Generic: CYCLOPHOSPHAMIDE
1 INDICATIONS AND USAGE Cyclophosphamide for injection is an alkylating drug indicated for treatment of adults and pediatric patients with: Malignant Diseases: malignant lymphomas: Hodgkin’s disease, lymphocytic lymphoma, mixed-cell type lymphoma, histiocytic lymphoma, Burkitt’s lymphoma; multiple myeloma, leukemias, mycosis fungoides, neuroblastoma, adenocarcinoma of ovary, retinoblastoma, breast carcinoma ( 1.1 ) Minimal Change Nephrotic Syndrome in Pediatric Patients: biopsy proven minimal ch...
1 INDICATIONS AND USAGE Cyclophosphamide for injection is an alkylating drug indicated for treatment of adults and pediatric patients with: Malignant Diseases: malignant lymphomas: Hodgkin’s disease, lymphocytic lymphoma, mixed-cell type lymphoma, histiocytic lymphoma, Burkitt’s lymphoma; multiple myeloma, leukemias, mycosis fungoides, neuroblastoma, adenocarcinoma of ovary, retinoblastoma, breast carcinoma ( 1.1 ) Minimal Change Nephrotic Syndrome in Pediatric Patients: biopsy proven minimal change nephrotic syndrome patients who failed to adequately respond to or are unable to tolerate adrenocorticosteroid therapy ( 1.2 ) Limitations of Use: The safety and effectiveness for the treatment of nephrotic syndrome in adults or other renal disease has not been established. (1.2) 1.1 Malignant Diseases Cyclophosphamide for injection is indicated for the treatment of adult and pediatric patients with: malignant lymphomas (Stages III and IV of the Ann Arbor staging system), Hodgkin's disease, lymphocytic lymphoma (nodular or diffuse), mixed-cell type lymphoma, histiocytic lymphoma, Burkitt's lymphoma multiple myeloma leukemias: chronic lymphocytic leukemia, chronic granulocytic leukemia (it is usually ineffective in acute blastic crisis), acute myelogenous and monocytic leukemia, acute lymphoblastic (stem-cell) leukemia (cyclophosphamide given during remission is effective in prolonging its duration) mycosis fungoides (advanced disease) neuroblastoma (disseminated disease) adenocarcinoma of the ovary retinoblastoma carcinoma of the breast Cyclophosphamide, although effective alone in susceptible malignancies, is more frequently used concurrently or sequentially with other antineoplastic drugs. 1.2 Minimal Change Nephrotic Syndrome in Pediatric Patients Cyclophosphamide for injection 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. Limitations of Use: The safety and effectiveness of cyclophosphamide for injection for the treatment of nephrotic syndrome in adults or other renal disease has not been established.
5 WARNINGS AND PRECAUTIONS Myelosuppression, Immunosuppression, Bone Marrow Failure and Infections: Severe immunosuppression may lead to serious and sometimes fatal infections. Close hematological monitoring is required. ( 5.1 ) Urinary Tract and Renal Toxicity: Hemorrhagic cystitis, pyelitis, ureteritis, and hematuria can occur. Urotoxicity can be fatal. Exclude or correct any urinary tract obstructions prior to treatment. ( 5.2 ) Cardiotoxicity: Myocarditis, myopericarditis, pericardial effusi...
5 WARNINGS AND PRECAUTIONS Myelosuppression, Immunosuppression, Bone Marrow Failure and Infections: Severe immunosuppression may lead to serious and sometimes fatal infections. Close hematological monitoring is required. ( 5.1 ) Urinary Tract and Renal Toxicity: Hemorrhagic cystitis, pyelitis, ureteritis, and hematuria can occur. Urotoxicity can be fatal. Exclude or correct any urinary tract obstructions prior to treatment. ( 5.2 ) Cardiotoxicity: Myocarditis, myopericarditis, pericardial effusion, arrythmias and congestive heart failure, which may be fatal, have been reported. Monitor patients, especially those with risk factors for cardiotoxicity or pre-existing cardiac disease. ( 5.3 ) Pulmonary Toxicity: Pneumonitis, pulmonary fibrosis and pulmonary veno-occlusive disease leading to respiratory failure may occur. Monitor patients for signs and symptoms of pulmonary toxicity. ( 5.4 ) Secondary malignancies ( 5.5 ) Veno-occlusive Liver Disease: Fatal outcome can occur. ( 5.6 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential of the portential risk to a fetus and to use effective contraception. ( 5.7 , 8.1 , 8.3 ) 5.1 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 [see Adverse Reactions ( 6.2 )] . 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/mm 3 and platelets < 50,000/mm 3 . 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. 5.2 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 [see Contraindications ( 4 )] . 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. 5.3 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. 5.4 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. 5.5 Secondary Malignancies Cyclophosphamide is genotoxic [see Nonclinical Toxicology ( 13.1 )] . 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. 5.6 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. 5.7 Embryo-Fetal Toxicity Based on its mechanism of action and published reports of effects in pregnant patients or animals, cyclophosphamide for injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 ), Clinical Pharmacology ( 12.1 ), and Nonclinical Toxicology ( 13.1 )] . 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 pregnant women and females of reproductive potential of the potential risk to a fetus [see Use in Specific Populations ( 8.1 )] . Advise females of reproductive potential to use effective contraception during treatment with cyclophosphamide for injection and for up to 1 year after completion of therapy. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with cyclophosphamide for injection and for 4 months after completion of therapy [see Use in Specific Populations ( 8.1 , 8.3 )] . 5.8 Infertility Male and female reproductive function and fertility may be impaired in patients being treated with cyclophosphamide for injection. 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 ( 8.3 and 8.4 )] . 5.9 Impairment of Wound Healing Cyclophosphamide may interfere with normal wound healing. 5.10 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.
6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling. Hypersensitivity [see Contraindications ( 4 )] Myelosuppression, Immunosuppression, Bone Marrow Failure, and Infections [see Warnings and Precautions ( 5.1 )] Urinary Tract and Renal Toxicity [see Warnings and Precautions ( 5.2 )] Cardiotoxicity [see Warnings and Precautions ( 5.3 )] Pulmonary Toxicity [see Warnings and Precautions ( 5.4 )] Secondary Malignancies [see Warnings and ...
6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling. Hypersensitivity [see Contraindications ( 4 )] Myelosuppression, Immunosuppression, Bone Marrow Failure, and Infections [see Warnings and Precautions ( 5.1 )] Urinary Tract and Renal Toxicity [see Warnings and Precautions ( 5.2 )] Cardiotoxicity [see Warnings and Precautions ( 5.3 )] Pulmonary Toxicity [see Warnings and Precautions ( 5.4 )] Secondary Malignancies [see Warnings and Precautions ( 5.5 )] Veno-occlusive Liver Disease [see Warnings and Precautions ( 5.6 )] Infertility [ see Warnings and Precautions ( 5.8 ) and Use in Specific Populations ( 8.3 , 8.4 )] Impaired Wound Healing [see Warnings and Precautions ( 5.9 )] Hyponatremia [see Warnings and Precautions ( 5.10 )] Adverse reactions reported most often include neutropenia, febrile neutropenia, fever, alopecia, nausea, vomiting, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact XGen Pharmaceuticals DJB, Inc. at 1-866-390-4411 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials and Postmarketing Experience The following adverse reactions associated with the use of cyclophosphamide were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The most common adverse reactions were neutropenia, febrile neutropenia, fever, alopecia, nausea, vomiting, and diarrhea. 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, nausea, vomiting, diarrhea 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, febrile neutropenia. 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, alopecia. 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.
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