Cyclophosphamide Injection, Solution

Q: Is Cyclophosphamide Injection, Solution available over the counter?

Cyclophosphamide Injection, Solution is a prescription medication. You will need a valid prescription from a licensed healthcare provider.

Prescription

品牌名称： Cyclophosphamide

剂型

Injection

给药途径

INTRAVENOUS

生产厂商

Baxter Healthcare Company

About This Medication

11 DESCRIPTION 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 g/mol. Cyclophosphamide is soluble in water, saline, or ethanol. Cyclophosphamide Injection is a 200 mg/mL sterile clear colorless solution for intravenous use and is available as 500 mg and 1,000 mg strength vials. • 500 mg vial contains 534.5 mg cyclophosphamide monohydrate equivalent to 500 mg cyclophosphamide and 83.9% (v/v) dehydrated alcohol. • 1,000 mg vial contains 1,069 mg cyclophosphamide monohydrate equivalent to 1,000 mg cyclophosphamide and 83.9% (v/v) dehydrated alcohol. Cyclophosphamide Structural Formula.jpg

活性成分

成分	规格
Cyclophosphamide	-

适应证与用法

1 INDICATIONS AND USAGE 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. Cyclophosphamide Injection is an alkylating drug indicated for treatment of adult 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 )

作用原理

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.

用法用量

2 DOSAGE AND ADMINISTRATION Malignant Diseases: Adult and Pediatric Patients ( 2.2 ) • Intravenous: Initial course for patients with no hematologic deficiency: 40 mg/kg to 50 mg/kg in divided doses over 2 to 5 days. Other regimens include 10 mg/ kg to 15 mg/ kg given every 7 to 10 days or 3 mg/ kg to 5 mg/ kg twice weekly. • See full prescribing information for instructions on preparation, handling, and administration. ( 2.3 ) 2.1 Important Dosing 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 Adults and Pediatric Patients Intravenous When used as the only oncolytic drug therapy, the initial course of Cyclophosphamide Injection for patients with no hematologic deficiency usually consists of 40 mg/kg to 50 mg/kg given intravenously in divided doses over a period of 2 to 5 days. Other intravenous regimens include 10 mg/kg to 15 mg/kg given every 7 to 10 days or 3 mg/kg to 5 mg/kg twice weekly. Dosages may also be adjusted based on antitumor activity and/or leukopenia. The total leukocyte count may be used to manage dosage. When Cyclophosphamide Injection is included in combined cytotoxic regimens, it may be necessary to reduce the dose of Cyclophosphamide Injection as well as that of the other drugs. 2.3 Preparation, Handling and Administration Cyclophosphamide Injection is a hazardous drug. 1 Follow applicable special handling and disposal procedures. 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 Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use Cyclophosphamide Injection vials if there are signs of particulate matter. Cyclophosphamide Injection does not contain any antimicrobial preservative and thus care must be taken to assure the sterility of prepared solutions. Use aseptic technique. For Direct Intravenous Injection Aseptically withdraw the prescribed dose from the vial. 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 Do not use Sterile Water for Injection, USP because it results in a hypotonic solution and should not be injected directly. 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 Injection Solution: If not used immediately, for microbiological integrity, cyclophosphamide solutions should be stored as described in Table 1 : Table 1: Storage of Cyclophosphamide Injection Solutions Diluent Storage Room Temperature Refrigerated Diluted solutions (20 mg/mL) 0.9% Sodium Chloride Injection, USP up to 24 hrs up to 6 days 0.45% Sodium Chloride Injection, USP up to 24 hrs up to 6 days 5% Dextrose Injection, USP up to 24 hrs up to 6 days 5% Dextrose and 0.9% Sodium Chloride Injection, USP up to 24 hrs up to 6 days Diluted Solutions (2 mg/mL) 0.9% Sodium Chloride Injection, USP up to 24 hrs up to 6 days 0.45% Sodium Chloride Injection, USP up to 24 hrs up to 6 days 5% Dextrose Injection, USP up to 24 hrs up to 6 days 5% Dextrose and 0.9% Sodium Chloride Injection, USP up to 24 hrs up to 6 days Storage of Undiluted Cyclophosphamide Injection 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.

Side Effects Overview

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling. • Hypersensitivity [see Contraindications (4) ] • Myelosuppression, Immunosuppression, Bone Marrow Failure, and Infections [see Warnings and Precautions (5.1) ] • Urinary Tract and Renal Toxicity [see Warnings and Precautions (5.2) ] • Cardiotoxicity [see Warnings and Precautions (5.3) ] • Pulmonary Toxicity [see Warnings and Precautions (5.4) ] • Secondary Malignancies [see Warnings and Precautions (5.5) ] • Veno-occlusive Liver Disease [see Warnings and Precautions (5.6) ] • Alcohol Content [see Warnings and Precautions (5.7) ] • Infertility [see Warnings and Precautions (5.9) 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) ] Most common adverse reactions reported are neutropenia, febrile neutropenia, fever, alopecia, nausea, vomiting, and diarrhea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare at 1-866-888-2472 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 post-marketing 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.

警告与注意事项

5 WARNINGS AND PRECAUTIONS • Myelosuppression, Immunosuppression, Bone Marrow Failure and Infections - Severe immunosuppression may lead to serious and sometimes fatal infections. Close hematological monitoring is required. ( 5.1 ) • Urinary Tract and Renal Toxicity - Hemorrhagic cystitis, pyelitis, ureteritis, and hematuria can occur. Exclude or correct any urinary tract obstructions prior to treatment. ( 5.2 ) • Cardiotoxicity - Myocarditis, myopericarditis, pericardial effusion, arrhythmias and congestive heart failure, which may be fatal, have been reported. Monitor patients, especially those with risk factors for cardio toxicity or pre-existing cardiac disease. ( 5.3 ) • Pulmonary Toxicity - Pneumonitis, pulmonary fibrosis and pulmonary veno-occlusive disease leading to respiratory failure may occur. Monitor patients for signs and symptoms of pulmonary toxicity. ( 5.4 ) • Secondary Malignancies - Have been reported in patients treated with cyclophosphamide-containing regimens. ( 5.5 ) • Veno-occlusive Liver Disease - Fatal outcome can occur. ( 5.6 ) • Alcohol Content - The alcohol content in a dose of Cyclophosphamide Injection may affect the central nervous system. This may include impairment of a patient’s ability to drive or use machines immediately after infusion. ( 5.7 ) • Embryo-Fetal Toxicity - Can cause fetal harm. Advise patients of reproductive potential of the potential risk to a fetus and 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 (6.1) ] . 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/mm 3 and platelets < 50,000/mm 3 . Cyclophosphamide Injection treatment may not be indicated, or should be interrupted, or the dose reduced, in patients who have or who develop a serious infection. G-CSF may be administered to reduce the risks of neutropenia complications associated with cyclophosphamide use. Primary and secondary prophylaxis with G-CSF should be considered in all patients considered to be at increased risk for neutropenia complications. The nadirs of the reduction in leukocyte count and thrombocyte count are usually reached in weeks 1 and 2 of treatment. Peripheral blood cell counts are expected to normalize after approximately 20 days. Bone marrow failure has been reported. Severe myelosuppression may be expected particularly in patients pretreated with and/or receiving concomitant chemotherapy and/or radiation therapy. 5.2 Urinary Tract and Renal Toxicity Hemorrhagic cystitis, pyelitis, ureteritis, and hematuria have been reported with cyclophosphamide. Medical and/or surgical supportive treatment may be required to treat protracted cases of severe hemorrhagic cystitis. Discontinue cyclophosphamide 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 6 months after start of cyclophosphamide) appears to be associated with increased mortality. Pneumonitis may develop years after treatment with cyclophosphamide. Monitor patients for signs and symptoms of pulmonary toxicity. 5.5 Secondary Malignancies Cyclophosphamide is genotoxic [see Nonclinical Toxicology (13.1) ] . Secondary malignancies (urinary tract cancer, myelodysplasia, acute leukemias, lymphomas, thyroid cancer, and sarcomas) have been reported in patients treated with cyclophosphamide-containing regimens. The risk of bladder cancer may be reduced by prevention of hemorrhagic cystitis. 5.6 Veno-occlusive Liver Disease Veno-occlusive liver disease (VOD) including fatal outcome has been reported in patients receiving cyclophosphamide-containing regimens. A cytoreductive regimen in preparation for bone marrow transplantation that consists of cyclophosphamide in combination with whole-body irradiation, busulfan, or other agents has been identified as a major risk factor. VOD has also been reported to develop gradually in patients receiving long-term low-dose immunosuppressive doses of cyclophosphamide. Other risk factors predisposing to the development of VOD include preexisting disturbances of hepatic function, previous radiation therapy of the abdomen, and a low performance status. 5.7 Alcohol Content The alcohol content in a 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 Cyclophosphamide Injection at 50 mg per kg delivers 0.166 g/kg of ethanol over 2 to 5 days. For a 75 kg patient this would deliver 12.45 grams of ethanol over 2 to 5 days [see Description (11) ] . Other cyclophosphamide products may have a different amount of alcohol or no alcohol. 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 a pregnant woman [see Use in Specific Populations (8.1) , Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1) ] . Exposure to cyclophosphamide during pregnancy may cause birth defects, miscarriage, fetal growth retardation, and fetotoxic effects in the newborn. Cyclophosphamide is teratogenic and embryo-fetal toxic in mice, rats, rabbits and monkeys. Advise pregnant women and females of reproductive potential of the potential risk to a fetus [see Use in Specific Populations (8.1) ] . Advise females of reproductive potential to use effective contraception during treatment with Cyclophosphamide Injection and for up to 1 year after completion of therapy. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Cyclophosphamide Injection and for 4 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 and 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 a syndrome resembling SIADH (syndrome of inappropriate secretion of antidiuretic hormone), which may be fatal, has been reported.

禁忌证

4 CONTRAINDICATIONS 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) ] . • Severe hypersensitivity to cyclophosphamide ( 4 ) • Urinary outflow obstruction ( 4 )

药代动力学

12.3 Pharmacokinetics Pharmacokinetics are linear over the dose range used clinically. Distribution Cyclophosphamide volume of distribution approximates total body water (30 to 50 L). Cyclophosphamide is approximately 20% protein bound, with no dose dependent changes. Some metabolites are greater than 60% protein bound. Elimination The cyclophosphamide elimination half-life ranges from 3 to 12 hours with total body clearance (CL) values of 4 to 5.6 L/h following IV administration. Cyclophosphamide appears to induce its own metabolism. This auto-induction results in an increase in the total clearance, increased formation of active 4-hydroxyl metabolites and shortened elimination half-life values following repeated administration at 12- to 24-hour interval. When cyclophosphamide was administered at 4.0 g/m 2 (approximately 2 times the approved recommended dosage) over a 90-minutes infusion, saturable elimination in parallel with first-order renal elimination describe the kinetics of the drug. Metabolism The liver is the major site of cyclophosphamide activation. Approximately 75% of the administered dose of cyclophosphamide is activated by hepatic microsomal cytochrome P450s including CYP2A6, 2B6, 3A4, 3A5, 2C9, 2C18 and 2C19, with 2B6 displaying the highest 4-hydroxylase activity. Cyclophosphamide is activated to form 4-hydroxycyclophosphamide, which is in equilibrium with its ring-open tautomer aldophosphamide. 4-hydroxycyclophosphamide and aldophosphamide can undergo further oxidation by aldehyde dehydrogenases to form the inactive metabolites 4-ketocyclophosphamide and carboxyphosphamide, respectively. Aldophosphamide can undergo β-elimination to form active metabolites phosphoramide mustard and acrolein. This spontaneous conversion can be catalyzed by albumin and other proteins. Less than 5% of cyclophosphamide may be directly detoxified by side chain oxidation, leading to the formation of inactive metabolites 2-dechloroethylcyclophosphamide. At high doses, the fraction of parent compound cleared by 4-hydroxylation is reduced resulting in non-linear elimination of cyclophosphamide in patients. Excretion Cyclophosphamide is primarily excreted as metabolites. 10 to 20% is excreted unchanged in the urine and 4% is excreted in the bile following IV administration. Specific Populations Renal Impairment Cyclophosphamide exposure increased as the renal function decreased following one-hour intravenous infusion to renally impaired patients. Mean dose-corrected cyclophosphamide AUC increased by 38% in the moderate renal group, (Creatinine clearance (CLcr of 25 to 50 mL/min), by 64% in the severe renal group (CLcr of 10 to 24 mL/min) and by 23% in the hemodialysis group (CLcr of < 10mL/min) compared to the control group. Cyclophosphamide is dialyzable. Dialysis clearance calculated by arterial-venous difference and actual drug recovery in dialysate averaged 104 mL/min, which is in the range of the metabolic clearance of 95 mL/min for the drug. A mean of 37% of the administered dose of cyclophosphamide was removed during hemodialysis. The elimination half- life (t1/2) was 3.3 hours in patients during hemodialysis, a 49% reduction of the 6.5 hours to the elimination half-life reported in uremic patients. Hepatic Impairment Total body clearance (CL) of cyclophosphamide is decreased by 40% in patients with severe hepatic impairment and elimination half-life (t½) is prolonged by 64%. Mean CL and t½ were 45 ± 8.6 L/kg and 12.5 ± 1.0 hours respectively, in patients with severe hepatic impairment and 63 ± 7.6 L/kg and 7.6 ± 1.4 hours respectively in the control group.

Frequently Asked Questions

1 INDICATIONS AND USAGE 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 …

2 DOSAGE AND ADMINISTRATION Malignant Diseases: Adult and Pediatric Patients ( 2.2 ) • Intravenous: Initial course for patients with no hematologic deficiency: 40 mg/kg to 50 mg/kg in divided doses over 2 to 5 days. Other regimens include 10 mg/ kg to 15 mg/ kg given every 7 to 10 days or 3 mg/ kg to 5 mg/ kg twice weekly. • See full prescribing information for instructions on preparation, handling, and administration. ( 2.3 ) 2.1 Important Dosing …

5 WARNINGS AND PRECAUTIONS • Myelosuppression, Immunosuppression, Bone Marrow Failure and Infections - Severe immunosuppression may lead to serious and sometimes fatal infections. Close hematological monitoring is required. ( 5.1 ) • Urinary Tract and Renal Toxicity - Hemorrhagic cystitis, pyelitis, ureteritis, and hematuria can occur. Exclude or correct any urinary tract obstructions prior to treatment. ( 5.2 ) • Cardiotoxicity - Myocarditis, myopericarditis, pericardial effusion, arrhythmias and congestive heart failure, which may be fatal, have been reported. Monitor patients, …

4 CONTRAINDICATIONS 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) ] . • Severe hypersensitivity to cyclophosphamide ( 4 ) • Urinary outflow obstruction ( 4 )

Cyclophosphamide Injection, Solution is a prescription medication. You will need a valid prescription from a licensed healthcare provider.

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References & Data Sources

• DailyMed — Cyclophosphamide Injection, Solution drug label (National Library of Medicine)
• openFDA — Cyclophosphamide Injection, Solution label data (U.S. Food & Drug Administration)
• RxNorm — RXCUI 2386859 (NLM Normalized Drug Names)
• NDC Directory — Cyclophosphamide Injection, Solution (FDA National Drug Code)

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数据来源： DailyMed (NLM), openFDA, MFDS