英文药名: Procytox(cyclophosphamide injection vial)

中文药名: 环磷酰胺注射液/片

给药说明
中文别名：环磷氮芥，安道生，癌得星，癌得散。
外文名：Cyclophosphamide, Cytoxan, En-doxan, Neosar, Procytox, Sendoxan, Cyclophos-phan, Cytophosphan, Genoxal。
药理作用
CTX为HN2的衍生物，其作用与HN2类似，但抗瘤谱比HN2广，毒性亦比HN2小，亦为细胞周期非特异性药物，但对G2期作用显著。本品在体外无活性，在体内经肝微烂漫混合功能氧化酶P450活化后方具有烷化活力。首先是其环N原子邻近的C被氧化，生成4-羟基环烯磷酰胺，自发开环生成醛磷酰胺（aldophosphoramide），4-羟基环磷酰胺与醛磷酰胺两者维持动态平衡，经可溶性酶分别氧化成4-酮基环磷酰胺和羧基磷酰胺，后两者无细胞毒作用，是从尿中排泄的失活性产物，约占CTX用量的80%。未经氧化的醛磷酰胺可自发生成丙烯醋和磷酰胺氮芥（PM），PM是CTX的活性代谢物，具有烷化活性和细胞毒作用。4-羟基环磷酰胺和醛磷酰胺不具有烷化活性，是一种转运型化合物，将高度极性的PM转运到细胞内和血液循环中，PM和DNA形成交叉联结，影响DNA功能，抑制肿瘤细胞生长与繁殖。CTX在临床上的耐药机制正在研究中，许多学者认为与多药耐药基因及P糖蛋白有关。
药动学
本品口服后易被吸收，迅速分布全身，生物利用度为74%~97%，血液浓度1小时后达高峰，与血浆蛋白结合不足20%。在肝脏转化释放出磷酰胺氮芥，半衰期为4~6.5小时；48小时内由肾脏排出50%~70%，68%为代谢物，32%为原形。静脉给药60mg/kg后，血浆峰浓度500umol/L,血浆半衰期为3~10小时。环磷酰胺能少量通过血脑屏障，脑脊液中的浓度仅为血浆的20%。
适应症
本品为目前广泛应用的烷化剂之一。
（1）非霍奇金淋巴瘤：单用有效率为55%~65%，联合用药可选CHOP方案。
（2）小细胞肺癌：单用有效率为38%，联合用药可选COMVP方案。
（3）乳腺癌：单药有效率为33%，联合用药可选CAF方案。
（4）对卵巢癌、多发性骨髓瘤、神经母细胞瘤、睾丸肿瘤、胸腺癌等均有一定疗效。
（5）对儿童急性淋巴细胞性白血病、慢性淋巴细胞性白血病等有较好疗效。
（6）用于宫颈癌、头颈部癌、结肠癌、前列腺癌及肉瘤术后化疗，可提高远期生存率。
（7）作为免疫抑制剂，可用于流行性出血热、肾移植；对Weger肉芽肿及激素耐药的系统性坏死血管炎可作为首选药。
用法用量
成人：
静脉注射，每次15~20mg/kg，或600mg/m2，每周1次，总量8~12g为1疗程；冲击疗法，一般每次不超过1500mg，用生理盐水稀释，由皮管缓慢注射，每周1次，冲击2~3次，治疗无效则停药。
口服，每日2~4mg/kg或50~200mg，作维持治疗，总量10~15g；用于免疫抑制，可每日1.5~3mg，分1~2次口服，连服4~6周。
动脉注射：每次200~400mg，每日或隔日1次，总量8~10g。
儿童：
静脉注射，每次2~6mg/kg，每日或隔日1次，2~3g为1疗程；冲击疗法，每次10~20mg/kg,每周1次，或分2次，以生理盐水20ml稀释后缓慢注射。
口服，每日2~8mg/kg，分2次口服。
任何疑问，请遵医嘱！
不良反应
（1）骨髓抑制：以白细胞下降为最常见，在用药后的8~15日达到最低点，但恢复较快，一般在用药后18~25日即可恢复正常；血小板减少不常出现。
（2）胃肠道反应：常见有食欲下降，恶心，呕吐，少见腹泻，偶可引起口腔炎、胃肠粘膜溃疡，口因部感觉异常。
（3）泌尿系统反应：5%~15%的患者可能出现出血性膀胱炎，表现为尿频、尿急、尿痛等，停药后可恢复，但膀胱损伤是永久性的；大剂量静脉注射时可引起少尿、血尿、蛋白尿等，系本品代谢物丙烯醛对尿路刺激所致，治疗白血病或淋巴瘤时因破坏大量瘤细胞，易发生高尿酸血症及尿酸性肾痛。
（4）心脏毒性：高剂量时可产生心肌坏死，可能引起心脏毒性，出现急性心衰而致死，多发生于首次给药15日内；放射治疗、与色霉素合用均可促使心脏毒性发生。
（5）肝脏毒性：有时可出现肝功能损害，黄疸等。
（6）皮肤反应：损害毛囊，造成脱发；皮炎，皮肤和甲术色素沉着，指甲变形，荨麻疹等。
（7）其它反应：头晕，不安，幻视，久用可致闭经或精子减少，个别可发生肺纤维化，长期使用可发生继发性肿瘤。
禁忌症
（1）孕妇及哺乳妇女禁用。
（2）肝肾功能损害、感染、骨髓抑制、痛风、泌尿系结石和曾接受放疗或化疗患者慎用。
注意事项
（1）使用本品采用大剂量冲击或中等剂量间歇给药比小剂量连续给药疗效好。
（2）当使用冲击疗法或大剂量给药时，应注意膀胱刺激症状，应鼓励患者多饮水，大量补液，碱化尿液，每日尿量保持在2000~3000ml，以减轻刺激。
（3）本品与别嘌呤醇合用，有可能加重其骨髓抑制；与苯二氮卓类药物同用时，可能使肝药酶受诱导，使本品代谢产物增多，毒性增加。本品还可增加血清尿酸水平，与阿霉素同用可增加心脏毒性。
（4）本品溶解度小，应强力摇匀，必须在完全溶解后才能注射用。
Cyclophosphamide
Pronunciation: SYE-kloe-FOS-fa-mide
Class: Nitrogen mustard, Alkylating agent
Trade Names
Cyclophosphamide
- Tablets 25 mg
- Tablets 50 mg
- Injection, powder for solution 500 mg
- Injection, powder for solution 1 g
- Injection, powder for solution 2 g
Procytox (Canada)
Pharmacology
Cyclophosphamide is first hydroxylated by hepatic microsomal enzymes to the intermediate metabolites 4-hydroxycyclophosphamide and aldophosphamide. These are oxidized to the active antineoplastic alkylating compounds acrolein and phosphoramide mustard. The mechanism of action of the active metabolites is thought to involve cross-linking of DNA, which interferes with growth of susceptible neoplasms and normal tissues.
Pharmacokinetics
Absorption
Well absorbed orally. T max is 2 to 3 h for metabolites (IV dose).
Distribution
More than 75% bioavailable after oral administration. More than 60% of metabolites are bound to plasma proteins. Low protein binding for cyclophosphamide.
Metabolism
Converted to active alkylating metabolites in the liver.
Elimination
The half-life is 3 to 12 h (unchanged drug). Eliminated primarily as metabolites. 5% to 25% is excreted in urine as unchanged drug.
Special Populations
Renal Function Impairment
Metabolites may be elevated, but increased toxicity has not been seen. Dosage adjustment required in severe renal impairment.
Indications and Usage
Malignant diseases
Malignant lymphomas (stages III and IV of the Ann Arbor staging system); Hodgkin disease; lymphocytic lymphoma (nodular or diffuse); mixed-cell type lymphoma; histocytic lymphoma; Burkitt lymphoma; multiple myeloma; chronic lymphocytic leukemia; chronic granulocytic leukemia; acute myelogenous and monocytic leukemia; acute lymphoblastic (stem cell) leukemia in children; mycosis fungoides (advanced disease); neuroblastoma (disseminated disease); adenocarcinoma of the ovary; retinoblastoma; carcinoma of the breast.
Nephrotic syndrome
Biopsy-proven minimal change nephrotic syndrome in children, but not as primary therapy.
Unlabeled Uses
Multiple sclerosis; Wegener granulomatosis; other steroid-resistant vasculitis; severe progressive rheumatoid arthritis; SLE; polyarteritis nodosa; bronchogenic, small cell lung, endometrial, prostate, and testicular carcinomas; sarcomas; hematopoietic stem cell transplantation (HSCT).
Contraindications
Previous hypersensitivity to the drug; continued use in severely depressed bone marrow function.
Dosage and Administration
Malignant Diseases
Adults and Children PO
1 to 5 mg/kg daily for both initial and maintenance treatment.
IV
When used as the only oncolytic agent in patients with no hematologic deficiency, the initial dose is 40 to 50 mg/kg in divided doses over a period of 2 to 5 days. Alternatively, other regimens have included 10 to 15 mg/kg every 7 to 10 days or 3 to 5 mg/kg twice weekly.
Dosage adjustment
Adjust dosage according to evidence of antitumor activity and/or leukopenia. Total leukocyte count is an objective indicator for regulating dosage. Transient decreases in the total WBC count to 2,000 cells/mm 3 (following short courses) or more persistent reduction to 3,000 cells/mm 3 (with continuing therapy) are tolerated without serious risk of infection if there is no marked granulocytopenia.
Nephrotic Syndrome (Biopsy-Proven Minimal Change)
Children
PO 2.5 to 3 mg/kg daily for 60 to 90 days is recommended. Oligospermia and azoospermia increase if the duration of treatment exceeds 60 days. Treatment beyond 90 days increases the probability of sterility.
Severe Renal Function Impairment
Dosage reduction to 75% of the usual dosage may be necessary in patients with severe renal failure (CrCl 0 to 10 mL/min). After hemodialysis, some clinicians recommend supplementing with 50% of the original dose.
Hepatic Function Impairment
For patients with bilirubin of 3.1 to 5 mg/dL or AST more than 180 units/L, administer 75% of the usual dosage. Do not give to patients with bilirubin more than 5 mg/dL.
General Advice
•Administer tablets on an empty stomach.
•Injection may be administered by IV injection, IV infusion (over 1 to 2 h), IM, intraperitoneally, or intrapleurally.
•Reduce the cyclophosphamide dose when cyclophosphamide is included in combination with cytotoxic regimens.
•Extemporaneous liquid preparations for oral administration may be prepared by dissolving cyclophosphamide for injection in aromatic elixir, N.F, to a concentration of 1 to 5 mg/mL.
•Follow safe handling procedures when dispensing and discarding oral chemotherapy. Wear gloves and avoid skin exposure and inhalation of fumes.
Storage/Stability
Store tablets and vials below 77°F. The tablets will withstand brief exposure to temperatures up to 86°F. Store extemporaneous oral liquid preparation refrigerated in glass containers and use within 14 days. Constituted cyclophosphamide is stable for 24 h at room temperature or for 6 days in the refrigerator.
Drug Interactions
Allopurinol
The myelosuppressive effects of cyclophosphamide may be enhanced, possibly increasing the risk of bleeding or infection. Monitor hematologic function. If an interaction is suspected, it may be necessary to discontinue allopurinol.
Anticoagulants (eg, warfarin)
Increased hypoprothrombinemic effect may occur. Monitor coagulation parameters during and after cyclophosphamide therapy. Adjust the warfarin dose as needed.
Chloramphenicol
Cyclophosphamide half-life may be increased and metabolite concentrations may be decreased. Use an alternative antibiotic if possible.
Digoxin
May cause decreased serum levels of digoxin. Monitor digoxin serum concentrations and the clinical response of the patient. Adjust the digoxin dose as needed.
Doxorubicin
Doxorubicin-induced cardiotoxicity may be potentiated. Use with caution. Monitor for symptoms of cardiotoxicity.
Enzyme inducers (eg, barbiturates [eg, phenobarbital], phenytoin)
Exposure to the active cyclophosphamide metabolites may be increased, increasing the risk of toxicity. If administration cannot be avoided, consider reducing the initial dose of cyclophosphamide and monitoring the concentration of the 4-hydroxycyclophosphamide metabolite as a guide to cyclophosphamide dosing. Valproic acid derivatives or gabapentin may be alternatives to the use of phenytoin.
Enzyme inhibitors (eg, azole antifungal agents [eg, fluconazole, itraconazole], carbamazepine)
Exposure to cyclophosphamide and its metabolites may be increased, increasing the risk of adverse reactions. Closely monitor for cyclophosphamide adverse reactions. Adjust the cyclophosphamide dose as needed to minimize toxicity.
Pentostatin
Additive or synergistic toxicity. Respiratory distress, hypotension, hypothermia, confusion, and death may occur after the coadministration of pentostatin and cyclophosphamide. Avoid coadministration if possible.
Quinolones (eg, ciprofloxacin)
The antimicrobial effects of quinolones may be decreased. Monitor the clinical response of the patient, and adjust the quinolone dose as needed.
Succinylcholine
Prolongation of neuromuscular blockade by cyclophosphamide's inhibition of pseudocholinesterase may occur. Prolonged respiratory depression with extended periods of apnea may occur. Use with caution. If this combination is used, prior measurement of plasma cholinesterase activity with close monitoring of neuromuscular function and appropriate adjustment of succinylcholine dosage is recommended.
Thiazide diuretics
Antineoplastic-induced leukopenia may be prolonged. Monitor hematologic function. Use with caution.
Trastuzumab
The risk of trastuzumab-induced cardiac dysfunction may be increased by coadministration of cyclophosphamide. Close clinical monitoring for signs of cardiac dysfunction is indicated when trastuzumab and cyclophosphamide are coadministered.
Tumor necrosis factor (TNF)–blocking agents (eg, etanercept)
The incidence of noncutaneous solid malignancies may be increased in patients receiving TNF–blocking agents with cyclophosphamide. Coadministration is not recommended.
Vaccines, live
The risk of live vaccine–induced adverse reactions may be increased by coadministration of cyclophosphamide. The use of live vaccines in patients receiving cyclophosphamide should be deferred.
Adverse Reactions
Cardiovascular
Acute cardiac toxicity, CHF, hemopericardium, hemorrhagic myocarditis, myocardial necrosis, pericarditis.
CNS
Asthenia, malaise (postmarketing).
Dermatologic
Alopecia (common); nail changes, skin pigmentation, skin rash; Stevens-Johnson syndrome, TEN (postmarketing).
Endocrine
SIADH.
GI
Nausea and vomiting (common); abdominal discomfort or pain, anorexia, diarrhea, hemorrhagic colitis, oral mucosal ulceration, nausea, vomiting.
Genitourinary
Amenorrhea associated with decreased estrogen and increased gonadotropin secretion, atypical urinary bladder epithelial cells in the urine, azoospermia, cystitis, hematuria, hemorrhagic cystitis, hemorrhagic ureteritis, impairment of fertility, oligospermia, ovarian fibrosis, renal tubular necrosis, sterility, testicular atrophy, urinary bladder fibrosis.
Hepatic
Jaundice.
Hematologic-Lymphatic
Anemia, leukopenia, neutropenia with or without fever, thrombocytopenia.
Hypersensitivity
Anaphylactic reactions, including death.
Respiratory
Interstitial pneumonitis, interstitial pulmonary fibrosis (postmarketing).
Miscellaneous
Secondary malignancies (eg, urinary bladder, myeloproliferative, or lymphoproliferative malignancies; carcinoma of the renal pelvis).
Precautions
Monitor
Monitor hematologic profile, particularly neutrophils and platelets, regularly to determine the degree of hematopoietic suppression. Examine urine regularly for RBCs, which may precede hemorrhagic cystitis.
Pregnancy
Category D . Contraindicated during the first trimester.
Lactation
Excreted in breast milk. Contraindicated in breast-feeding.
Elderly
Select dose with caution, usually starting at the low end of the dosing range, and adjust as necessary based on response.
Hypersensitivity
Death associated with anaphylactic reactions has been reported.
Renal Function
Use with caution; there is no consistent evidence indicating a need for dosage modification.
Hepatic Function
Use cautiously. There is no evidence indicating a need for modified dosage in these patients.
Carcinogenesis
Secondary malignancies have developed with cyclophosphamide alone or with other antineoplastic drugs or radiation therapy. These most frequently have been urinary bladder, myeloproliferative, and lymphoproliferative malignancies. In some cases, the second malignancy developed several years after the discontinuation of cyclophosphamide.
Fertility
Cyclophosphamide interferes with oogenesis and spermatogenesis. It may cause sterility in men and women. Amenorrhea associated with decreased estrogen and increased gonadotropin secretion develops in a significant proportion of women treated with cyclophosphamide.
Special Risk Patients
Administer with caution to patients with leukopenia, thrombocytopenia, tumor cell infiltration of bone marrow, previous radiation therapy, or previous cytotoxic therapy.
Adrenalectomy patients
Adjustment of the doses of replacement steroids and cyclophosphamide may be necessary for the adrenalectomized patient.
Cardiac toxicity
Few instances of cardiac dysfunction have occurred. No causal relationship has been established.
GU
Acute hemorrhagic cystitis may occur. Rarely, this may be severe and even fatal. Urinary bladder fibrosis may also develop with or without accompanying cystitis. Ample fluid intake and frequent voiding help to prevent cystitis. Vigorous hydration and frequent urination reduce the risk of hemorrhagic cystitis. Encourage patients to drink extra fluids to maintain urine output.
Hematologic
Leukopenia of less than 2,000 cells/mm 3 develops commonly in patients treated with an initial loading dose of the drug. Thrombocytopenia or anemia develop occasionally. Recovery from leukopenia usually begins in 7 to 10 days after cessation of therapy.
Immunosuppression
May cause significant suppression of immune responses. Serious, sometimes fatal, infections may develop in severely immunosuppressed patients.
Oligospermia and azoospermia
Oligospermia and azoospermia increase if the duration of treatment exceeds 60 days. Treatment beyond 90 days increases the probability of sterility.
Wound healing
May interfere with normal wound healing.
Overdosage
Symptoms
No information is available.
Patient Information
•Advise patients to take tablets preferably on an empty stomach. If GI upset is severe, advise patients to take with food.
•Advise patients to notify health care provider if the following symptoms occur: blood in urine or painful/frequent urination, chills, cough, fever, flank or stomach pain, lack of menstrual flow, severe nausea or vomiting, shortness of breath, sore throat, unusual bleeding or bruising, unusual lumps or masses, yellow discoloration of the skin or eyes.
•Recommend contraceptive measures during therapy for men and women.
•Advise patients that irreversible sterility may develop.
•Advise women not to breast-feed.
•Advise patients to drink extra fluids and void frequently.
•Advise patients undergoing general anesthesia to inform the anesthesiologist of treatment with cyclophosphamide.

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【原产地英文商品名】CYTOXAN 500mg/ml/vial
【原产地英文药品名】CYCLOPHOSPHAMIDE
【中文参考商品译名】
注：以下产品不同的规格和不同的价格，购买时请以咨询为准
·CYTOXAN 500毫克/毫升/瓶
·CYTOXAN 500毫克/12毫升/瓶
·CYTOXAN 2克/毫升/瓶
·CYTOXAN 2克/12毫升/瓶
·CYTOXAN 1克/毫升/瓶 
【中文参考药品译名】环磷酰胺
【生产厂家中文参考译名】百特
【生产厂家英文名】BAXTER HLTHCARE
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【产地英文商品名】CYCLOPHOSPHAMIDE(CYTOXAN GENERIC)500mg/vial
【原产地英文药品名】CYCLOPHOSPHAMIDE
【中文参考商品译名】
注：以下产品不同的规格和不同的价格，购买时请以咨询为准
·环磷酰胺(CYTOXAN仿制药)500毫克/瓶
·环磷酰胺(CYTOXAN仿制药)2克/瓶
·环磷酰胺(CYTOXAN仿制药)1克/瓶
【中文参考药品译名】环磷酰胺
【生产厂家中文参考译名】百特
【生产厂家英文名】BAXTER HLTHCARE
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【原产地英文商品名】CYCLOPHOSPHAMIDE(CYTOXAN GENERIC)50mg/tab 30tabs/bottle
【原产地英文药品名】CYCLOPHOSPHAMIDE
【中文参考商品译名】
注：以下产品不同的规格和不同的价格，购买时请以咨询为准
·环磷酰胺(CYTOXAN仿制药)50毫克/片 30片/瓶
·环磷酰胺(CYTOXAN仿制药)25毫克/片 100片/瓶
【中文参考药品译名】环磷酰胺
【生产厂家中文参考译名】ROXANE
【生产厂家英文名】ROXANE