Cyclophosphamide

1 INDICATIONS AND USAGE Malignant Diseases Cyclophosphamide Injection is indicated for the treatment of adult patients with: • malignant lymphomas (Stages III and IV of the Ann Arbor staging system), Hodgkin’s lymphoma, 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. Limitations of Use This cyclophosphamide product is not indicated for use in pediatric patients due to the to the alcohol and propylene glycol content in this product. If treatment with cyclophosphamide is indicated in a pediatric patient, use a different cyclophosphamide product [see Warnings and Precautions ( 5.7 ), Use in Specific Populations ( 8.4 ), and Description ( 11 )] . Cyclophosphamide Injection is an alkylating drug indicated for treatment of adult patients with: Malignant Diseases: malignant lymphomas: Hodgkin’s lymphoma, lymphocytic lymphoma, mixed-cell type lymphoma, histiocytic lymphoma, Burkitt’s lymphoma; multiple myeloma, leukemias, mycosis fungoides, neuroblastoma, adenocarcinoma of ovary, retinoblastoma, breast carcinoma. ( 1 ) Limitations of Use This cyclophosphamide product is not indicated for use in pediatric patients due to the alcohol and propylene glycol content in this product. If treatment with cyclophosphamide is indicated in a pediatric patient, use a different cyclophosphamide product. ( 1 )

2 DOSAGE AND ADMINISTRATION During or immediately after Cyclophosphamide Injection administration, administer adequate amounts of fluid to reduce the risk of urinary tract toxicity ( 2.1 ). Malignant Diseases: Adult Patients ( 2.2 ) • Intravenous: Initial course for patients with no hematologic deficiency: 40 mg/kg to 50 mg/kg in divided doses over 2 to 5 days. Other regimens include 10 mg/kg to 15 mg/kg given every 7 to 10 days or 3 mg/kg to 5 mg/kg twice weekly. ( 2.2 ) • See full prescribing information for instructions on preparation, handling, and administration. ( 2.3 ) 2.1 Important Administration Information 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 Injection should be administered in the morning. 2.2 Recommended Dosage for Malignant Diseases Intravenous Use When used as the only oncolytic drug therapy, the recommended dosage for the initial course of Cyclophosphamide Injection for patients with no hematologic deficiency is 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. Adjust the dosage of Cyclophosphamide Injection based on the specific regimen administered, response to treatment, myelosuppression or other adverse reactions, and patient risk factors [see Warnings and Precautions ( 5 )] . 2.3 Preparation, Handling and Administration Cyclophosphamide Injection is a hazardous drug. Follow applicable special handling and disposal procedures 1 . Caution should be exercised when handling and preparing Cyclophosphamide Injection. To minimize the risk of dermal exposure, always wear gloves when handling vials containing Cyclophosphamide Injection. Cyclophosphamide Injection 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 Injection vials if there are signs of particulate matter. Cyclophosphamide Injection 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 Aseptically withdraw the prescribed dose from the vial and dilute to a concentration of 20 mg/mL by using any of the following diluents: • 5% Dextrose Injection • 0.45% Sodium Chloride Injection • 0.9% Sodium Chloride Injection For Intravenous Infusion Aseptically withdraw the prescribed dose from the vial and dilute to a concentration of 2 mg/mL by using any of the following diluents: • 0.9% Sodium Chloride Injection • 0.45% Sodium Chloride Injection • 5% Dextrose Injection To reduce the likelihood of adverse reactions that appear to be administration rate dependent (e.g., facial swelling, headache, nasal congestion, scalp burning), Cyclophosphamide Injection 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. Each vial is recommended for no more than a total of eight (8) dose withdrawals. Storage of Diluted Cyclophosphamide Injection Solution: If the diluted solution is not used immediately, store at room temperature at 68°F to 77°F (20°C to 25°C) for up to 24 hours or refrigerated at 36°F to 46°F (2°C to 8°C) for up to 6 days. Storage of Undiluted Cyclophosphamide Injection Solution: After first use, the partially used vial should be stored in the refrigerator in the original carton at 2°C to 8°C (36ºF to 46°F) up to 28 days. Discard unused portion after 28 days.

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: Have been reported in patients treated with cyclophosphamide containing regimens. ( 5.5 ) • Veno-occlusive Liver Disease: Fatal outcome can occur. ( 5.6 ) • Alcohol Content: This product is not indicated for use in pediatric patients. The alcohol content in a dose of Cyclophosphamide Injection may affect the central nervous system. This may include impairment of a patient's ability to drive or use machines immediately after infusion. ( 5.7 ) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception. Advise males with female partners of reproductive potential to use effective contraception ( 5.8 , 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 Injection should not be administered to patients with neutrophils ≤1,500/mm3 and platelets < 50,000/mm 3 . Cyclophosphamide Injection 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 Injection 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 t…

4 CONTRAINDICATIONS Severe Hypersensitivity Cyclophosphamide Injection is contraindicated in patients who have a history of severe hypersensitivity reactions to cyclophosphamide, any of its metabolites, or to other components of the product. Anaphylactic reactions including death have been reported with cyclophosphamide. Cross-sensitivity with other alkylating agents can occur. Urinary Outflow Obstruction Cyclophosphamide Injection is contraindicated in patients with urinary outflow obstruction [see Warnings and Precautions ( 5.2 )]. • Severe hypersensitivity to cyclophosphamide ( 4 ) • Urinary outflow obstruction ( 4 )

7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on Cyclophosphamide Exposure Protease Inhibitors Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites and may enhance the toxicities of cyclophosphamide, including higher incidence of infections, neutropenia, and mucositis. Monitor for increased toxicities in patients receiving protease inhibitors. 7.2 Drugs that Potentiate Cyclophosphamide Toxicities Radiation therapy or drugs with similar toxicities to Cyclophosphamide Injection can potentiate toxicities for cyclophosphamide. Monitor for increased toxicities in patients receiving radiation therapy or drugs known to cause: • Myelosuppression and/or immunosuppression [see Warnings and Precautions ( 5.1 )] • Nephrotoxicity including hemorrhagic cystitis [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 )] • Hepatotoxicity including liver necrosis and VOD [see Warnings and Precautions ( 5.6) ] 7.3 Effect of Cyclophosphamide on Other Drugs Metronidazole Acute encephalopathy has been reported in a patient receiving cyclophosphamide and metronidazole. Monitor for neurologic toxicities in patients receiving metronidazole. Tamoxifen Concomitant use of tamoxifen and a cyclophosphamide-containing chemotherapy regimen may increase the risk of thromboembolic complications. Monitor for signs and symptoms of thromboembolic events in patients receiving tamoxifen. Coumarins Both increased and decreased warfarin effect have been reported in patients receiving warfarin and cyclophosphamide. Monitor anticoagulant activity closely in patients receiving warfarin or other coumarins. Cyclosporine Concomitant administration of cyclophosphamide may decrease serum concentrations of cyclosporine. This interaction may result in an increased incidence of graft-versus-host disease. Monitor for signs and symptoms of graft-versus-host disease in patients receiving cyclosporine. Depolarizing muscle relaxants If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, alert the anesthesiologist. Cyclophosphamide causes a marked and persistent inhibition of cholinesterase activity. Prolonged apnea may occur with concurrent depolarizing muscle relaxants (e.g., succinylcholine).

8.1 Pregnancy Risk Summary Based on its mechanism of action and published reports of effects in pregnant patients or animals, Cyclophosphamide Injection can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 ) and Nonclinical Toxicology ( 13.1 )] . Exposure to cyclophosphamide during pregnancy may cause fetal malformations, miscarriage, fetal growth retardation, and toxic effects in the newborn [see Data] . Cyclophosphamide is teratogenic and embryo-fetal toxic in mice, rats, rabbits and monkeys [see Data] . Advise pregnant women and females of reproductive potential of the potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Data 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.

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 )] • Alcohol Content [see Warnings and Precautions ( 5.7 )] • Infertility [see Warnings and Precautions ( 5.9 ) ] • Impaired Wound Healing [see Warnings and Precautions ( 5.10 )] • Hyponatremia [see Warnings and Precautions ( 5.11 )] The most common adverse reactions are neutropenia, febrile neutropenia, fever, alopecia, nausea, vomiting, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 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 glucos…