How Effective Is Capecitabine for Breast Cancer?

Capecitabine tablets, adjuvant chemotherapy for colon cancer: Capecitabine is a single-agent adjuvant therapy for colon cancer patients who have undergone Dukes'C, primary tumor resection and only received fluoropyrimidine therapy. Its disease-free survival (DFS) is no less than that of 5-fluorouracil and formyltetrahydrofolate combined therapy (5-FU / LV). Capecitabine alone or in combination with other drugs cannot extend overall survival (OS), but experimental data have shown that capecitabine can improve disease-free survival compared to 5-FU / LV in a combination chemotherapy regimen. Physicians can refer to the results of the above studies when prescribing capecitabine monotherapy for adjuvant treatment of Dukes'C colon cancer. The data used to support this indication come from foreign clinical studies (see the [Clinical Trials] section). Colorectal cancer: When patients with metastatic colorectal cancer are treated with fluoropyrimidine alone, capecitabine can be used as first-line chemotherapy. When capecitabine is combined with other drugs, the survival time is better than 5-FU / LV single-agent chemotherapy. There is no evidence to confirm the survival advantage of capecitabine monotherapy. The safety and survival advantages of capecitabine in replacing 5-FU / LV in combination chemotherapy need to be further studied. Breast Cancer Combined Chemotherapy: Capecitabine can be used in combination with docetaxel to treat metastatic breast cancer that has failed chemotherapy with anthracyclines. Single-agent chemotherapy for breast cancer: Capecitabine can also be used alone to treat drugs that are resistant to both paclitaxel and anthracycline-containing chemotherapy regimens or resistant to paclitaxel and can no longer be treated with anthracyclines (such as having received cumulative dose 400 mg / m2 doxorubicin or a doxorubicin analog) in patients with metastatic breast cancer. Drug resistance is defined as continued disease progression (with or without initial remission) during treatment, or relapse within 6 months after completion of adjuvant chemotherapy with anthracyclines. Gastric cancer: Capecitabine is suitable for first-line treatment of inoperable advanced or metastatic gastric cancer.

Drug Name: Capecitabine

Drug type: Prescription drugs, medicines for medical workers' injuries
Use classification: Cytotoxic drugs

Capecitabine Ingredients

The main ingredient of this product is capecitabine,
Chemical name: 5'-deoxy-5-fluoro-N-[(pentyloxy) carbonyl] -cytosine (pyrimidine riboside) Chemical structural formula:

Molecular formula: C ₁₅ H ₂₂ FN ₃ O ₆
Molecular weight: 359.35

Capecitabine traits

0.15g: Biconvex, rectangular, light peach-colored coated tablets, white after removal of coating. XELODA on one side and 150 on the other;
0.5g: Double-convex, rectangular, peach-colored coated tablets, white after removal of coating. XELODA on one side and 500 on the other.

Capecitabine Tablet Specifications

(1) 0.15g; (2) 0.5g.

Capecitabine usage and dosage

The recommended dose of capecitabine is 1250 mg / m ² orally twice daily (morning and evening once; equal to the total daily dose of 2500 mg / m [sup] 2 [/ sup]), and the drug is discontinued after 2 weeks of treatment1 Week, 3 weeks is a course of treatment. Capecitabine tablets should be swallowed with water within 30 minutes after a meal. When combined with docetaxel, the recommended dose of capecitabine is 1250 mg / m 2 twice a day, and the drug is discontinued for 1 week after 2 weeks of treatment. The recommended dose of docetaxel in combination with 75 mg is 75 mg. / m ² , once every 3 weeks, intravenous drip for 1 hour. According to the instructions for docetaxel, before using docetaxel in patients receiving capecitabine and docetaxel combined chemotherapy, some chemotherapy adjuvant drugs should be routinely applied.
Table 1 shows the total daily dose of capecitabine and the number of tablets required for each dose based on body surface area.
When used as an adjuvant treatment for patients with Dukes' C colon cancer, the recommended treatment time is 6 months, that is, capecitabine 1250 mg / m ² orally twice daily, and the drug is discontinued for 1 week after 2 weeks of treatment. Take 3 weeks as a course, a total of 8 courses (24 weeks).
Table 1. Capecitabine dose based on body surface area 1250mg / m ² Number of tablets to be taken orally twice daily (morning and evening)
Body surface area (m2) Total daily dose * (mg) 150mg 500mg
1.25 3000 0 3
1.26-1.37 3300 1 3
1.38-1.51 3600 2 3
1.52-1.65 4000 0 4
1.66-1.77 4300 1 4
1.78-1.91 4600 2 4
1.92-2.05 5000 0 5
2.06-2.17 5300 1 5
2.18 5600 2 5
* The total daily dose is divided into 2 oral doses, and the morning and evening doses are equal. <Br Guide to dose adjustment:
The dosage of capecitabine may need to be adjusted during use to meet the individual needs of patients. Adverse reactions should be closely monitored during use, and the dose should be adjusted as necessary to enable the patient to tolerate the treatment (see [Clinical Trials] section). The adverse reactions caused by capecitabine can be treated through symptomatic treatment, withdrawal and dose adjustment. Once the drug is reduced, the dose should not be increased in the future.
When phenytoin and coumarin derivatives are used in combination with capecitabine, a reduction may be required (see [Drug Interactions]: Anticoagulants).
In the event of adverse reactions, the dose adjustment plan of capecitabine can be referred to the following table (see Table 2 and Table 3)
Table 2. NCIC Toxicity Ratings for Dose Adjustment Protocols for Capecitabine and Docetaxel Chemotherapy: 2 Degrees 3 Degrees 4 Degrees * Except for Hand-Foot Syndrome, Common Toxicity Ratings developed by the National Cancer Institute of Canada (NCIC) Standard (CTC) (see [Precautions]).
First appearance:
When the second degree occurred within 14 days of capecitabine treatment: the capecitabine treatment was suspended until the adverse reactions resolved to grade 0-1. During the course of the treatment, the original capecitabine dose continued to be treated. Capecitabine dose is no longer replenished. When possible, auxiliary measures can be used to prevent adverse reactions.
If a Grade 2 adverse reaction persists until the next capecitabine / docetaxel course: Delay treatment until the adverse reaction resolves to grade 0-1, then use the original doses of capecitabine and docetaxel Continue treatment. When possible, auxiliary measures can be used to prevent adverse reactions.
When the third degree occurred within 14 days of capecitabine treatment: the capecitabine treatment was suspended until the adverse reactions eased to grade 0-1, and the treatment was continued at 75% of the original capecitabine dose during the course of treatment. The missed dose of capecitabine is no longer replenished. When possible, auxiliary measures can be used to prevent adverse reactions.
If grade 3 adverse reactions persist until the next capecitabine / docetaxel course: Delay treatment until the adverse reactions have resolved to grade 0-1. For patients with grade 3 adverse reactions at any time during the course of treatment, when the adverse reactions resolved to grade 0-1, continue the subsequent course with 75% of the original capecitabine dose and docetaxel 55mg / m2. When possible, auxiliary measures can be used to prevent adverse reactions.
The treatment was discontinued at 4 degrees, unless the physician in charge decided that continued treatment with 50% of the original capecitabine dose was in the best interest of the patient.
The same adverse reaction recurs:
When the second degree occurred within 14 days of capecitabine treatment: The capecitabine treatment was suspended until the adverse reactions resolved to grade 0-1. During this course, treatment was continued at 75% of the original capecitabine dose. During the course of treatment, The missed dose of capecitabine is no longer replenished. When possible, auxiliary measures can be used to prevent adverse reactions.
If a Grade 2 adverse reaction persists until the next capecitabine / docetaxel course: Delay treatment until the adverse reaction resolves to Grade 0-1. For patients who recurred with Grade 2 adverse reactions at any time during the course of treatment, when the adverse reactions resolved to Grade 0-1, continue the subsequent course with 75% of the original capecitabine dose and docetaxel 55mg / m ² . When possible, auxiliary measures can be used to prevent adverse reactions.
When the third degree occurred within 14 days of capecitabine treatment: the capecitabine treatment was suspended until the adverse reactions eased to grade 0-1, and the treatment was continued at 50% of the original capecitabine dose during the course of treatment. The missed dose of capecitabine is no longer replenished. When possible, auxiliary measures can be used to prevent adverse reactions.
If a Grade 3 adverse reaction persists until the next capecitabine / docetaxel course: Delay treatment until the adverse reaction resolves to Grade 0-1. For patients who have grade 3 adverse reactions again at any time during the course of treatment, when the adverse reactions have resolved to grade 0-1, continue the subsequent course of treatment with 50% of the original capecitabine dose and discontinue the use of docetaxel. When necessary, use auxiliary measures to prevent adverse reactions.
The treatment was stopped at 4 degrees.
The same adverse reaction occurred for the third time:
When the second degree occurred within 14 days of capecitabine treatment: the capecitabine treatment was suspended until the adverse reactions resolved to grade 0-1; during this course, treatment was continued at 50% of the original capecitabine dose, The missed dose of capecitabine is no longer replenished. When possible, auxiliary measures can be used to prevent adverse reactions.
If Grade 2 adverse reactions persist until the next capecitabine / docitabide course: Delay treatment until the adverse reactions have resolved to Grade 0-1. For patients who had Grade 2 adverse reactions for the third time at any time during the course of treatment, when the adverse reactions resolved to Grade 0-1, continue the subsequent course of treatment with 50% of the original capecitabine dose and discontinue the use of docetaxel. When possible, auxiliary measures can be used to prevent adverse reactions.
Terminate treatment at 3 degrees.
The same adverse reaction occurred for the fourth time:
The treatment was suspended at 2 degrees.
See Table 3 for dose adjustments of capecitabine when used as monotherapy.
Table 3. Dose adjustment protocol for capecitabine single-agent chemotherapy. NCIC grades of adverse reactions * Dose adjustment for the next course of treatment during treatment (% starting dose)
· Level 1 maintains the original dose · Level 2-the first time the medication is suspended until it returns to 100% of the level 0-1
-Second suspension of medication until regained level 0-1 75%
-The third time the medication was suspended until it returned to level 0-1 50%
-The fourth time the treatment was permanently discontinued · Level 3-The first time the medication was suspended until it returned to 75% of the level 0-1
-The second time the drug was suspended until it returned to level 0-1 50%
-The third time a permanent discontinuation of treatment. Grade 4-The first time a permanent discontinuation of treatment or if the physician believes that continued treatment is the best for the patient, the medication is suspended until the remission reaches level 0-1. 50%
* In addition to hand-foot syndrome, the common toxic reaction grading standards established by the National Cancer Institute of Canada (see [Notes]).
In the case of Grade 1 adverse reactions, dose adjustment is not recommended. If grade 2 or 3 adverse reactions occur, capecitabine treatment should be suspended. Once the adverse effects have disappeared or the severity has decreased to Grade 1, treatment can be restarted with the original dose of capecitabine or the dose adjusted according to the table above. If a Grade 4 adverse reaction occurs, treatment should be suspended until the adverse reaction disappears or the severity decreases to Grade 1, and then restart treatment at 50% of the original dose. Capecitabine doses missed due to toxic reactions are no longer supplemented or restored; patients continue to plan treatment sessions.
Adjustment of starting dose for special populations:
Hepatic impairment: For patients with mild to moderate hepatic dysfunction caused by liver metastasis, it is not necessary to adjust the starting dose, but patients should be closely monitored. No studies have been performed on patients with severe liver dysfunction.
Renal impairment: For patients with mild renal impairment (creatinine clearance = 51-80ml / min [Cockroft and Gault, calculation formulas are detailed below]), it is not recommended to adjust the starting dose of capecitabine. For patients with moderate renal impairment (baseline creatinine clearance = 30-50ml / min), when used in monotherapy or combined with docetaxel, it is recommended to reduce the starting dose of capecitabine to 75% of the standard dose % (From 1250mg / m2, twice daily to 950mg / m2 twice daily) (see [Pharmacokinetics]: special population). After patients with Grade 2 to Grade 4 adverse events (see [Cautions]), the corresponding dose adjustment recommendations are based on the requirements of Tables 2 and 3. Suggestions for adjusting the starting dose of patients with moderately impaired renal function can be applied to both capecitabine monotherapy and combined capecitabine and docetaxel.
Cockroft and Gault equations:
Male creatinine clearance = (140-age [years]) (weight [kg]) / (72) (serum creatinine [mg / dl])
Female creatinine clearance = 0.85 x male creatinine clearance in elderly patients: Doctors should closely monitor the effects of capecitabine on elderly patients. There is insufficient data to support the recommendations for dose adjustment.
In combination with cisplatin, the recommended dose of capecitabine is 1000 mg / m 2 twice a day, and the drug is discontinued for 1 week after 2 weeks of treatment. The dose of cisplatin was 80 mg / m ^{2. On} the first day of every 3 week course, intravenous drip was given, and the drip was completed in 2 hours. The first dose of capecitabine was taken in the evening on the first day, and the last dose was taken in the morning on the 15th day.
Patients receiving combined capecitabine and cisplatin should be given adequate hydration and antiemetic treatment in accordance with the cisplatin product manual before administration of cisplatin.
In combination with cisplatin, there are toxic and side effects that are not considered serious or life-threatening by the attending doctor, such as hair loss, appetite change, nail discoloration, etc., and the treatment can be continued at the initial dose without reduction or interruption. If you need further information about cisplatin, please refer to the cisplatin manual information.
For Hemotoxic Dosage Adjustment If the patient's absolute neutrophil count (ANC) is greater than 1000 x 106 / l and the platelet count is greater than 100,000 x 106 / l at the beginning of the course of treatment, a new 3-week course can be started. Otherwise, treatment needs to be postponed until blood indicators have recovered. See Table 4 for detailed guidelines for hematological dose adjustment.
Table 4. Capecitabine (X) in combination with cisplatin (P) during a planned treatment based on hematologic toxicity. Neutrophil absolute platelet count (x 106 / l) Dose-adjusted ANC count at treatment restart (x 106 / l)
1500 and 100,000 X: 100% starting dose without delay P: 100% starting dose without delay 1000 and [1500 and 100,000 X: 75% starting dose without delay P: 75% starting dose without delay [ 1000 and / or [100,000 X: Delayed until ANC 1000 and platelets 100,000, and then when ANC 1000 to [
75% of the initial dose at 1500, 100% of the initial dose at ANC 1500
P: Delay until ANC 1000 and platelets 100,000, and then when ANC 1000 to [1500, the treatment amount is 75% of the original dose,
100% of the starting dose when ANC 1500
If unplanned assessments during treatment reveal dose-limiting toxicity, capecitabine administration must be discontinued during this course, and capecitabine and cisplatin should be reduced during subsequent courses, see Table 5.
Table 5. Dose adjustment protocol for capecitabine (X) combined with cisplatin (P) during hematological toxicity Dose-limiting toxicity Capecitabine and cisplatin dose adjustment Level 4 neutropenia exceeds 5 Day X: 75% starting dose P: 75% starting dose Grade 4 thrombocytopenia X: 50% starting dose P: 50% starting dose neutropenic fever, neutrophil X: discontinue treatment unless the physician believes After the blood toxicity returns to 0-1,
Reduced septicemia, neutropenic infection continues to be treated at 50% of the starting dose, which is most beneficial for patients P: Discontinue treatment, unless the physician believes that blood toxicity has returned to level 0-1,
Continuation of treatment at 50% of the starting dose, which is most beneficial for patients with non-hematological toxicity: Capecitabine Capecitabine dose adjustment recommendations apply to toxic side effects related to capecitabine rather than to cisplatin or combination Treatment related toxic side effects. For example, neurotoxicity or ototoxicity does not require a reduction in capecitabine dose. If a grade 2, 3, or 4 non-hematological toxicity occurs, capecitabine treatment must be discontinued or discontinued immediately, as shown in Table 2 (see also section 1, Precautions). Discontinuation of capecitabine treatment should be counted as a lack of treatment time. Missing doses are not supplemented. The original treatment plan should be maintained. If the calculated creatinine clearance is less than 30 ml / min during treatment, capecitabine treatment should be discontinued. Table 6 summarizes capecitabine and cisplatin dose adjustments based on creatinine clearance.
Non-hematological dose adjustments: The recommendations for cisplatin and cisplatin dose adjustments apply to the toxic and side effects associated with cisplatin treatment rather than those associated with capecitabine or co-administration. For cisplatin dosage adjustment, please refer to the information of cisplatin manual. Renal toxicity: The creatinine clearance should be greater than 60ml / min before treatment, and the creatinine clearance should be calculated according to the Cockroft-Gault formula before each course of treatment. After the first course, if the creatinine clearance is <60ml / min, it must be recalculated after 24 hours of hydration.
In patients with impaired renal function, the adjustment of cisplatin dosage must be consistent with the instructions in the cisplatin data sheet.
In clinical studies using capecitabine and cisplatin, cisplatin dose adjustments are shown in Table 6.
Table 6. Dose adjustment protocol for cisplatin and capecitabine based on creatinine clearance. Creatinine clearance rate Dose of cisplatin 60 ml / min Full dose 41-59 ml / min Full dose cisplatin mg / m ² The value is the same as the total creatinine clearance in ml / min. For example, the creatinine clearance is 45
ml / min with a dose of 45 mg / m ²
40 ml / min
30 ml / min permanently discontinue capecitabine * If creatinine clearance is less than 40ml / min, you can continue to use capecitabine alone, as long as the creatinine clearance is 30 ml / min.
Nausea or vomiting: For grades 3 and 4 nausea or vomiting, despite adequate prevention, cisplatin should be reduced to 60 mg / m ^{2 during} subsequent treatments.
Ototoxicity: Hearing loss, new onset of tinnitus, or significant loss of high-frequency hearing in new audiograms. Cisplatin should be discontinued, but capecitabine should be continued.
Neurotoxicity: Cisplatin should be discontinued in patients with grade 2 NCI-CTC neurotoxicity, but capecitabine should be continued.

Capecitabine adverse reactions

Researchers believe that adverse reactions may occur when capecitabine is used for monotherapy (adjuvant colon cancer, metastatic colorectal cancer, and metastatic breast cancer) for different indications and combined chemotherapy. Based on the highest incidence of the seven clinical trials, various adverse reactions were classified into the corresponding categories in the table below. In each frequency classification, the adverse reactions are ranked from severe to light. Frequency is divided into very common (1 / 10), common (5 / 100- <1/10) and uncommon (1 / 1000-<1/100).
Xeloda Monotherapy-Information on the safety of Xeloda monotherapy comes from reports of adjuvant colon cancer treatment and patients with metastatic breast or colorectal cancer. Safety information includes 1 phase III adjuvant colon cancer treatment trial (995 patients received Xeloda and 974 patients received 5-FU / LV intravenous infusion), 4 women's breast cancer phase II trials (N = 319 ) And 3 (1 phase II trial, 2 phase III trials) male and female colon cancer trials (N = 630). The safety of Xeloda monotherapy is similar in patients with adjuvant colon cancer treatment as in patients with breast metastatic or colorectal cancer. The severity of adverse reactions was graded according to the toxicological grade of the NCIC CTC classification system.

Data from seven completed clinical trials indicate that less than 2% of patients have skin cracks that may be related to capecitabine treatment (N = 949).
The following are the known toxicities of fluoropyrimidine therapy, which have been reported to occur in less than 5% of the 7 completed clinical trials (N = 949) and may be related to capecitabine use.
-Gastrointestinal disorders: dry mouth, bloating, mucosal inflammation / ulcers, such as esophagitis, gastritis, duodenitis, colitis and gastrointestinal bleeding;
-Cardiac disorders: lower extremity edema, cardiogenic chest pain (such as angina pectoris), cardiomyopathy, myocardial ischemia / infarction, heart failure, sudden death, tachycardia, arrhythmia (such as atrial fibrillation, ventricular premature beats);
Nervous system disorders: taste disorders, insomnia, confusion, encephalopathy, cerebellar dysfunction (such as ataxia, dysphonia, balance dysfunction, abnormal ataxia);
-Infectious and infectious diseases: diseases related to bone marrow suppression, immune system damage and / or impaired mucosal barriers, such as local and fatal systemic infections (including bacterial, viral, fungal) and sepsis;
Blood and lymphatic diseases: anemia, bone marrow suppression, various types of hemocytopenia;
-Diseases of the skin and subcutaneous tissue: pruritus, local epidermal exfoliation, skin pigmentation, non-fungal onychomycosis, photosensitivity, radiotherapy recall syndrome;
-Systemic conditions and sites of administration: weakness, limb pain, lethargy, chest pain (non-heart disease patients);
-Eyes: astringency;
-Respiratory system: dyspnea, cough;
-Musculoskeletal: back pain, myalgia, joint pain;
-Mental disorders: depression;
-Liver failure and cholestatic hepatitis have been reported in clinical trials and post-marketing studies. A causal relationship between these two diseases and capecitabine use cannot yet be given.
Capecitabine combined treatment < br Table 8 lists the adverse reactions that occur when Xeloda is combined with multiple chemotherapy regimens for various indications, or occurs more frequently, but Xelodabine is excluded Adverse drug reactions observed during drug treatment. Safety information was similar across indications and joint protocol groups. When Xeloda combined with other chemotherapy treatments, the incidence of these adverse events was 5%. According to the highest incidence in each clinical trial, adverse events were classified into the various events in the table below. Some adverse reactions are common during chemotherapy (such as peripheral sensory neuropathy during docetaxel or oxaliplatin treatment, and hypertension during bevac humanized monoclonal antibody treatment); however, exacerbation of Xeloda treatment cannot be ruled out These adverse reactions are possible.

When Xeloda combined with chemotherapy, reports of hypersensitivity (2%) and myocardial ischemia / myocardial infarction events (3%) were common, but their incidence was less than 5%.
The rare or uncommon adverse reactions reported by Xeloda in combination with other chemotherapy are consistent with the adverse reactions reported by Xeloda alone or with the combination chemotherapy drug (see Prescription Information for Combination Therapies).
Laboratory abnormalities < br The table below lists laboratory abnormalities (regardless of treatment-related) observed in capecitabine in 995 patients with colon cancer and 949 patients with metastatic breast and colorectal cancer.

The table below shows laboratory abnormalities in 302 patients with gastric cancer treated with capecitabine and cisplatin, whether or not these abnormalities are treatment-related.

Post-marketing reports < br The following adverse reactions were found after marketing:
Very rare: lacrimal duct narrowing NOS.
Very rare: Liver failure and cholestatic hepatitis have been reported in clinical trials and post-marketing reports.

Capecitabine Taboo

People who are known to be allergic to capecitabine or any of its ingredients are contraindicated.
Capecitabine should not be used in patients with a previous severe, unexpected response to fluorouracil or known allergies to fluorouracil.
Like other fluorouracil drugs, capecitabine is contraindicated in patients with known defects in dihydropyrimidine dehydrogenase (DPD).
Capecitabine should not be administered at the same time as solivudine or its analogs (such as bromudine) (see [Drug Interactions]).
Capecitabine is contraindicated in patients with severe renal impairment (creatinine clearance below 30 mL / min).
In combination chemotherapy, the use of any combination drug should be avoided if there are contraindications associated with it.
The contraindications to cisplatin also apply to the combination of capecitabine and cisplatin.

Capecitabine precautions

Diarrhea: Capecitabine can cause diarrhea, sometimes severe. Patients with severe diarrhea should be closely monitored, and if the patient begins to develop dehydration, fluids and electrolytes should be replenished immediately. To the extent reasonable, standard antidiarrheal medications (such as loperamide) should be started early. If necessary, reduce the dosage (see [Dosage and Administration]).
Dehydration: Dehydration should be prevented and corrected when starting capecitabine treatment. Patients who develop anorexia, weakness, nausea, vomiting, or diarrhea can quickly become dehydrated. When symptoms of Grade 2 (or above) dehydration occur, treatment with this product must be stopped immediately, and dehydration should be corrected. Until the patient's dehydration symptoms disappear and the immediate cause of dehydration is corrected and controlled, the treatment of this product can be restarted. For the occurrence of adverse events, it is necessary to adjust the dosage.
The cardiotoxicity of capecitabine that has been observed is similar to that of fluorouracil drugs, including myocardial infarction, angina pectoris, arrhythmia, cardiac arrest, heart failure, and ECG changes. These adverse events may be more common in patients with a previous history of coronary artery disease.
Rare, unpredictable serious toxicity (such as oral inflammation, diarrhea, neutropenia, and neurotoxicity) associated with 5-fluorouracil due to dihydropyrimidine dehydrogenase deficiency (DPD) has previously occurred. Therefore, it is impossible to rule out a link between a decrease in DPD levels and an increase in the potential lethal toxicity of 5-fluorouracil.
Capecitabine can cause hand-foot syndrome (palm-plantar bluntness or extremity erythema due to chemotherapy), a skin toxicity. Patients with cancer metastases received capecitabine monotherapy with a median hand-foot syndrome of 79 days (ranging from 11 to 360 days) with a severity of grades 1 to 3.
Level 1 is defined as the occurrence of any of the following: numbness of the hands and / or feet, dullness / paresthesia, tingling, erythema, and / or discomfort that does not affect normal activity. Grade 2 hand-foot syndrome is defined as painful erythema and swelling of the hands and / or feet and / or discomfort affecting the patient's daily life. Grade 3 hand and foot syndrome is defined as wet desquamation of hands and / or feet, ulcers, blisters or severe pain and / or severe discomfort that prevents the patient from working or performing daily activities.
The use of capecitabine should be discontinued in patients with grade 2 or 3 hand-foot syndrome until normal or severity decreases to grade 1. After the occurrence of grade 3 hand-foot syndrome, the dose should be reduced when re-using capecitabine (see [Dosage and Administration]). When capecitabine is combined with cisplatin, vitamin B6 (pyridoxine) is not recommended to improve symptoms or secondary prevention for hand-foot syndrome, because there are public reports that vitamin B6 may reduce the efficacy of cisplatin.
Capecitabine can cause hyperbilirubinemia. If drug-related bilirubin is elevated] 3.0 X ULN or liver transaminase (ALT, AST) is increased] 2.5 X ULN, the use of capecitabine should be discontinued immediately. When bilirubin decreases to 3.0 X ULN or liver transaminase 2.5 XULN, capecitabine can be resumed.
A drug interaction study showed that when capecitabine was administered in combination with a single dose of warfarin, the mean AUC of S-warfarin increased significantly (+ 57%). The results suggest that this interaction may be due to the inhibitory effect of capecitabine on the cytochrome P450-2C9 isoenzyme system. Patients who use capecitabine at the same time as oral coumarin derivative anticoagulants should closely monitor their anticoagulant response (INR or PT) and adjust the dose of anticoagulant accordingly (see [Drug Interactions]).
The toxicity of capecitabine treatment should be closely monitored. Most adverse reactions are reversible. Although dosage may need to be limited or reduced, there is no need to discontinue medication (see [Dosage and Administration]).
Renal Impairment < br Capytabine should be used with caution in patients with impaired renal function. As with 5-fluorouracil, patients with moderate renal impairment (creatinine clearance of 30-50 mL / 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 of 30-50 mL / min [Cockroft and Gault]), it is recommended that the initial dose of capecitabine be reduced to 75% of the standard dose. This dose adjustment recommendation applies to both capecitabine monotherapy and capecitabine combination therapy. If a patient has a grade 2 to 4 adverse event, it should be closely monitored and the drug should be suspended immediately. For subsequent dose adjustments, refer to the corresponding dose adjustment table.
Liver impairment Capecitabine should be closely monitored when used in patients with liver impairment. The effect of non-hepatic metastatic liver injury or severe liver injury on the distribution of capecitabine is unclear (see Pharmacokinetics and Special Medication Guidelines for Specific Populations).

Capecitabine for pregnant and lactating women

Pregnancy < br No study of capecitabine in pregnant women has been conducted. Based on the pharmacological and toxicological properties of capecitabine, it can be inferred that capecitabine may cause fetal damage in pregnant women. In animal reproductive toxicity studies, capecitabine caused embryo death and deformity. These findings are all within the expected effects of fluoropyrimidine derivatives. Capecitabine may be a human teratogenic agent. Capecitabine is prohibited during pregnancy. If capecitabine is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be informed of the potential risk of the drug to the fetus. Women of childbearing age should be advised to avoid pregnancy while receiving capecitabine.
Breastfeeding women It is uncertain whether the drug is secreted by human milk. A large dose of capecitabine metabolites was found in breast milk after oral administration of a single dose of capecitabine in lactating mice. Because capecitabine may cause serious adverse reactions in breast-fed infants, it is recommended that lactating women stop breastfeeding when receiving capecitabine.

Capecitabine tablets for children

The safety and efficacy of capecitabine in patients under 18 years of age have not been proven.

Capecitabine tablets for elderly

Capecitabine alone is used to treat metastatic colorectal cancer. The incidence of gastrointestinal toxicity in cancer patients aged 60-79 years is similar to that of the general population. Reversible grade 3 or 4 gastrointestinal adverse reactions occur more frequently in patients over 80 years of age, such as diarrhea, nausea, and vomiting (see Special Medication Guide). When Xeloda was used in combination with other drugs, older patients (65 years of age) experienced more grade 3, 4 and adverse reactions that led to discontinuation compared with young patients. A safety analysis of capecitabine combined with docetaxel in patients over 60 years of age showed that the incidence of treatment-related grade 3 and 4 adverse events, treatment-related serious adverse events, and early withdrawal from treatment due to adverse events were higher than Patient group under 60 years.

Capecitabine Drug Interactions

Coumarin anticoagulants: Patients who have been treated with capecitabine and coumarin derivatives such as warfarin and phenprocoumon have changed blood clotting parameters and / or have bleeding Report. These conditions occurred within days to months after capecitabine treatment, and some patients appeared within 1 month of capecitabine discontinuation. In a drug-drug interaction study, capecitabine was administered after a single 20 mg warfarin, and the average AUC of S-warfarin increased by 57% and the INR increased by 91%. Patients who use capecitabine with oral coumarin derivatives anticoagulants should routinely monitor their anticoagulant parameters (INR or PT) and adjust the dose of anticoagulants accordingly.
Cytochrome P-450 2C9 substrate: In addition to warfarin, the interactions of capecitabine with other known cytochrome P-450 2C9 metabolites have not been formally studied. Capecitabine should be used with such drugs with caution.
Phenytoin: Capecitabine and phenytoin have been reported to increase the plasma concentration of phenytoin. Patients had adverse reactions associated with elevated phenytoin levels. No formal studies have been conducted on the interaction of capecitabine with phenytoin, but it is speculated that the mechanism of interaction may be that capecitabine inhibits CYP2C9 isoenzymes (see Coumarin anticoagulants). For patients taking capecitabine while taking phenytoin, the plasma concentration of phenytoin should be routinely monitored.
Drug-Food Interactions: Patients were instructed to take capecitabine within 30 minutes of a meal in all clinical trials. Existing safety and efficacy data are based on taking with food, so capecitabine is recommended to be taken with food.
Antacids: The effect of an antacid (Maalox) containing aluminum hydroxide and magnesium hydroxide on the pharmacokinetics of capecitabine was studied in cancer patients. The plasma concentration of capecitabine and one of its metabolites (5'-DFCR) increased slightly; it had no effect on the three major metabolites (5'-DFUR, 5-FU, and FBAL).
Formyltetrahydrofolate (Folic acid): The effect of formyltetrahydrofolate on the pharmacokinetics of capecitabine has been studied in cancer patients. The results show its pharmacokinetics of capecitabine and its metabolites no effect. However, formyltetrahydrofolate has an impact on the pharmacodynamics of capecitabine and may increase the toxicity of capecitabine.
Sovridine and its isoforms: The literature shows that due to the inhibition of dihydropyrimidine dehydrogenase by Sovridine, there is a significant clinical interaction between Sovridine and 5-fluorouracil drugs. This interaction leads to increased toxicity of fluoropyrimidine and is potentially lethal. Therefore, capecitabine should not be administered at the same time as sofodilidine and its isoforms (such as bromudine) (see [Contraindications]). There must be a waiting period of at least 4 weeks between the end of treatment with solvidine and its analogs (eg, bromudine) and the start of capecitabine treatment.
Oxaliplatin: When oxaliplatin is used in combination with capecitabine (with or without bevacizumab), capexitabine or its metabolites, free platinum or total platinum exposure is not clinically significant Significant differences.
Bevacizumab: Bevacizumab has no significant clinically significant effect on the pharmacokinetic parameters of carbetabine or its metabolites.

Capecitabine overdose

Acute overdose manifestations include: nausea, vomiting, diarrhea, mucositis, gastrointestinal irritation, bleeding, and bone marrow suppression.
Medical treatment of overdose should include: conventional treatment, supportive care (to correct clinical manifestations), and prevention of complications.

Capecitabine clinical trial

Exploring continuous capecitabine therapy (1331 mg / m ² / day orally twice daily, n = 39) and intermittent capecitabine therapy in patients with advanced and / or metastatic colorectal cancer through an open randomized clinical study (2510 mg / m ² , orally twice daily, n = 34) and capecitabine in combination with oral formyltetrahydrofolate (LV) (capecitabine 1657 mg / m ² , twice daily orally, n = 35 ; 60 mg / day of formyltetrahydrofolate), and the recommended dose of capecitabine was determined with it. Capecitabine and formyltetrahydrofolate did not have a significant advantage in improving remission rate, but adverse reactions increased. Based on the overall safety and efficacy, the regimen of capecitabine 1250 mg / m 2 was taken orally twice daily, and the regimen was discontinued for 1 week after 2 weeks of treatment for further clinical research.
Adjuvant chemotherapy for colon cancer <br A multicenter randomized controlled phase III clinical trial was performed in Dukes'C stage colon cancer patients. The study provided data on capecitabine adjuvant therapy for patients with colon cancer. This study aimed to compare the disease-free survival (DFS) of capecitabine and 5-fluorouracil / formyltetrahydrofolate (5-FU / LV) intravenous infusion. In this study, 1987 patients were randomized to receive capecitabine or 5-fluorouracil and formyltetrahydrofolate.1250 mg/m ² 2 2 13 8 24 5-425 mg/m ²20 mg/m ² 1 5 4 6 2418 75 Dukes C 8 ECOG 0 21(KPS70%)ANC1.5x109/L100×109/L1.5 ULN1.5 ULN/(AST/ALT)2.5 ULN
11 5FU/LV

1250 mg/m ²30 50 mL/min12

53 DFS5-FU/LV 0.8795%0.76-1.00)1.205-FU/LV 1.2075%5-FU/LV
53 0.8895%CI 0.74-1.05p=0.169

1207 120 1 2 603 1250 mg/m222 1 3 604 5-FU 20 mg/m ²5425mg/m ²1 528
WHO IRCIRC
5-FU/LV 14

III 15 16

1 2 5-FU/LV5-FU 5-FU/LV 5-FU/LV 10 5-FU 5-FU/LV 5-FU/LV 1 2
95%5-FU/LV 5-FU/LV 50%25-FU/LV 61%1 10%5-FU/LV 50%5-FU/LV 5-FU/LV 15 161
 

I III I 3 14 7 3 75 mg/m ²1250 mg/m ² 2 2 1 3 100 mg/m ²III
75 511 255 3 1250 mg/m ² 2 2 1 75 mg/m ²1 256 3 100 mg/m ²1 17

18 2 3

24 162 IV 50%1 1255mg/m ² 2 2 1 3 n=162n=135196

43 102 255 13518.5%1 24 135 2090 306

42 /C/S()

316 160 1000 mg/m ²2 2 1 80 mg/m ² 2 3 156 5-FU800 mg/m ² 1 5 3 1 80mg/m ²1 2 3 1 (21)

5-FU//5-FU/10%20%2245

127 /63 5-FU/64 /(PFS)5-FU//5-FU/(OS)(TTP)FP 236 7

5-FU 5--2-FdUMP5-FUTPFdUMP N ⁵ ¹⁰ -TS2'-[]DNARNA UTPFUTPRNA
 Ames V79/HPRT
760mg/kg/5'-DFUR AUC 0.7

5-5-FU

60KD 5'--5-5'-DFCR5'-DFCR 5'--5-5'-DFURdThdPase5'-DFUR 5-FU

Pharmacokinetics in colorectal tumors and adjacent healthy tissues:
The median ratio of 5-FU concentrations in colorectal tumors to adjacent tissues after capecitabine was taken orally 7 days before surgery in colorectal cancer patients was 2.9 (from 0.9 to 8.0). These ratios have not been evaluated in breast cancer patients and have not been compared with 5-FU infusions.
Human pharmacokinetics:
The pharmacokinetic data of capecitabine and its metabolites were evaluated in approximately 200 cancer patients, with doses ranging from 500-3500 mg / m [sup] 2 [/ sup] / day. Within this dose range, the pharmacokinetics of capecitabine and its metabolite 5'-DFCR are proportional to the dose and do not change over time. However, the increase in area under the curve (AUC) of 5'-DFUR and 5-FU was greater than the increase of dose. The AUC of 5-FU on day 14 was 34% higher than that on day 1. The elimination half-life of both parental capecitabine and 5-FU is approximately 3/4 hours. The 5-FU maximum plasma concentration and AUC variability between patients was greater than 85%.
Absorption, distribution, metabolism and excretion:
Capecitabine reached peak plasma concentrations approximately 1.5 hours (Tmax) after oral administration, and 5-FU reached peak concentrations later (2 hours). Food will decrease the absorption rate and extent of capecitabine, with average Cmax and AUC0- reduced by 60% and 35%, respectively. Food also reduced CFU and AUC of 5-FU by 43% and 21%, respectively. Food also delayed the Tmax of capecitabine and 5-FU by 1.5 hours (see [Cautions] and [Dosage and Administration]).
The plasma protein binding rate of capecitabine and its metabolites is less than 60%, regardless of concentration. Capecitabine binds primarily to human albumin (approximately 35%).
Capecitabine is metabolized to 5-FU by enzymes. Dihydropyrimidine dehydrogenase hydrogenates capecitabine metabolite 5-FU to a much less toxic 5-fluoro-5,6-dihydrofluorouracil (FUH2). Dihydropyrimidinase cleaves the pyrimidine ring to produce 5-fluoroureidopropionic acid (FUPA). Finally, -ureapropionase cleaves FUPA to -fluoro--alanine (FBAL) and clears it from the urine.
Capecitabine and its metabolites are mostly excreted from the urine. 95.5% of capecitabine taken in the urine. Very little excretion from feces (2.6%). The main metabolite excreted from the urine is FBAL, accounting for 57% of the dose used. About 3% of the drug is excreted from the urine in its original form.
A phase I clinical study was performed in 26 patients with solid tumors to evaluate the effect of capecitabine on the pharmacokinetics of docetaxel and the effect of docetaxel on the pharmacokinetics of capecitabine. Capecitabine has no effect on the pharmacokinetics (Cmax and AUC) of docetaxel, and docetaxel has no effect on the pharmacokinetics of capecitabine and 5-FU precursor 5'-DFUR.
Special population:
Two large controlled trials enrolled 505 patients with colorectal cancer who took capecitabine 1250mg / m2 twice a day. Analysis of the combined patient population revealed gender (202 females, 303 males) and ethnicity (455 white / Caucasian, 22 black, 28 patients of other races) for 5'-DFUR, 5-FU, and FBAL The pharmacokinetics have no effect. In the range of 27 to 86 years, age has no significant effect on the pharmacokinetics of 5'-DFUR and 5-FU. For FBAL, a 20% increase in age results in a 15% increase in AUC (see [Cautions] and [Dosage and Administration]).
Liver insufficiency:
In 13 patients with mild to moderate hepatic dysfunction caused by liver metastasis (determined based on the combined scores of bilirubin, AST / ALT and alkaline phosphatase), a single dose of capecitabine 1255mg / m [sup] 2 [/ sup]. Compared with patients with normal liver function (n = 14), the AUC0- and Cmax of capecitabine increased by 60%, while the AUC0- and Cmax of 5-FU were not affected. For patients with mild to moderate liver dysfunction caused by liver metastasis, use capecitabine with caution (see [Cautions] and [Dosage and Administration]).
Renal insufficiency:
Cancer patients with varying degrees of renal impairment take capecitabine 1250 mg / m ² orally. After 2 times a day, moderate renal impairment (creatinine clearance = 30-50ml / min) and severe impairment (creatinine clearance <30ml) The patients with FBAL content on the first day were 85% and 258% higher than those with normal renal function (creatinine clearance <80ml / min). Patients with moderate and severe renal impairment have a body 5'-DFUR content that is 42% and 71% higher than that of normal patients, respectively. Patients with moderate and severe renal impairment have about 25% higher capecitabine than normal patients (see [Contraindications], [Cautions], and [Dosage and Administration]).

Capecitabine Storage

Store in a tightly closed container at 25 ° C, or between 15-30 ° C. Keep medicines out of reach of children.

Capecitabine Tablets Packaging

0.15g in aluminum-plastic packaging: 30 tablets / box, 60 tablets / box; 0.5g: 12 tablets / box, 60 tablets / box.

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