate averaged 104 mL/min, which is in the range of the metabolic clearance of 95 mL/min for the drug. A mean of 37% of the administered dose of cyclophosphamide was removed during hemodialysis. The elimination half-life (t1/2) was 3.3 hours in patients during hemodialysis, a 49% reduction of the 6.5 hours to t1/2 reported in uremic patients. Reduction in t1/2, larger dialysis clearance than metabolic clearance, high extraction efficiency, and significant drug removal during dialysis, suggest that cyclophosphamide is dialyzable.

Hepatic Impairment

  • Total body clearance (CL) of cyclophosphamide is decreased by 40% in patients with severe hepatic impairment and elimination half-life (t1/2) is prolonged by 64%. Mean CL and t1/2 were 45 ± 8.6 L/kg and 12.5 ± 1.0 hours respectively, in patients with severe hepatic impairment and 63 ± 7.6 L/kg and 7.6 ± 1.4 hours respectively in the control group.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

  • Cyclophosphamide administered by different routes, including intravenous, subcutaneous or intraperitoneal injection, or in drinking water, caused tumors in both mice and rats. In addition to leukemia and lymphoma, benign and malignant tumors were found at various tissue sites, including urinary bladder, mammary gland, lung, liver, and injection site.
  • Cyclophosphamide was mutagenic and clastogenic in multiple in vitro and in vivo genetic toxicology studies.
  • Cyclophosphamide is genotoxic in male and female germ cells. Animal data indicate that exposure of oocytes to cyclophosphamide during follicular development may result in a decreased rate of implantations and viable pregnancies, and in an increased risk of malformations. Male mice and rats treated with cyclophosphamide show alterations in male reproductive organs (e.g., decreased weights, atrophy, changes in spermatogenesis), and decreases in reproductive potential (e.g., decreased implantations and increased post-implantation loss) and increases in fetal malformations when mated with untreated females.

Clinical Studies

There is limited information regarding Clinical Studies of Cyclophosphamide in the drug label.

How Supplied

  • Cyclophosphamide for Injection, USP is a sterile white powder containing cyclophosphamide and is supplied in vials for single dose use.
  • Cyclophosphamide for Injection, USP
  • NDC 0781-3233-94- 500 mg vial, carton of 1
  • NDC 0781-3244-94- 1 g vial, carton of 1
  • NDC 0781-3255-94- 2 g vial, carton of 1

Storage

  • Store vials at or below 25°C (77°F). During transport or storage of cyclophosphamide vials, temperature influences can lead to melting of the active ingredient, cyclophosphamide.
  • Cyclophosphamide is an antineoplastic product. Follow special handling and disposal procedures.

Images

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Patient Counseling Information

Advise the patient of the following:

  • Inform patients of the possibility of myelosuppression, immunosuppression, and infections. Explain the need for routine blood cell counts. Instruct patients to monitor their temperature frequently and immediately report any occurrence of fever.
  • Advise the patient to report urinary symptoms (patients should report if their urine has turned a pink or red color) and the need for increasing fluid intake and frequent voiding.
  • Advise patients to contact a healthcare professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, palpitations, weight gain of more than 5 pounds in 24 hours, dizziness or loss of consciousness.
  • Warn patients of the possibility of developing non-infectious pneumonitis. Advise patients to report promptly any new or worsening respiratory symptoms.
  • Advise female patients of reproductive potential to use highly effective contraception during treatment and for up to 1year after completion of therapy. There is a potential for harm to a fetus if a patient becomes pregnant during this period. Patients should immediately contact their healthcare provider if they become pregnant or if pregnancy is suspected during this period.
  • Advise male patients who are sexually active with a female partner who is or may become pregnant to use condoms during treatment and for up to 4 months after completion of therapy. There is a potential for harm to a fetus if a patient fathers a child during this period. Patients should immediately contact their healthcare provider if their female partner becomes pregnant or if pregnancy is suspected during this period.
  • Advise nursing mothers treated with cyclophosphamide to discontinue nursing or discontinue cyclophosphamide, taking into account the importance of the drug to the mother.
  • Explain to patients that side effects such as nausea, vomiting, stomatitis, impaired wound healing, amenorrhea, premature menopause, sterility and hair loss may be associated with cyclophosphamide administration. Other undesirable effects (including, e.g., dizziness, blurred vision, visual impairment) could affect the ability to drive or use machines.

Precautions with Alcohol

  • Alcohol-Cyclophosphamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

  • Cytoxan
  • Cytoxan Lyophilized

Look-Alike Drug Names

There is limited information regarding Cyclophosphamide Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.


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