CYCLOPHOSPHAMIDE

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

Cyclophosphamide is an alkylating drug indicated for treatment of: 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. 1.1 Malignant Diseases Cyclophosphamide is indicated for the treatment of: 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 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 for the treatment of nephrotic syndrome in adults or other renal disease has not been established.

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. Malignant Diseases: Adult and Pediatric Patients ( 2.1 ) 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. Oral: Usually 1 mg per kg per day to 5 mg per kg per day for both initial and maintenance dosing. Minimal Change Nephrotic Syndrome in Pediatric Patients ( 2.2 ) Recommended oral dose: 2 mg per kg daily for 8 to 12 weeks (maximum cumulative dose 168 mg per kg). Treatment beyond 90 days increases the probability of sterility in males. 2.1 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. 2.2 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 [see Use in Specific Populations ( 8.4 )]. 2.3 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. Shake the vial vigorously 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. Table 1: Reconstitution for Direct Intravenous Injection Strength Volume of 0.9% Sodium Chloride Cyclophosphamide Concentration 500 mg 25 mL 20 mg per mL 1 g 50 mL 2 g 100 mL 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 shake it vigorously to dissolve the drug completely. Table 2: Reconstitution in preparation for Intravenous Infusion Strength Volume of Diluent Cyclophosphamide Concentration 500 mg 25 mL 20 mg per mL 1 g 50 mL 2 g 100 mL 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. Table 3: Storage of Cyclophosphamide Solutions Diluent Storage Room Temperature Refrigerated Reconstituted Solution (Without Further Dilution) 0.9% Sodium Chloride Injection, USP up to 24 hrs up to 6 days Sterile Water for Injection, USP Do not store; use immediately Diluted Solutions Storage time is the total time cyclophosphamide is in solution including the time it is reconstituted in 0.9% Sterile Sodium Chloride Injection, USP or Sterile Water for Injection, USP. 0.45% Sodium Chloride Injection, USP up to 24 hrs up to 6 days 5% Dextrose Injection, USP up to 24 hrs up to 36 hrs 5% Dextrose and 0.9% Sodium Chloride Injection, USP up to 24 hrs up to 36 hrs 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.

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 [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 ) ] Embryo-Fetal Toxicity [see Warnings and Precautions ( 5.7 ) ] Reproductive System Toxicity [see Warnings and Precautions ( 5.8 ) and Use in Specific Populations ( 8.4 and 8.6 ) ] 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 Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. 6.2 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.

Cyclophosphamide is a pro-drug that is activated by cytochrome P450s [see Clinical Pharmacology ( 12.3 )]. 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 Pentostatin 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.