CYCLOPHOSPHAMIDE

Cyclophosphamide is an alkylating drug. It is an 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: Cyclophosphamide has a molecular formula of C 7 H 15 Cl 2 N 2 O 2 P•H 2 O and a molecular weight of 279.1. Cyclophosphamide is soluble in water, saline, or ethanol. Cyclophosphamide Injection is a 200 mg/mL sterile clear colorless solution available as 1 g and 2 g strength vials. 1 g vial contains 1069.0 mg cyclophosphamide monohydrate equivalent to 1 g cyclophosphamide, 3.1 g Ethanol, 0.17 g Propylene Glycol, 0.17 g Polyethylene glycol 400 and 0.69 mg Monothioglycerol. 2 g vial contains 2138.0 mg cyclophosphamide monohydrate equivalent to 2 g cyclophosphamide, 6.2 g Ethanol, 0.34 g Propylene glycol, 0.34 g Polyethylene glycol 400 and 1.38 mg Monothioglycerol. Structure

Cyclophosphamide 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 ) 1.1 Malignant Diseases Cyclophosphamide 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.

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 and Pediatric Patients ( 2.2 ) Intravenous: Initial course for patients with no hematologic deficiency: 40 mg per kg to 50 mg per kg in divided doses over 2 to 5 days. Other 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. 2.1 Important Administration Instructions During or immediately after the administration of Cyclophosphamide Injection, 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 Adults and Pediatric Patients 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 10mg 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. 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 Aseptically withdraw the prescribed dose from the vial. Dilute the prescribed dose of Cyclophosphamide Injection to a concentration of 20 mg per mL by using any of the following diluents: 0.9% Sodium Chloride Injection, USP 0.45% Sodium Chloride Injection, USP 5% Dextrose Injection, USP 5% Dextrose and 0.9% Sodium Chloride Injection, USP For Intravenous Infusion Aseptically withdraw the prescribed dose from the vial. Dilute the prescribed dose of Cyclophosphamide Injection to a concentration of 2 mg per mL by using any of the following diluents: 0.9% Sodium Chloride Injection, USP 0.45% Sodium Chloride Injection, USP 5% Dextrose Injection, USP 5% Dextrose and 0.9% 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 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. Storage of Diluted Cyclophosphamide Solution: If not used immediately, for microbiological integrity, cyclophosphamide solutions should be stored as described in Table 1: Table 1: Storage of Cyclophosphamide Solutions Diluent Storage Room Temperature Refrigerated Diluted solutions (20 mg/mL) 0.9% Sodium Chloride Injection, USP up to 24 hours Up to 6 days 0.45% Sodium Chloride Injection, USP up to 24 hours Up to 6 days 5% Dextrose Injection, USP up to 24 hours Up to 6 days 5% Dextrose and 0.9% Sodium chloride Injection, USP up to 24 hours Up to 6 days Diluted Solutions (2 mg/mL) 0.9% Sodium Chloride Injection, USP up to 24 hours Up to 6 days 0.45% Sodium Chloride Injection, USP up to 24 hours up to 6 days 5% Dextrose Injection, USP up to 24 hours up to 6 days 5% Dextrose and 0.9% Sodium chloride Injection, USP up to 24 hours up to 6 days Storage of Undiluted Cyclophosphamide Solution: After first use, store partially used multiple-dose vial in the original carton at 2°C to 8°C (36ºF to 46°F) for up to 28 days. Discard unused portion after 28 days.

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 ) ]. Hypersensitivity to cyclophosphamide ( 4 ) Urinary outflow obstruction ( 4 )

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) and Use in Specific Populations ( 8.3 and 8.4 )] Impaired Wound Healing [see Warnings and Precautions (5.10) ] Hyponatremia [see Warnings and Precautions (5.11) ] Adverse reactions reported most often include neutropenia, febrile neutropenia, fever, alopecia, nausea, vomiting, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories, Inc. at + 1 888-375-3784 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.

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).