[Drug Name]

Common name: Isocyclophosphamide for injection

English name: ifosfamide for Injection

Chinese Pinyin: Zhusheyong Yihuanlinxian'an

Ingredients

The main ingredient of this product is ifosfamide.

Chemical name: 3-（ α－ Chloroethyl) -2- [(2-chloroethyl) amino] - tetrahydro-2H-1,3,2-oxaphosphor-2-oxide.

Molecular formula: C7H15Cl2N2O2P

Molecular weight: 261.09

Excipients used: glycine, mannitol.

【 Description 】 This product is a white or almost white loose block or powder.

[Indications] It is applicable to testicular cancer, ovarian cancer, breast cancer, sarcoma, malignant lymphoma and lung cancer.

[Specification] 1.0g

[Usage and Dosage]

This product is dissolved and diluted with 0.9% sodium chloride injection, then slowly intravenous drip for at least 30 minutes.

Single drug treatment: Intravenous injection is administered with a body surface area of 1.2-2.5g/m2 per day for 5 consecutive days as a course of treatment.

The combination therapy is administered intravenously with a body surface area of 1.2-2.0 g/m2 per day for 5 consecutive days as a course of treatment.

At the same time of administration and 4 hours and 8 hours after administration, 0.4g of mesylate sodium dissolved in physiological saline was administered intravenously.

The dosage of medication for patients with impaired liver and kidney function has not been determined yet.

Adverse reactions

For patients who only use ifosfamide monotherapy, the limited dose toxicity is bone marrow suppression and urinary toxicity. The dosage should be applied in stages, with a large amount of water intake and the use of protective agents such as methotrexate, which can significantly reduce the incidence of hemorrhagic cystitis complicated by hematuria, especially visible hematuria. The daily dose is 1.2g/m2, used continuously for 5 days. If there is a decrease in white blood cells, it is usually mild to moderate. Other significant side effects include hair loss, nausea, vomiting, and central nervous system toxicity.

1. Hematological toxicity: Bone marrow suppression is a dose dependent and dose limited toxicity. The main cause is a decrease in white blood cells, followed by a decrease in platelets. 50% of patients who use only 1.2g/m2 of cyclophosphamide daily for 5 consecutive days may experience a white blood cell count below 3000/ μ L. Approximately 20% of patients experience thrombocytopenia (<100000) at this dose/ μ l) . If a higher dose is used, almost all cases have a decrease in white blood cells. During the total dose of 10-12g/m2 treatment, half of the patients had white blood cells below 1000/ μ l. 8% of patients have platelets below 50000/ μ L. Bone marrow suppression is usually reversible and can be treated again every 3-4 weeks. When ifosfamide is used in combination with other bone marrow suppressants, the dosage must be adjusted. Patients with severe bone marrow suppression may increase the risk of infection.

2. Digestive system: 58% of patients receiving this medication experience nausea and vomiting, which can usually be controlled with standard antiemetic therapy. Other gastrointestinal side effects include anorexia, diarrhea, and in some cases, constipation.

3. Urinary system: Urethral toxicity includes hemorrhagic cystitis, painful urination, frequent urination, and other bladder irritation symptoms. 6% to 92% of patients treated with this medication experience hematuria. By consuming a large amount of water and administering protective agents such as mesodium in doses, the incidence and severity of hematuria can be significantly reduced. A daily dose of 1.2g/m2 was used continuously for 5 days. About half of the patients who did not use protective agents had microscopic hematuria, and about 8% of the patients had visible hematuria.

6% of patients treated with ifosfamide alone experience nephrotoxicity. The clinical indication is an increase in blood urea nitrogen (BUN) or serum creatinine, or a decrease in creatinine clearance rate, usually temporary. These may be related to damage to the renal tubules. There is a reported case of occasional renal tubular acidosis progressing to chronic renal failure, and in rare cases, proteinuria and acidosis also occur. There is a study that found that the dosage of this drug is 2-2.5g/m2 per day for a total of 4 days, and 31% of patients experience metabolic acidosis. There have also been reports of renal tubular acidosis, Fanconi syndrome, and nephrotic rickets. Therefore, it is recommended to closely monitor serum and urinary chemistry, including phosphorus, potassium, alkaline phosphatase, and other appropriate laboratory tests. Appropriate alternative therapies should be used.

4. Central nervous system: 12% of patients treated with this medication experience central nervous system side effects. The most common ones include drowsiness, mental disorder, depressive psychosis, and hallucinations. Other rare symptoms include dizziness, loss of directional ability, and neurological dysfunction in the brain. Occasional reports of seizures and fatal coma. The incidence of central nervous system toxicity is higher in patients with renal function changes.

5. Other: About 83% of patients treated with ifosfamide monotherapy experience hair loss. When combined with medication, the incidence can reach up to 100%, depending on the other drugs in the chemotherapy regimen. 3% of patients experience elevated levels of liver enzymes and/or bilirubin. Other rare side effects include phlebitis, pulmonary symptoms, unexplained fever, allergic reactions, stomatitis, cardiotoxicity, and polyneuropathy.

Long term medication can lead to immunosuppression, pituitary dysfunction, infertility, and secondary tumors.

The taboo is not yet clear.

【 Precautions 】

1. Urinary system: The use of ifosfamide often leads to toxic side effects in the urinary system, especially hemorrhagic cystitis. Therefore, it is recommended to perform urine routine analysis before administering each dose of this drug. If there is hematuria during microscopic examination (more than 10 red blood cells per high-power field of view), it should be discontinued until hematuria is completely eliminated. In the future, the application of this medicine should be accompanied by drinking a large amount of water or injecting a large amount of aqueous solution.

2. Hematopoietic system: When used in combination with other chemotherapy drugs, cyclophosphamide often leads to severe bone marrow suppression. Therefore, it is recommended to closely monitor hematological indicators. White blood cell, platelet count, and hemoglobin measurements should be taken before each medication and at appropriate intervals. Unless clinically necessary, white blood cells are less than 2000/ μ L and/or platelet count less than 50000/ μ Patients with l should not be given cyclophosphamide.

3. Central nervous system: Neurological symptoms reported after treatment with ifosfamide include drowsiness, mental confusion, hallucinations, and in some cases, coma. Stop using this medication when these symptoms occur. These symptoms are usually reversible and symptomatic supportive therapy can be taken until they completely disappear.

4. Isocyclophosphamide should be used with caution in the following situations: those with impaired liver and kidney function; Individuals with impaired bone marrow function, such as decreased white blood cells and granulocytes; Widespread metastasis of bone marrow cancer; Those who have undergone radiation therapy or have previously been treated with other cytotoxic drugs; Hypoalbuminemia; Women of childbearing age.

5. Laboratory examination: During treatment, the patient's blood (especially neutrophils and platelets) should be regularly tested to understand the degree of hematopoietic suppression. Regular examination of red blood cells in urine should also be conducted, as they may appear before hemorrhagic cystitis.

6. The aqueous solution of this product is unstable and needs to be prepared and used immediately. When dispensing, gloves should be worn. If accidentally touched with this product, skin reactions may occur. It should be thoroughly washed with soap and water immediately.

【 Pregnant and lactating women's medication 】

Animal studies have shown that this product has mutagenic and teratogenic effects, which can cause fetal death or congenital malformations. It is contraindicated for pregnant women. This product can be excreted in breast milk and breastfeeding must be terminated when starting medication.

The medication for children is not yet clear.

The medication for the elderly is not yet clear.

Drug interactions

Previously used cisplatin in patients can exacerbate bone marrow suppression, neurotoxicity, and nephrotoxicity of ifosfamide.

2. Using anticoagulants simultaneously may lead to a risk of bleeding.

3. Simultaneously using hypoglycemic drugs can enhance the hypoglycemic effect.

When used in combination with other cytotoxic drugs, the dosage should be reduced as appropriate.

5. Simultaneous radiation therapy can exacerbate skin reactions caused by radiation therapy.

[Drug overdose] There is no special antidote for excessive poisoning caused by ifosfamide. Generally, supportive therapy is used to maintain the patient's life.

Pharmacology and Toxicology

Pharmacological effects

This product has no anti-cancer activity in vitro. When it enters the body, it is hydrolyzed by phosphatases or phosphatases present in the liver or tumors, becoming active phosphamide nitrogen mustard and acting. Its mechanism of action may involve cross binding with DNA, inhibiting DNA synthesis, and interfering with RNA function, making it a non-specific drug in the cell cycle. This product has a wide anti-tumor spectrum and has inhibitory effects on various types of tumors.

Toxicological research

Genetic toxicity: Both in vitro bacterial mutation tests and experiments conducted in mammalian cells have shown that this product has mutagenic effects. In vivo, it can cause mutations in mouse and Drosophila melanogaster embryonic cells, and significantly increase dominant lethal mutations in male mice and recessive linked lethal mutations in Drosophila.

Reproductive toxicity: Pregnant mice were given 30mg/m2 of ifosfamide on the 11th day of pregnancy, and increased embryo absorption was observed on the 19th day. After administering 54mg/m2 of ifosfamide on the 6th to 15th day of pregnancy in rats, embryonic lethality was observed. From the 6th to the 18th day after mating in rabbits, embryo toxicity was observed by administering 88mg/m2 of cyclophosphamide. The number of abnormal embryos increased significantly compared to the control group.

Carcinogenicity: Studies in rats have shown that this product is carcinogenic, with female rats exhibiting more pronounced production of leiomyosarcoma and breast fibroma.

Pharmacokinetics

After entering the body, it is widely metabolized, and the metabolites may vary among different individuals. Metabolic saturation occurs at high doses. According to the body surface area, a single intravenous injection of 3.8-5.0g/m2 results in a biphasic attenuation of blood drug concentration, with a half-life of approximately 15 hours for final elimination; According to the body surface area, a single intravenous injection of 1.6-2.4g/m2 results in a single-phase attenuation of blood drug concentration, with a half-life of approximately 7 hours for final elimination; 70% to 80% are excreted through the kidneys; When injecting 5.0g/m2 of body surface area at once, 61% is discharged in its original form; When administered intravenously with a surface area of 1.2-2.4g/m2, only 12% to 18% are discharged in their original form.

【 Storage 】 Store in a dark and cold place.

【 Packaging 】 Controlled glass bottle, 1 piece/box.

【 Validity 】 36 months.

[Executive Standard] National Drug Standard YBH11862005

[Approval Number] National Pharmaceutical Approval Letter H20055196