Cyclophosphamide

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]

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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

• Mantle cell lymphoma, 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.
• Mantle cell lymphoma, 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.

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

• Mantle cell lymphoma, 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.
• Mantle cell lymphoma, 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.

Minimal change disease, In patients who fail to 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.

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

• Cyclophosphamide is contraindicated in patients with urinary outflow obstruction.

Warnings

Myelosuppression, Immunosuppression, Bone Marrow Failure and Infections

• Cyclophosphamide can cause myelosuppression (leukopenia, neutropenia, thrombocytopenia and anemia), bone marrow failure, and severe immunosuppression which may lead to serious and sometimes fatal infections, including sepsis and septic shock. Latent infections can be reactivated.

• 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

• Myocarditis, myopericarditis, pericardial effusion including cardiac tamponade, and congestive heart failure, which may be fatal, have been reported with cyclophosphamide therapy.

• Supraventricular arrhythmias (including atrial fibrillation and flutter) and ventricular arrhythmias (including severe QT prolongation associated with ventricular tachyarrhythmia) have been reported after treatment with regimens that included cyclophosphamide.

• 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

• Cyclophosphamide is genotoxic. Secondary malignancies (urinary tract cancer, myelodysplasia, acute leukemias, lymphomas, thyroid cancer, and sarcomas) have been reported in patients treated with cyclophosphamide-containing regimens. The risk of bladder cancer may be reduced by prevention of hemorrhagic cystitis.

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.

• Hypersensitivity.
• Myelosuppression, Immunosuppression, Bone Marrow Failure, and Infections
• Urinary Tract and Renal Toxicity
• Cardiotoxicity
• Pulmonary Toxicity
• Secondary Malignancies
• Veno-occlusive Liver Disease
• Embryo-Fetal Toxicity
• Reproductive System Toxicity
• Impaired Wound Healing
• Hyponatremia

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:

• Nausea and vomiting 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.

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.

• Cardiac: cardiac arrest, ventricular fibrillation, ventricular tachycardia, cardiogenic shock, pericardial effusion (progressing to cardiac tamponade), myocardial hemorrhage, myocardial infarction, cardiac failure (including fatal outcomes), cardiomyopathy, myocarditis, pericarditis, carditis, atrial fibrillation, supraventricular arrhythmia, ventricular arrhythmia, bradycardia, tachycardia, palpitations, QT prolongation.

• Congenital, Familial and Genetic: intra-uterine death, fetal malformation, fetal growth retardation, fetal toxicity (including myelosuppression, gastroenteritis).

• Ear and Labyrinth: deafness, hearing impaired, tinnitus.

• Endocrine: water intoxication.

• Eye: visual impairment, conjunctivitis, lacrimation.

• Gastrointestinal: gastrointestinal hemorrhage, acute pancreatitis, colitis, enteritis, cecitis, stomatitis, constipation, parotid gland inflammation.

• General Disorders and Administrative Site Conditions: multiorgan failure, general physical deterioration, influenza-like illness, injection/infusion site reactions (thrombosis, necrosis, phlebitis, inflammation, pain, swelling, erythema), pyrexia, edema, chest pain, mucosal inflammation, asthenia, pain, chills, fatigue, malaise, headache.

• Hematologic: myelosuppression, bone marrow failure, disseminated intravascular coagulation and hemolytic uremic syndrome (with thrombotic microangiopathy).

• Hepatic: veno-occlusive liver disease, cholestatic hepatitis, cytolytic hepatitis, hepatitis, cholestasis; hepatotoxicity with hepatic failure, hepatic encephalopathy, ascites, hepatomegaly, blood bilirubin increased, hepatic function abnormal, hepatic enzymes increased.

• Immune: immunosuppression, anaphylactic shock and hypersensitivity reaction.

• Infections: The following manifestations have been associated with myelosuppression and immunosuppression caused by cyclophosphamide: increased risk for and severity of pneumonias (including fatal outcomes), other bacterial, fungal, viral, protozoal and, parasitic infections; reactivation of latent infections, (including viral hepatitis, tuberculosis), Pneumocystis jiroveci, herpes zoster, Strongyloides, sepsis and septic shock.

• Investigations: blood lactate dehydrogenase increased, C-reactive protein increased.

• Metabolism and Nutrition: hyponatremia, fluid retention, blood glucose increased, blood glucose decreased.

• Musculoskeletal and Connective Tissue: rhabdomyolysis, scleroderma, muscle spasms, myalgia, arthralgia.

• Neoplasms: acute leukemia, myelodysplastic syndrome, lymphoma, sarcomas, renal cell carcinoma, renal pelvis cancer, bladder cancer, ureteric cancer, thyroid cancer.

• Nervous System: encephalopathy, convulsion, dizziness, neurotoxicity has been reported and manifested as reversible posterior leukoencephalopathy syndrome, myelopathy, peripheral neuropathy, polyneuropathy, neuralgia, dysesthesia, hypoesthesia, paresthesia, tremor, dysgeusia, hypogeusia, parosmia.

• Pregnancy: premature labor.

• Psychiatric: confusional state.

• Renal and Urinary: renal failure, renal tubular disorder, renal impairment, nephropathy toxic, hemorrhagic cystitis, bladder necrosis, cystitis ulcerative, bladder contracture, hematuria, nephrogenic diabetes insipidus, atypical urinary bladder epithelial cells.

• Reproductive System: infertility, ovarian failure, ovarian disorder, amenorrhea, oligomenorrhea, testicular atrophy, azoospermia, oligospermia.

• Respiratory: pulmonary veno-occlusive disease, acute respiratory distress syndrome, interstitial lung disease as manifested by respiratory failure (including fatal outcomes), obliterative bronchiolitis, organizing pneumonia, alveolitis allergic, pneumonitis, pulmonary hemorrhage; respiratory distress, pulmonary hypertension, pulmonary edema, pleural effusion, bronchospasm, dyspnea, hypoxia, cough, nasal congestion, nasal discomfort, oropharyngeal pain, rhinorrhea.

• Skin and Subcutaneous Tissue: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, palmar-plantar erythrodysesthesia syndrome, radiation recall dermatitis, toxic skin eruption, urticaria, dermatitis, blister, pruritus, erythema, nail disorder, facial swelling, hyperhidrosis.

• Tumor lysis syndrome: like other cytotoxic drugs, cyclophosphamide may induce tumor-lysis syndrome and hyperuricemia in patients with rapidly growing tumors.

• Vascular: pulmonary embolism, venous thrombosis, vasculitis, peripheral ischemia, hypertension, hypotension, flushing, hot flush.

Drug Interactions

• Cyclophosphamide is a pro-drug that is activated by cytochrome P450s.

• 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:

• ACE inhibitors: ACE inhibitors can cause leukopenia.
• Natalizumab
• Paclitaxel: Increased hematotoxicity has been reported when cyclophosphamide was administered after paclitaxel infusion.
• Thiazide diuretics
• Zidovudine

• Increased cardiotoxicity may result from a combined effect of cyclophosphamide and, for example:

• Anthracyclines
• Cytarabine
• ppPentostatin]]
• Radiation therapy of the cardiac region
• Trastuzumab

• 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:

• Amphotericin B
• Indomethacin: Acute water intoxication has been reported with concomitant use of indomethacin

• Increase in other toxicities:

• Azathioprine: Increased risk of hepatotoxicity (liver necrosis)
• Busulfan: Increased incidence of hepatic veno-occlusive disease and mucositis has been reported.
• Protease inhibitors: Increased incidence of mucositis

• 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):

• Pregnancy Category

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

There is no FDA guidance on the use of Cyclophosphamide with respect to nursing mothers.

Pediatric Use

There is no FDA guidance on the use of Cyclophosphamide with respect to pediatric patients.

Geriatic Use

There is no FDA guidance on the use of Cyclophosphamide with respect to geriatric patients.

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

There is no FDA guidance on the use of Cyclophosphamide in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Cyclophosphamide in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Cyclophosphamide in women of reproductive potentials and males.

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.

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.

• 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.

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

Acute Overdose

Signs and Symptoms

• Description

Management

• Description

Chronic Overdose

There is limited information regarding Chronic Overdose of Cyclophosphamide in the drug label.

Pharmacology

There is limited information regarding Cyclophosphamide Pharmacology in the drug label.

Mechanism of Action

Structure

File:Cyclophosphamide01.png

This image is provided by the National Library of Medicine.

Pharmacodynamics

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

Pharmacokinetics

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

Nonclinical Toxicology

There is limited information regarding Nonclinical Toxicology of Cyclophosphamide in the drug label.

Clinical Studies

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

How Supplied

Storage

There is limited information regarding Cyclophosphamide Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Patient Counseling Information of Cyclophosphamide in the drug label.

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

• ®

Look-Alike Drug Names

• A® — B®

Drug Shortage Status

Price

References

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

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