Xeloda Capecitabine希罗达(卡培他滨片)

 

【 Function and Indication 】
Adjuvant chemotherapy for colon cancer:
Xeloda is suitable for Dukes’C stage, after radical resection of primary tumor, and is suitable for single-drug adjuvant treatment of colon cancer patients who receive fluorouracil alone. The disease-free survival time (DFS) is no less than that of 5- fluorouracil combined with leucovorin (5-FU/LV). Xeloda alone or in combination with other drugs can not prolong the overall survival (OS), but the experimental data show that Xeloda can improve the disease-free survival compared with 5-FU/LV in combination chemotherapy.
Doctors can refer to the above research results when prescribing Xeloda monotherapy for Dukes’C colon cancer. The data used to support this indication come from foreign clinical research (see the part of [Clinical Trial]).

Colorectal cancer:
Xeloda can be used as first-line chemotherapy when patients with metastatic colorectal cancer are first treated with fluoropyrimidines alone. The survival time of xeloda combined with other drugs is better than that of 5-FU/LV chemotherapy alone. At present, there is no evidence to prove the survival advantage of xeloda monotherapy. The safety and survival advantage of Xeloda replacing 5-FU/LV in combined chemotherapy need further study.

Breast cancer:
Combined chemotherapy for breast cancer: Xeloda can be combined with docetaxel to treat metastatic breast cancer with anthracycline-containing chemotherapy failure.
Single-drug chemotherapy for breast cancer: Xeloda can also be used alone to treat metastatic breast cancer patients who are resistant to paclitaxel and anthracycline-containing chemotherapy schemes or who are resistant to paclitaxel and can no longer be treated with anthracycline drugs (for example, they have received a cumulative dose of 400mg/m2 adriamycin or its analogues).
The definition of drug resistance is that the disease continues to progress (with or without initial remission) during treatment, or recurs within 6 months after completing adjuvant chemotherapy containing anthracyclines.

Gastric cancer:
Xeloda is suitable for the first-line treatment of inoperable advanced or metastatic gastric cancer.

“Model and specification”
The biconvex, rectangular and peach-colored coated tablets are white after coating is removed. There is XELODA on one side and 500 on the other.

【 Usage and dosage 】
The recommended dose of Xeloda is 1250mg/m2, taken orally twice a day (once in the morning and once in the evening; Equal to the total daily dose of 2500mg/m2). After 2 weeks of treatment, the drug was stopped for 1 week, and 3 weeks was a course of treatment.

Xeloda tablets should be swallowed with water within 30 minutes after meals. When combined with docetaxel, the recommended dose of xeloda is 1250mg/m2, twice a day, and the drug is stopped for one week after two weeks of treatment. The recommended dose of docetaxel combined with xeloda is 75mg/m2, once every three weeks and given intravenously for one hour.

According to the instructions of docetaxel, some adjuvant drugs should be routinely used before docetaxel is used in patients who receive xeloda and docetaxel combined chemotherapy.

The following table lists the total daily dose of Xeloda and the number of tablets to be taken for each dose calculated by body surface area.

When used as adjuvant therapy for Dukes’C colon cancer patients, the recommended treatment time is 6 months, that is, Xeloda 1250mg/m2, taken orally twice a day. After 2 weeks of treatment, the drug is stopped for 1 week, and 3 weeks is a course of treatment, with a total of 8 courses (24 weeks).

[Clinical research]
At present, there are not enough studies to evaluate the carcinogenicity of Xeloda. Xeloda did not cause mutation in bacteria (Ames test) or mammalian cells (China hamster V79/HPRT gene mutation analysis) in vitro. Xeloda can break human peripheral blood lymphocytes in vitro, but it has no breaking effect in mouse bone marrow in vivo (micronucleus test). Fluorouracil causes mutation in bacteria and yeast, and also causes chromosome abnormality in micronucleus test in mice.

In the study of fertility and total reproductive performance of mice, taking Xeloda 760mg/kg/ day orally disturbed estrus and led to the decline of fertility. In pregnant mice, no embryos survived at this dose. The disturbance of estrus is reversible. This dose caused degenerative changes in males in this experiment, including a decrease in the number of spermatocytes and sperm cells. A separate pharmacokinetic study showed that the dose corresponding to the 5′-DFURAUC value in mice was about 0.7 times the daily recommended dose of patients.

【 Precautions 】
Diarrhea: Xeloda can cause diarrhea, sometimes more serious. Patients with severe diarrhea should be closely monitored. If patients begin to dehydrate, fluids and electrolytes should be supplemented immediately. Under appropriate circumstances, we should start using standard antidiarrheal drugs (such as loperamide) as soon as possible. Reduce the dosage if necessary.

Dehydration: dehydration must be prevented and corrected in time when dehydration occurs. Dehydration can occur early when patients have anorexia, weakness, nausea, vomiting or diarrhea. When there are symptoms of dehydration of grade 2 (or above), the treatment of Xeloda must be stopped immediately, and dehydration must be corrected at the same time. Xeloda treatment can not be resumed until the symptoms of dehydration disappear and the direct cause of dehydration is corrected and controlled. In view of this adverse event, it is necessary to adjust the dosage.

The observed cardiotoxicity of Xeloda is similar to that of fluorouracil, including myocardial infarction, angina pectoris, arrhythmia, cardiac arrest, heart failure and ECG changes. These adverse events may be more common in patients with previous history of coronary artery disease.

In the past, there were rare and unpredictable serious toxicity related to 5- fluorouracil (such as oral inflammation, diarrhea, neutropenia and neurotoxicity) caused by dihydropyrimidine dehydrogenase deficiency (DPD). Therefore, it is impossible to rule out the possibility that there is a correlation between the decrease of DPD level and the enhancement of the potentially lethal toxic effect of 5- fluorouracil.

Xeloda can cause hand-foot syndrome (palm-sole redness and pain or acromegaly caused by chemotherapy), a kind of skin toxicity. Patients with metastatic tumor received Xeloda monotherapy. The median time of hand-foot syndrome was 79 days (ranging from 11 to 360 days), and the severity was 1-3.

Grade 1 hand-foot syndrome is defined as any of the following phenomena: numbness of hands and/or feet, insensitive/abnormal sensation, tingling sensation, erythema and/or discomfort that does not affect normal activities. Grade 2 hand-foot syndrome is defined as painful erythema and swelling of hands and/or feet and/or discomfort affecting patients’ daily life. Grade 3 hand-foot syndrome is defined as wet desquamation, ulcer, blister or severe pain of hands and/or feet and/or severe discomfort that prevents patients from working or carrying out daily activities.

When there is grade 2 or 3 hand-foot syndrome, the use of Xeloda should be suspended until it returns to normal or the severity is reduced to grade 1. After grade 3 hand-foot syndrome, the dosage should be reduced when xeloda is used again. When xeloda is combined with cisplatin, it is not recommended to use vitamin B6 (pyridoxine) to improve symptoms or secondary prevention for hand-foot syndrome, because it is reported that vitamin B6 may reduce the curative effect of cisplatin.

Xeloda can cause hyperbilirubinemia. If the drug-related bilirubin increase is > 3.0xULN or the liver transaminase (ALT, AST) increase is > 2.5xULN, the use of Xeloda should be suspended immediately. When bilirubin is reduced to ≤3.0xULN or liver transaminase ≤2.5xULN, Xeloda can be resumed.

A drug interaction study showed that the average AUC of S- warfarin increased significantly (+57%) when Xeloda was combined with a single dose of warfarin. The results suggest that the interaction may be due to the inhibition of Xeloda on cytochrome P450-2C9 isoenzyme system.

The anticoagulation reaction (INR or PT) should be closely monitored in patients taking Xeloda and taking coumarin derivative anticoagulant orally, and the dosage of anticoagulant should be adjusted accordingly. The toxic reaction of xeloda treatment should be closely monitored. Most adverse reactions are reversible, although the dosage may need to be limited or reduced, but there is no need to stop using the drug.

Renal dysfunction: Xeloda should be used with caution in patients with renal dysfunction. Like 5- fluorouracil, patients with moderate renal function impairment (creatinine clearance rate is 30-50mL/min[Cockroft and Gault]) have a higher incidence of treatment-related grade 3 or 4 adverse events.

For patients with moderate renal impairment (creatinine clearance rate is 30-50mL/min[Cockroft and Gault]), it is suggested that the initial dosage of Xeloda should be reduced to 75% of the standard dosage. This suggestion of dose adjustment is suitable for xeloda monotherapy and xeloda combination therapy. If the patient has grade 2-4 adverse events, it should be closely monitored and the medication should be suspended immediately. For subsequent dose adjustment, please refer to the corresponding dose adjustment table.

Liver function damage: Xeloda should be closely monitored when used in patients with liver function damage. The effect of liver injury caused by non-liver metastasis or severe liver injury on the distribution of xeloda in vivo is not clear.

[Adverse reactions and contraindications]
Digestive system: The most common adverse reactions are reversible gastrointestinal reactions, such as diarrhea, nausea, vomiting, abdominal pain and gastritis. Serious (grade 3-4) adverse reactions are relatively rare.

Skin: Hand-foot syndrome occurs in almost half of patients who use it: numbness, insensitivity, paresthesia, tingling, no pain or pain, skin swelling or erythema, desquamation, blisters or severe pain. Dermatitis and alopecia are common, but severe cases are rare.

General adverse reactions: fatigue is common but serious is rare. Other common adverse reactions are mucositis, fever, weakness and lethargy, but they are not serious.

It is forbidden for those who are known to be allergic to Xeloda or any of its components.

Xeloda is prohibited for patients who have had serious and unexpected reactions to fluorouracil in the past or are known to be allergic to fluorouracil.

Xeloda, like other fluorouracil drugs, is contraindicated in patients with known dihydropyrimidine dehydrogenase (DPD) deficiency.

Xeloda should not be administered at the same time as solivudine or its analogues (such as stinking).

Xeloda is contraindicated in patients with severe renal function injury (creatinine clearance rate is less than 30mL/ min).

In combination chemotherapy, if there are any contraindications related to the combination drug, the drug should be avoided.

Contraindications to cisplatin also apply to the combination therapy of xeloda and cisplatin.

[Medication for pregnant women]
Pregnant and lactating women are prohibited.

[Drug for children]
The safety and efficacy of Xeloda in patients under 18 years old have not been confirmed.

[Drug Interaction]
Coumarin anticoagulants: There have been reports of changes in coagulation indexes and/or bleeding in patients treated with Xeloda accompanied by coumarin derivatives anticoagulants such as warfarin and phenylpropyl coumarin. These cases occurred within days to months after Xeloda treatment, and some patients appeared within one month after Xeloda was stopped. In a drug-drug interaction study, the average AUC of S- warfarin increased by 57% and INR increased by 91% after a single dose of 20mg warfarin was given to Xeloda. The anticoagulant parameters (INR or PT) of patients taking Xeloda and taking coumarin derivatives orally should be monitored routinely, and the dosage of anticoagulant should be adjusted accordingly.

Cytochrome P-4502C9 substrate: The interaction between Xeloda and other drugs known to be metabolized by cytochrome P-4502C9 has not been formally studied. Xeloda should be used with caution.

Phenytoin: It is reported that taking Xeloda and phenytoin at the same time will increase the plasma concentration of phenytoin. The interaction between Xeloda and phenytoin has not been formally studied, but it is speculated that the mechanism of the interaction may be that Xeloda inhibits CYP2C9 isoenzyme (see coumarin anticoagulant). The plasma concentration of phenytoin should be routinely monitored in patients who take Xeloda and phenytoin at the same time.

Drug-food interaction: In all clinical trials, patients were instructed to take Xeloda within 30 minutes after meals. The existing safety and efficacy data are based on taking it with food, so Xeloda is recommended to take it with food.

Acid generator: The effect of an acid generator (Maalox) containing aluminum hydroxide and magnesium hydroxide on the pharmacokinetics of Xeloda was studied in patients with malignant tumor. The plasma concentrations of Xeloda and its metabolite (5′-DFCR) increased slightly. There was no effect on three main metabolites (5′-DFUR, 5-FU and FBAL).

Formyltetrahydrofolate (folinic acid): The effect of formyltetrahydrofolate on the pharmacokinetics of xeloda was studied in patients with malignant tumor. The results showed that formyltetrahydrofolate had no effect on the pharmacokinetics of xeloda and its metabolites. However, formyltetrahydrofolate has an effect on the pharmacodynamics of Xeloda and may increase the toxicity of Xeloda.

SOVOLIDINE and its analogues: Literature shows that there is a significant clinical interaction between SOVOLIDINE and 5- fluorouracil due to its inhibitory effect on dihydropyrimidine dehydrogenase. This interaction leads to the increase of toxicity of fluoropyrimidine, which may be fatal. Therefore, xeloda should not be administered at the same time as SOVOLIDINE and its analogues (such as Tofu Ding).

Oxaliplatin: When oxaliplatin is combined with cabetabine (with or without bevacizumab), there is no significant difference in the exposure of cabetabine or its metabolites, free platinum or total platinum.
Bevacizumab: Bevacizumab has no significant clinical effect on the pharmacokinetic parameters of cabetabine or its metabolites.

[storage]
Sealed storage at 25°C, 15-30 C is also acceptable.

[Manufacturer]
Roche pharmaceutical co., ltd