ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling.oHypersensitivity [see Contraindications (4)]oMyelosuppression, Immunosuppression, Bone Marrow Failure, and Infections [see Warnings and Precautions (5.1)]oUrinary Tract and Renal Toxicity [see Warnings and Precautions (5.2)]oCardiotoxicity [see Warnings and Precautions (5.3)]oPulmonary Toxicity [see Warnings and Precautions (5.4)]oSecondary Malignancies [see Warnings and Precautions (5.5)]oVeno-occlusive Liver Disease [see Warnings and Precautions (5.6)]oAlcohol Content [see Warnings and Precautions (5.7)]oInfertility [see Warnings and Precautions (5.9)]oImpaired Wound Healing [see Warnings and Precautions (5.10)]oHyponatremia [see Warnings and Precautions (5.11)]. oHypersensitivity [see Contraindications (4)]. oMyelosuppression, Immunosuppression, Bone Marrow Failure, and Infections [see Warnings and Precautions (5.1)]. oUrinary Tract and Renal Toxicity [see Warnings and Precautions (5.2)]. oCardiotoxicity [see Warnings and Precautions (5.3)]. oPulmonary Toxicity [see Warnings and Precautions (5.4)]. oSecondary Malignancies [see Warnings and Precautions (5.5)]. oVeno-occlusive Liver Disease [see Warnings and Precautions (5.6)]. oAlcohol Content [see Warnings and Precautions (5.7)]. oInfertility [see Warnings and Precautions (5.9)]. oImpaired Wound Healing [see Warnings and Precautions (5.10)]. oHyponatremia [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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Cyclophosphamide administered by different routes, including intravenous, subcutaneous or intraperitoneal injection, or in drinking water, caused tumors in both mice and rats. In addition to leukemia and lymphoma, benign and malignant tumors were found at various tissue sites, including urinary bladder, mammary gland, lung, liver, and injection site [see Warnings and Precautions (5.5)]. Cyclophosphamide was mutagenic and clastogenic in multiple in vitro and in vivo genetic toxicology studies. Cyclophosphamide is genotoxic in male and female germ cells. Animal data indicate that exposure of oocytes to cyclophosphamide during follicular development may result in decreased rate of implantations and viable pregnancies, and in an increased risk of malformations. Male mice and rats treated with cyclophosphamide show alterations in male reproductive organs (e.g., decreased weights, atrophy, changes in spermatogenesis), and decreases in reproductive potential (e.g., decreased implantations and increased post-implantation loss) and increases in fetal malformations when mated with untreated females [see Use in Specific Populations 8.3 )].

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action has not been fully characterized. However, cross-linking of tumor cell DNA may be involved.The active alkylating metabolites of cyclophosphamide interfere with the growth of susceptible rapidly proliferating malignant cells.. 12.2 Pharmacodynamics Cyclophosphamide exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized.. 12.3 Pharmacokinetics Cyclophosphamide is prodrug. Cyclophosphamide pharmacokinetics are linear over the approved recommended dose range.DistributionThe volume of distribution of cyclophosphamide is 30 to 50 L. Cyclophosphamide is approximately 20% protein bound, with no dose dependent changes. Some metabolites are greater than 60% protein bound.EliminationThe elimination half-life (t 1/2 of cyclophosphamide ranges from to 12 hours, and clearance (CL) ranges from to 5.6 L/h.When cyclophosphamide was administered at g/m2 (approximately times the approved recommended dosage) over 90-minutes infusion, concentration-time data demonstrate saturable elimination in parallel with first-order renal elimination.MetabolismCyclophosphamide is metabolized by cytochrome P450s including CYP2A6, 2B6, 3A, 2C9, and 2C19. Cyclophosphamide is activated to form 4-hydroxycyclophosphamide, which is in equilibrium with its ring-open tautomer aldophosphamide. 4-hydroxycyclophosphamide and aldophosphamide can undergo oxidation by aldehyde dehydrogenases to form the inactive metabolites 4-ketocyclophosphamide and carboxyphosphamide, respectively. Aldophosphamide can undergo -elimination to form active metabolites phosphoramide mustard and acrolein. This spontaneous conversion can be catalyzed by albumin and other proteins. At high doses, the fraction of parent compound cleared by 4-hydroxylation is reduced resulting in non-linear elimination of cyclophosphamide.Cyclophosphamide appears to induce its own metabolism. This auto-induction results in an increase in CL, increased formation of active 4-hydroxycyclophosphamide and shortened 1/2 following multiple doses administered at 12-to-24-hour interval.ExcretionCyclophosphamide and its metabolites are eliminated by hepatic and renal pathways. Cyclophosphamide is primarily excreted as metabolites. Ten to 20% is excreted unchanged in the urine. small percentage of cyclophosphamide may be eliminated unchanged in bile.Specific PopulationsRenal ImpairmentFollowing one-hour intravenous infusion, cyclophosphamide AUC increased by 38% in patients with CLcr of 25 to 50 mL/min, by 77% in patients with CLcr of 10 to 24 mL/min and by 23% in the hemodialysis group (CLcr of 10 mL/min) compared to the control group (CLcr>= 80 mL/min).Cyclophosphamide is dialyzable. Dialysis clearance averaged 104 mL/min, which is similar to the metabolic clearance of 95 mL/min for cyclophosphamide. mean of 37% of the administered dose of cyclophosphamide was removed during 4-hour hemodialysis period. The 1/2 was 3.3 hours in patients during hemodialysis, 49% reduction compared to 1/2 of 6.5 hours in uremic patients.Hepatic ImpairmentCyclophosphamide CL is decreased by 40% (45 +- 8.6 L/kg) and 1/2 is prolonged by 64% (12.5 +- hours) in patients with hepatic impairment with mean bilirubin 3.5 mg/dL and mean AST 90 IU/L compared to patients with normal hepatic function (mean bilirubin 0.5 mg/dL, mean AST 10 IU/L).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS Severe Hypersensitivity Cyclophosphamide Injection is contraindicated in patients who have 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 ObstructionCyclophosphamide Injection is contraindicated in patients with urinary outflow obstruction [see Warnings and Precautions (5.2)]. Severe Hypersensitivity. Cyclophosphamide Injection is contraindicated in patients who have 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.. oSevere hypersensitivity to cyclophosphamide (4)oUrinary outflow obstruction (4). oSevere hypersensitivity to cyclophosphamide (4). oUrinary outflow obstruction (4).

DESCRIPTION SECTION.

11 DESCRIPTION Cyclophosphamide is an alkylating drug. It is 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 white crystalline powder with the molecular formula C7H15Cl2N2O2PoH2O and molecular weight of 279.1. Cyclophosphamide is soluble in water and freely soluble in alcohol.Cyclophosphamide Injection, 100 mg/mL is sterile ready-to-dilute, clear, colorless to pale-yellow solution in multiple-dose vial available as 500 mg/5 mL, 1,000 mg/10 mL, and 2,000 mg/20 mL strengths.o500 mg vial contains 534.5 mg cyclophosphamide monohydrate equivalent to 500 mg cyclophosphamide, 2.92 dehydrated alcohol (equivalent to 73.9 v/v) and 0.96 propylene glycol.o1,000 mg vial contains 1,069 mg cyclophosphamide monohydrate equivalent to 1,000 mg cyclophosphamide, 5.85 dehydrated alcohol (equivalent to 73.9 v/v) and 1.92 propylene glycol.o2,000 mg vial contains 2,138 mg cyclophosphamide monohydrate equivalent to 2,000 mg cyclophosphamide, 11.69 dehydrated alcohol (equivalent to 73.9 v/v) and 3.84 propylene glycol.. o500 mg vial contains 534.5 mg cyclophosphamide monohydrate equivalent to 500 mg cyclophosphamide, 2.92 dehydrated alcohol (equivalent to 73.9 v/v) and 0.96 propylene glycol.. o1,000 mg vial contains 1,069 mg cyclophosphamide monohydrate equivalent to 1,000 mg cyclophosphamide, 5.85 dehydrated alcohol (equivalent to 73.9 v/v) and 1.92 propylene glycol.. o2,000 mg vial contains 2,138 mg cyclophosphamide monohydrate equivalent to 2,000 mg cyclophosphamide, 11.69 dehydrated alcohol (equivalent to 73.9 v/v) and 3.84 propylene glycol.. chemical-structure.

DOSAGE & ADMINISTRATION SECTION.

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)oIntravenous: Initial course for patients with no hematologic deficiency: 40 mg/kg to 50 mg/kg in divided doses over to days. Other regimens include 10 mg/kg to 15 mg/kg given every to 10 days or mg/kg to mg/kg twice weekly. (2.2)oSee full prescribing information for instructions on preparation, handling, and administration. (2.3). oIntravenous: Initial course for patients with no hematologic deficiency: 40 mg/kg to 50 mg/kg in divided doses over to days. Other regimens include 10 mg/kg to 15 mg/kg given every to 10 days or mg/kg to mg/kg twice weekly. (2.2). oSee 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 UseWhen 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 period of to days. Other intravenous regimens include 10 mg per kg to 15 mg per kg given every to 10 days or mg per kg to 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 hazardous drug. Follow applicable special handling and disposal procedures1. 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 InjectionIntravenous AdministrationParenteral 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 InjectionAseptically withdraw the prescribed dose from the vial and dilute to concentration of 20 mg/mL by using any of the following diluents:o5% Dextrose Injectiono0.45% Sodium Chloride Injectiono0.9% Sodium Chloride InjectionFor Intravenous InfusionAseptically withdraw the prescribed dose from the vial and dilute to concentration of mg/mL by using any of the following diluents:o0.9% Sodium Chloride Injectiono0.45% Sodium Chloride Injectiono5% Dextrose InjectionTo 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 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 68F to 77F (20C to 25C) for up to 24 hours or refrigerated at 36F to 46F (2C to 8C) for up to 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 2C to 8C (36oF to 46F) up to 28 days. Discard unused portion after 28 days.. o5% Dextrose Injection. o0.45% Sodium Chloride Injection. o0.9% Sodium Chloride Injection. o0.9% Sodium Chloride Injection. o0.45% Sodium Chloride Injection. o5% Dextrose Injection.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS Cyclophosphamide Injection is 100 mg/mL sterile, clear, colorless to pale-yellow solution in multiple-dose vial available in the following presentations:o500 mg/5 mLo1,000 mg/10 mLo2,000 mg/20 mL. o500 mg/5 mL. o1,000 mg/10 mL. o2,000 mg/20 mL. Injection: 500 mg/5 mL (100 mg/mL), 1,000 mg/10 mL (100 mg/mL), 2,000 mg/20 mL (100 mg/mL) in multiple-dose vials (3). Injection: 500 mg/5 mL (100 mg/mL), 1,000 mg/10 mL (100 mg/mL), 2,000 mg/20 mL (100 mg/mL) in multiple-dose vials (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on Cyclophosphamide Exposure Protease InhibitorsConcomitant 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:oMyelosuppression and/or immunosuppression [see Warnings and Precautions (5.1)]oNephrotoxicity including hemorrhagic cystitis [see Warnings and Precautions (5.2)]oCardiotoxicity [see Warnings and Precautions (5.3)]oPulmonary toxicity [see Warnings and Precautions (5.4)]oSecondary malignancies [see Warnings and Precautions (5.5)]oHepatotoxicity including liver necrosis and VOD [see Warnings and Precautions (5.6)]. oMyelosuppression and/or immunosuppression [see Warnings and Precautions (5.1)]. oNephrotoxicity including hemorrhagic cystitis [see Warnings and Precautions (5.2)]. oCardiotoxicity [see Warnings and Precautions (5.3)]. oPulmonary toxicity [see Warnings and Precautions (5.4)]. oSecondary malignancies [see Warnings and Precautions (5.5)]. oHepatotoxicity including liver necrosis and VOD [see Warnings and Precautions (5.6)]. 7.3 Effect of Cyclophosphamide on Other Drugs MetronidazoleAcute encephalopathy has been reported in patient receiving cyclophosphamide and metronidazole. Monitor for neurologic toxicities in patients receiving metronidazole.TamoxifenConcomitant use of tamoxifen and cyclophosphamide-containing chemotherapy regimen may increase the risk of thromboembolic complications. Monitor for signs and symptoms of thromboembolic events in patients receiving tamoxifen.CoumarinsBoth 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.CyclosporineConcomitant 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 relaxantsIf patient has been treated with cyclophosphamide within 10 days of general anesthesia, alert the anesthesiologist.Cyclophosphamide causes marked and persistent inhibition of cholinesterase activity. Prolonged apnea may occur with concurrent depolarizing muscle relaxants (e.g., succinylcholine).

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Cyclophosphamide Injection can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to the initiation of Cyclophosphamide Injection.ContraceptionFemalesAdvise female patients of reproductive potential to use effective contraception during treatment with Cyclophosphamide Injection and for up to year after therapy.MalesBased on findings in genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment with Cyclophosphamide Injection for months after therapy [see Nonclinical Toxicology (13.1)].InfertilityFemalesAmenorrhea, transient or permanent, associated with decreased estrogen and increased gonadotropin secretion develops in proportion of women treated with cyclophosphamide. Affected patients generally resume regular menses within few months after cessation of therapy. The risk of premature menopause with cyclophosphamide increases with age. Oligomenorrhea has also been reported in association with cyclophosphamide treatment.Animal data suggest an increased risk of failed pregnancy and malformations may persist after discontinuation of cyclophosphamide as long as oocytes/follicles exist that were exposed to cyclophosphamide during any of their maturation phases. The exact duration of follicular development in humans is not known but may be longer than 12 months [see Nonclinical Toxicology (13.1)].MalesMen treated with cyclophosphamide may develop oligospermia or azoospermia which are normally associated with increased gonadotropin but normal testosterone secretion.

GERIATRIC USE SECTION.

8.5 Geriatric Use There is insufficient data from clinical studies of cyclophosphamide available for patients 65 years of age and older to determine whether they respond differently than younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac functioning, and of concomitant disease or other drug therapy.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING Cyclophosphamide Injection, 100 mg/mL is sterile ready-to-dilute, clear, colorless to pale-yellow solution in multiple-dose vial available in the following strengths:StrengthNDC NumberVolume500 mg/5 mL0781-3528-10Carton of one mL Multiple-Dose Vial1,000 mg/10 mL0781-3529-10Carton of one 10 mL Multiple-Dose Vial2,000 mg/20 mL0781-3530-10Carton of one 20 mL Multiple-Dose VialStore vials refrigerated at 2C to 8C (36F to 46F). Cyclophosphamide is hazardous product. Follow special handling and disposal procedures.1.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE Malignant DiseasesCyclophosphamide Injection is indicated for the treatment of adult patients with:omalignant lymphomas (Stages III and IV of the Ann Arbor staging system), Hodgkins lymphoma, lymphocytic lymphoma (nodular or diffuse), mixed-cell type lymphoma, histiocytic lymphoma, Burkitts lymphomaomultiple myelomaoleukemias: 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)omycosis fungoides (advanced disease)oneuroblastoma (disseminated disease)oadenocarcinoma of the ovaryoretinoblastomaocarcinoma of the breastCyclophosphamide, although effective alone in susceptible malignancies, is more frequently used concurrently or sequentially with other antineoplastic drugs.Limitations of UseThis 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 pediatric patient, use different cyclophosphamide product [see Warnings and Precautions (5.7), Use in Specific Populations (8.4), and Description (11)].. omalignant lymphomas (Stages III and IV of the Ann Arbor staging system), Hodgkins lymphoma, lymphocytic lymphoma (nodular or diffuse), mixed-cell type lymphoma, histiocytic lymphoma, Burkitts lymphoma. omultiple myeloma. oleukemias: 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). omycosis fungoides (advanced disease). oneuroblastoma (disseminated disease). oadenocarcinoma of the ovary. oretinoblastoma. ocarcinoma of the breast. Cyclophosphamide Injection is an alkylating drug indicated for treatment of adult patients with:Malignant Diseases: malignant lymphomas: Hodgkins lymphoma, lymphocytic lymphoma, mixed-cell type lymphoma, histiocytic lymphoma, Burkitts lymphoma; multiple myeloma, leukemias, mycosis fungoides, neuroblastoma, adenocarcinoma of ovary, retinoblastoma, breast carcinoma. (1)Limitations of UseThis 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 pediatric patient, use different cyclophosphamide product. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patient of the following:Myelosuppression, Immunosuppression, Bone Marrow Failure, and InfectionsoInform patients of the possibility of myelosuppression, immunosuppression, and infections. Explain the need for routine blood cell counts. Instruct patients to monitor their temperature frequently and immediately report any occurrence of fever [see Warnings and Precautions (5.1)].Urinary Tract and Renal ToxicityoAdvise the patient to report urinary symptoms (patients should report if their urine has turned pink or red color) and the need for increasing fluid intake and frequent voiding [see Warnings and Precautions (5.2)].CardiotoxicityoInform patients of the possibility of cardiotoxicity (which may be fatal).oAdvise patients to contact healthcare professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, palpitations, weight gain of more than pounds in 24 hours, dizziness or loss of consciousness [see Warnings and Precautions (5.3)].Pulmonary ToxicityoWarn patients of the possibility of developing non-infectious pneumonitis. Advise patients to report promptly any new or worsening respiratory symptoms [see Warnings and Precautions (5.4)].Alcohol ContentoExplain to patients the possible effects of the alcohol content in Cyclophosphamide Injection, including possible effects on the central nervous system. Patients in whom alcohol should be avoided or minimized should consider the alcohol content of Cyclophosphamide Injection. Alcohol could impair their ability to drive or use machines immediately after infusion [see Warnings and Precautions (5.7)].Secondary MalignanciesoInform patients that there is an increased risk of secondary malignancies with Cyclophosphamide Injection [see Warnings and Precautions (5.5)].Embryo-Fetal ToxicityoInform female patients of the risk to fetus and potential loss of the pregnancy. Advise females to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1)].oAdvise females of reproductive potential to use effective contraception during treatment and for up to year after completion of therapy [see Warning and Precautions (5.8) and Use in Specific Population (8.1,8.3)].oAdvise male patients with female partners of reproductive potential to use effective contraception during treatment and for months after completion of therapy [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1,8.3)].LactationoAdvise women not to breastfeed during treatment and for week after the last dose of Cyclophosphamide Injection [see Use in Specific Populations (8.2)].InfertilityoAdvise patients that Cyclophosphamide Injection may impair fertility in males and females of reproductive potential [see Warnings and Precautions (5.9) and Use in Specific Populations (8.3, 8.4)].Common Adverse ReactionsoExplain to patients that side effects such as nausea, vomiting, stomatitis, impaired wound healing, amenorrhea, premature menopause, sterility, and hair loss may be associated with cyclophosphamide administration. Other undesirable effects (including, e.g., dizziness, blurred vision, visual impairment) could affect the ability to drive or use machines [see Adverse Reactions (6.1)].Hydration and Important Administration InstructionsoAdvise the patients that during or immediately after the administration, adequate amounts of fluid are required to reduce the risk of urinary tract toxicity [see Dosage and Administration (2.1)].Manufactured by FAREVA Unterach GmbH forSandoz Inc., Princeton, NJ 08540. oInform patients of the possibility of myelosuppression, immunosuppression, and infections. Explain the need for routine blood cell counts. Instruct patients to monitor their temperature frequently and immediately report any occurrence of fever [see Warnings and Precautions (5.1)].. oAdvise the patient to report urinary symptoms (patients should report if their urine has turned pink or red color) and the need for increasing fluid intake and frequent voiding [see Warnings and Precautions (5.2)].. oInform patients of the possibility of cardiotoxicity (which may be fatal).. oAdvise patients to contact healthcare professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, palpitations, weight gain of more than pounds in 24 hours, dizziness or loss of consciousness [see Warnings and Precautions (5.3)].. oWarn patients of the possibility of developing non-infectious pneumonitis. Advise patients to report promptly any new or worsening respiratory symptoms [see Warnings and Precautions (5.4)].. oExplain to patients the possible effects of the alcohol content in Cyclophosphamide Injection, including possible effects on the central nervous system. Patients in whom alcohol should be avoided or minimized should consider the alcohol content of Cyclophosphamide Injection. Alcohol could impair their ability to drive or use machines immediately after infusion [see Warnings and Precautions (5.7)].. oInform patients that there is an increased risk of secondary malignancies with Cyclophosphamide Injection [see Warnings and Precautions (5.5)].. oInform female patients of the risk to fetus and potential loss of the pregnancy. Advise females to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1)].. oAdvise females of reproductive potential to use effective contraception during treatment and for up to year after completion of therapy [see Warning and Precautions (5.8) and Use in Specific Population (8.1,8.3)].. oAdvise male patients with female partners of reproductive potential to use effective contraception during treatment and for months after completion of therapy [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1,8.3)].. oAdvise women not to breastfeed during treatment and for week after the last dose of Cyclophosphamide Injection [see Use in Specific Populations (8.2)].. oAdvise patients that Cyclophosphamide Injection may impair fertility in males and females of reproductive potential [see Warnings and Precautions (5.9) and Use in Specific Populations (8.3, 8.4)].. oExplain to patients that side effects such as nausea, vomiting, stomatitis, impaired wound healing, amenorrhea, premature menopause, sterility, and hair loss may be associated with cyclophosphamide administration. Other undesirable effects (including, e.g., dizziness, blurred vision, visual impairment) could affect the ability to drive or use machines [see Adverse Reactions (6.1)].. oAdvise the patients that during or immediately after the administration, adequate amounts of fluid are required to reduce the risk of urinary tract toxicity [see Dosage and Administration (2.1)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryCyclophosphamide is present in breast milk. Neutropenia, thrombocytopenia, low hemoglobin, and diarrhea have been reported in infants breast fed by women treated with cyclophosphamide. Because of the potential for serious adverse reactions in breastfed child, advise lactating women not to breastfeed during the treatment and for week after the last dose.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action The mechanism of action has not been fully characterized. However, cross-linking of tumor cell DNA may be involved.The active alkylating metabolites of cyclophosphamide interfere with the growth of susceptible rapidly proliferating malignant cells.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Cyclophosphamide administered by different routes, including intravenous, subcutaneous or intraperitoneal injection, or in drinking water, caused tumors in both mice and rats. In addition to leukemia and lymphoma, benign and malignant tumors were found at various tissue sites, including urinary bladder, mammary gland, lung, liver, and injection site [see Warnings and Precautions (5.5)]. Cyclophosphamide was mutagenic and clastogenic in multiple in vitro and in vivo genetic toxicology studies. Cyclophosphamide is genotoxic in male and female germ cells. Animal data indicate that exposure of oocytes to cyclophosphamide during follicular development may result in decreased rate of implantations and viable pregnancies, and in an increased risk of malformations. Male mice and rats treated with cyclophosphamide show alterations in male reproductive organs (e.g., decreased weights, atrophy, changes in spermatogenesis), and decreases in reproductive potential (e.g., decreased implantations and increased post-implantation loss) and increases in fetal malformations when mated with untreated females [see Use in Specific Populations 8.3 )].

OVERDOSAGE SECTION.

10 OVERDOSAGE No specific antidote for cyclophosphamide is known. Overdosage should be managed with supportive measures, including appropriate treatment for any concurrent infection, myelosuppression, or cardiac toxicity should it occur.Serious consequences of overdosage include manifestations of dose dependent toxicities such as myelosuppression, urotoxicity, cardiotoxicity (including cardiac failure), veno-occlusive hepatic disease, and stomatitis [see Warnings and Precautions (5.1, 5.2, 5.3 and 5.6)].Patients who received an overdose should be closely monitored for the development of toxicities, and hematologic toxicity in particular.Cyclophosphamide and its metabolites are dialyzable. Therefore, rapid hemodialysis is indicated when treating any suicidal or accidental overdose or intoxication.Cystitis prophylaxis with mesna may be helpful in preventing or limiting urotoxic effects with cyclophosphamide overdose.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 5 mL Carton. NDC 0781-3528-10SterileCyclophosphamide Injection500 mg/5 mL(100 mg/mL)Must Dilute Before Intravenous UseHazardous DrugRx OnlyOne mL Multiple-Dose VialSANDOZ. NDC 0781-3528-10Sterile. 5ml-carton.

PEDIATRIC USE SECTION.

8.4 Pediatric 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 pediatric patient, use different cyclophosphamide product. Since propylene glycol and alcohol are both metabolized by the same enzymes, co-administration of these excipients may raise systemic exposure to alcohol, particularly in pediatric patients. [see Indications and Usage (1), Warnings and Precautions (5.7), and Description (11)]. Other cyclophosphamide products may have different amount of alcohol or no alcohol.Pre-pubescent girls treated with cyclophosphamide generally develop secondary sexual characteristics normally and have regular menses. Ovarian fibrosis with apparent complete loss of germ cells after prolonged cyclophosphamide treatment in late pre-pubescence has been reported. Girls treated with cyclophosphamide who have retained ovarian function after completing treatment are at increased risk of developing premature menopause.Pre-pubescent boys treated with cyclophosphamide develop secondary sexual characteristics normally but may have oligospermia or azoospermia and increased gonadotropin secretion. Some degree of testicular atrophy may occur. Cyclophosphamide induced azoospermia is reversible in some patients, though the reversibility may not occur for several years after cessation of therapy.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics Cyclophosphamide exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Cyclophosphamide is prodrug. Cyclophosphamide pharmacokinetics are linear over the approved recommended dose range.DistributionThe volume of distribution of cyclophosphamide is 30 to 50 L. Cyclophosphamide is approximately 20% protein bound, with no dose dependent changes. Some metabolites are greater than 60% protein bound.EliminationThe elimination half-life (t 1/2 of cyclophosphamide ranges from to 12 hours, and clearance (CL) ranges from to 5.6 L/h.When cyclophosphamide was administered at g/m2 (approximately times the approved recommended dosage) over 90-minutes infusion, concentration-time data demonstrate saturable elimination in parallel with first-order renal elimination.MetabolismCyclophosphamide is metabolized by cytochrome P450s including CYP2A6, 2B6, 3A, 2C9, and 2C19. Cyclophosphamide is activated to form 4-hydroxycyclophosphamide, which is in equilibrium with its ring-open tautomer aldophosphamide. 4-hydroxycyclophosphamide and aldophosphamide can undergo oxidation by aldehyde dehydrogenases to form the inactive metabolites 4-ketocyclophosphamide and carboxyphosphamide, respectively. Aldophosphamide can undergo -elimination to form active metabolites phosphoramide mustard and acrolein. This spontaneous conversion can be catalyzed by albumin and other proteins. At high doses, the fraction of parent compound cleared by 4-hydroxylation is reduced resulting in non-linear elimination of cyclophosphamide.Cyclophosphamide appears to induce its own metabolism. This auto-induction results in an increase in CL, increased formation of active 4-hydroxycyclophosphamide and shortened 1/2 following multiple doses administered at 12-to-24-hour interval.ExcretionCyclophosphamide and its metabolites are eliminated by hepatic and renal pathways. Cyclophosphamide is primarily excreted as metabolites. Ten to 20% is excreted unchanged in the urine. small percentage of cyclophosphamide may be eliminated unchanged in bile.Specific PopulationsRenal ImpairmentFollowing one-hour intravenous infusion, cyclophosphamide AUC increased by 38% in patients with CLcr of 25 to 50 mL/min, by 77% in patients with CLcr of 10 to 24 mL/min and by 23% in the hemodialysis group (CLcr of 10 mL/min) compared to the control group (CLcr>= 80 mL/min).Cyclophosphamide is dialyzable. Dialysis clearance averaged 104 mL/min, which is similar to the metabolic clearance of 95 mL/min for cyclophosphamide. mean of 37% of the administered dose of cyclophosphamide was removed during 4-hour hemodialysis period. The 1/2 was 3.3 hours in patients during hemodialysis, 49% reduction compared to 1/2 of 6.5 hours in uremic patients.Hepatic ImpairmentCyclophosphamide CL is decreased by 40% (45 +- 8.6 L/kg) and 1/2 is prolonged by 64% (12.5 +- hours) in patients with hepatic impairment with mean bilirubin 3.5 mg/dL and mean AST 90 IU/L compared to patients with normal hepatic function (mean bilirubin 0.5 mg/dL, mean AST 10 IU/L).

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on its mechanism of action and published reports of effects in pregnant patients or animals, Cyclophosphamide Injection can cause fetal harm when administered to 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.DataHuman DataMalformations 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 DataAdministration 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.

RECENT MAJOR CHANGES SECTION.

Dosage and Administration (2.2)12/2024. Dosage and Administration (2.2)12/2024.

REFERENCES SECTION.

15 REFERENCES 1.OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.. 1.OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

SPL UNCLASSIFIED SECTION.

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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS oLactation: Advise not to breastfeed. (8.2)oRenal Impairment: Monitor for toxicity in patients with moderate and severe renal impairment. (8.6, 12.3). oLactation: Advise not to breastfeed. (8.2). oRenal Impairment: Monitor for toxicity in patients with moderate and severe renal impairment. (8.6, 12.3). 8.1 Pregnancy. Risk SummaryBased on its mechanism of action and published reports of effects in pregnant patients or animals, Cyclophosphamide Injection can cause fetal harm when administered to 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.DataHuman DataMalformations 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 DataAdministration 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.. 8.2 Lactation. Risk SummaryCyclophosphamide is present in breast milk. Neutropenia, thrombocytopenia, low hemoglobin, and diarrhea have been reported in infants breast fed by women treated with cyclophosphamide. Because of the potential for serious adverse reactions in breastfed child, advise lactating women not to breastfeed during the treatment and for week after the last dose.. 8.3 Females and Males of Reproductive Potential. Cyclophosphamide Injection can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to the initiation of Cyclophosphamide Injection.ContraceptionFemalesAdvise female patients of reproductive potential to use effective contraception during treatment with Cyclophosphamide Injection and for up to year after therapy.MalesBased on findings in genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment with Cyclophosphamide Injection for months after therapy [see Nonclinical Toxicology (13.1)].InfertilityFemalesAmenorrhea, transient or permanent, associated with decreased estrogen and increased gonadotropin secretion develops in proportion of women treated with cyclophosphamide. Affected patients generally resume regular menses within few months after cessation of therapy. The risk of premature menopause with cyclophosphamide increases with age. Oligomenorrhea has also been reported in association with cyclophosphamide treatment.Animal data suggest an increased risk of failed pregnancy and malformations may persist after discontinuation of cyclophosphamide as long as oocytes/follicles exist that were exposed to cyclophosphamide during any of their maturation phases. The exact duration of follicular development in humans is not known but may be longer than 12 months [see Nonclinical Toxicology (13.1)].MalesMen treated with cyclophosphamide may develop oligospermia or azoospermia which are normally associated with increased gonadotropin but normal testosterone secretion.. 8.4 Pediatric 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 pediatric patient, use different cyclophosphamide product. Since propylene glycol and alcohol are both metabolized by the same enzymes, co-administration of these excipients may raise systemic exposure to alcohol, particularly in pediatric patients. [see Indications and Usage (1), Warnings and Precautions (5.7), and Description (11)]. Other cyclophosphamide products may have different amount of alcohol or no alcohol.Pre-pubescent girls treated with cyclophosphamide generally develop secondary sexual characteristics normally and have regular menses. Ovarian fibrosis with apparent complete loss of germ cells after prolonged cyclophosphamide treatment in late pre-pubescence has been reported. Girls treated with cyclophosphamide who have retained ovarian function after completing treatment are at increased risk of developing premature menopause.Pre-pubescent boys treated with cyclophosphamide develop secondary sexual characteristics normally but may have oligospermia or azoospermia and increased gonadotropin secretion. Some degree of testicular atrophy may occur. Cyclophosphamide induced azoospermia is reversible in some patients, though the reversibility may not occur for several years after cessation of therapy.. 8.5 Geriatric Use There is insufficient data from clinical studies of cyclophosphamide available for patients 65 years of age and older to determine whether they respond differently than younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac functioning, and of concomitant disease or other drug therapy.. 8.6 Renal Impairment In patients with severe renal impairment, decreased renal excretion may result in increased plasma levels of cyclophosphamide and its metabolites. This may result in increased toxicity [see Clinical Pharmacology (12.3)]. Monitor patients with severe renal impairment (CLcr =10 mL/min to 24 mL/min) for signs and symptoms of toxicity. Cyclophosphamide and its metabolites are dialyzable [see Clinical Pharmacology (12.3)] although there are probably quantitative differences depending upon the dialysis system being used. Use of consistent interval between cyclophosphamide administration and dialysis should be considered in patients requiring dialysis.. 8.7 Hepatic Impairment Patients with severe hepatic impairment have reduced conversion of cyclophosphamide to the active 4-hydroxyl metabolite, potentially reducing efficacy [see Clinical Pharmacology (12.3)].The alcohol content of Cyclophosphamide Injection should be taken into account when given to patients with hepatic impairment [see Warnings and Precautions (5.7)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oMyelosuppression, Immunosuppression, Bone Marrow Failure, and Infections: Severe immunosuppression may lead to serious and sometimes fatal infections. Close hematological monitoring is required. (5.1) oUrinary 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)oCardiotoxicity: 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)oPulmonary 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)oSecondary Malignancies: Have been reported in patients treated with cyclophosphamide containing regimens. (5.5)oVeno-occlusive Liver Disease: Fatal outcome can occur. (5.6)oAlcohol Content: This product is not indicated for use in pediatric patients. The alcohol content in dose of Cyclophosphamide Injection may affect the central nervous system. This may include impairment of patients ability to drive or use machines immediately after infusion. (5.7)oEmbryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to fetus and to use effective contraception. Advise males with female partners of reproductive potential to use effective contraception (5.8, 8.1, 8.3). oMyelosuppression, Immunosuppression, Bone Marrow Failure, and Infections: Severe immunosuppression may lead to serious and sometimes fatal infections. Close hematological monitoring is required. (5.1) oUrinary 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). oCardiotoxicity: 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). oPulmonary 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). oSecondary Malignancies: Have been reported in patients treated with cyclophosphamide containing regimens. (5.5). oVeno-occlusive Liver Disease: Fatal outcome can occur. (5.6). oAlcohol Content: This product is not indicated for use in pediatric patients. The alcohol content in dose of Cyclophosphamide Injection may affect the central nervous system. This may include impairment of patients ability to drive or use machines immediately after infusion. (5.7). oEmbryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to 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/mm3. Cyclophosphamide Injection treatment may not be indicated, or should be interrupted, or the dose reduced, in patients who have or who develop 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 and 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 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 Injection 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 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. cytoreductive regimen in preparation for bone marrow transplantation that consists of Cyclophosphamide Injection in combination with whole-body irradiation, busulfan, or other agents has been identified as 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 low performance status.. 5.7 Alcohol Content Due to the alcohol and propylene glycol content of this product, this cyclophosphamide product is not indicated for use in pediatric patients [see Indications and Usage (1) and Use in Specific Populations (8.4)]. If treatment with cyclophosphamide is indicated for pediatric patient, use different cyclophosphamide product.The alcohol content in dose of Cyclophosphamide Injection may affect the central nervous system and should be taken into account for patients in whom alcohol intake should be avoided or minimized. Consideration should be given to the alcohol content in Cyclophosphamide Injection on the ability to drive or use machines immediately after the infusion. Each administration of this cyclophosphamide product at 25 mg/kg/day delivers 146.2 mg/kg of ethanol. For patient with BSA of 70 kg, this would deliver 10.23 grams of ethanol. Other cyclophosphamide products may have different amount of alcohol or no alcohol.Monitor patients for signs of alcohol intoxication during and after treatment. Counsel patients about the possible effects of the alcohol content in this cyclophosphamide product, including possible effects on the central nervous system.. 5.8 Embryo-Fetal Toxicity 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 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 fetus [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with Cyclophosphamide Injection and for up to year after completion of therapy. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Cyclophosphamide Injection and for months after completion of therapy [see Use in Specific Populations (8.1, 8.3)].. 5.9 Infertility Male and female reproductive function and fertility may be impaired in patients being treated with Cyclophosphamide 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 8.4 )].. 5.10 Impairment of Wound Healing Cyclophosphamide may interfere with normal wound healing.. 5.11 Hyponatremia Hyponatremia associated with increased total body water, acute water intoxication, and syndrome resembling SIADH (syndrome of inappropriate secretion of antidiuretic hormone), which may be fatal, has been reported.