Date of approval.
Date of revision.
Capecitabine Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Warnings
In patients taking concomitant capecitabine and coumarin-derived anticoagulants such as warfarin and phenprocoumarin, frequent monitoring of anticoagulant response indicators such as INR or prothrombin time should be performed to adjust the dosage of anticoagulant. Changes in coagulation parameters and/or bleeding, including death, have been reported during combined dosing.
Time of occurrence: Within a few days to several months after initiation of capecitabine therapy and may also be observed up to 1 month after discontinuation of capecitabine.
Susceptibility factors: age >60, diagnosis of cancer.
[Drug Name].
Generic name: Capecitabine tablets
English name: CapecitabineTablets
Hanyu Pinyin: Kapeitabin Pian
Ingredients
The main ingredient of this product is capecitabine.
Chemical name: 5′-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytidine (pyrimidine nucleoside)
Chemical structure formula.
Molecular formula: C15H22FN3O6
Molecular weight: 359.35
Properties]: This product is a film-coated tablet, which appears white or off-white after removing the coating.
Indications
Adjuvant chemotherapy for colon cancer: Capecitabine is indicated for monotherapy adjuvant treatment of colon cancer patients with Dukes’ stage C, after radical surgery of the primary tumor, and suitable for receiving fluoropyrimidines alone. The treatment has a disease free survival (DFS) and overall survival (OS) comparable to the combination regimen of 5-fluorouracil and formyltetrahydrofolate (5-FU/LV). Data from trials have shown that the combination of capecitabine and oxaliplatin chemotherapy improves disease-free survival and overall survival compared to 5-FU/LV. Physicians may refer to the above findings when prescribing capecitabine monotherapy for the adjuvant treatment of Dukes’ stage C colon cancer. The data used to support this indication are from foreign clinical studies.
Colorectal cancer: Capecitabine alone or in combination with oxaliplatin (XELOX) is indicated for the first-line treatment of metastatic colorectal cancer.
Combination chemotherapy for breast cancer: Capecitabine may be used in combination with docetaxel for the treatment of metastatic breast cancer that has failed chemotherapy with an anthracycline-containing regimen.
Breast cancer monotherapy: Capecitabine may also be used alone to treat patients with metastatic breast cancer who are resistant to both paclitaxel and anthracycline-containing chemotherapy regimens or who are resistant to paclitaxel and can no longer be treated with anthracyclines (e.g., have received a cumulative dose of 400 mg/m2 of adriamycin or its equivalent). Drug resistance was defined as continued disease progression (with or without initial remission) during treatment or relapse within 6 months after completion of adjuvant chemotherapy containing an anthracycline.
Gastric cancer: Capecitabine is indicated for first-line treatment of inoperable advanced or metastatic gastric cancer.
Adjuvant therapy for gastric cancer: Capecitabine in combination with oxaliplatin (XELOX) is used as adjuvant chemotherapy after radical resection for patients with stage II and III gastric adenocarcinoma.
Specification
0.5g
Dosage]
Capecitabine tablets should be swallowed whole with water within 30 minutes after a meal. Capecitabine tablets should not be crushed or cut (see [Adverse Reactions]). If a patient is unable to swallow a capecitabine tablet whole and must crush or cut it, this should be done by a person trained in the safe handling of cytotoxic drugs.
The recommended dose of capecitabine alone is 1250 mg/m2 orally twice daily (once in the morning and once in the evening; equal to a total daily dose of 2500 mg/m2) and is discontinued after 2 weeks of treatment for 1 week for a 3-week course. Capecitabine tablets should be swallowed with water within 30 minutes after a meal.
When used in combination with docetaxel, the recommended dose of capecitabine is 1250 mg/m2 twice daily with 1 week of discontinuation after 2 weeks of treatment, and the recommended dose of docetaxel in combination with it is 75 mg/m2 once every 3 weeks by intravenous drip over 1 hour. According to the instructions for docetaxel, some adjuvant chemotherapeutic agents should be routinely applied prior to the use of docetaxel in patients receiving combination chemotherapy with capecitabine and docetaxel.
When used in combination with oxaliplatin, the recommended dose of capecitabine is 1000 mg/m2 twice daily with 1 week of discontinuation after 2 weeks of treatment. Capecitabine therapy can be started the day after oxaliplatin is given to the patient (at a dose of 130 mg/m2 over 2 hours of intravenous infusion), and oxaliplatin must be administered before capecitabine. For more information on oxaliplatin dosing and the pretreatment medication given prior to dosing, see the drug insert for oxaliplatin.
Tables 1 and 2 describe the calculation of the standard and reduced doses when the starting dose of capecitabine is 1250 mg/m2 or 1000 mg/m2, respectively (see Dose Adjustment Guidelines).
When used as adjuvant therapy in patients with Dukes’ stage C colon cancer, the recommended duration of treatment is 6 months, i.e., capecitabine 1250 mg/m2 orally twice daily, with 1 week of discontinuation after 2 weeks of treatment, for a total of 8 courses of treatment (24 weeks) in 3-week increments.
Table 1. Standard and reduced doses of capecitabine based on body surface area, starting dose 1250 mg/m2
Dose level 1250mg/m2 (twice a day) Full dose
1250mg/m2 Number of tablets per dose
(morning and evening) Reduced dose
(75%)
950 mg/m2 reduced dose
(50%)
625 mg/m2 Body surface area (m2) Dose per administration* (mg) 150 mg 500 mg Dose per administration*
(mg) Dose per administration*
(mg)≤1.261500-311508001.27~1.3816501313008001.39~1.5218002314509501.53~1.662000-4150010001.67~1.78215014165010001.79~ 1.92230024180011501.93~2.062500-5195013002.07~2.1826501520001300≥2.1928002521501450*The total daily dose was divided into one oral dose in the morning and one in the evening, and the morning and evening doses were equal
Table 2. Standard and reduced doses of capecitabine based on body surface area, starting dose 1000 mg/m2
Dose level 1000mg/m2 (twice a day) Full dose
1000mg/m2 Number of tablets per dose
(morning and evening) Reduced dose
(75%)
750 mg/m2 reduced dose
(50%)
500 mg/m2 Body surface area (m2) Dose per administration* (mg) 150 mg 500 mg Dose per administration*
(mg) Dose per administration*
(mg)≤1.261150128006001.27~1.3813002210006001.39~1.5214503211007501.53~1.6616004212008001.67~1.7817505213008001.79~ 1.9218002314009001.93~2.062000-4150010002.07~2.1821501416001050≥2.1923002417501100*Total daily dose is divided into 1 oral dose in the morning and 1 in the evening, and the morning and evening doses are equal
Dose adjustment guidelines.
In-use capecitabine dosing may need to be adjusted to meet the needs of individualized patient therapy. Adverse reactions should be monitored closely during use and the dose should be adjusted as necessary to allow the patient to tolerate treatment. Adverse reactions due to capecitabine can be managed by symptomatic treatment, discontinuation of the drug and dose adjustment. Once the drug has been reduced, the dose should not be increased in the future.
Dose reductions may be required when phenytoin and coumarin-derived anticoagulants are used in combination with capecitabine (see [Drug Interactions]: Anticoagulants).
In the event of an adverse reaction, the dose adjustment regimen for capecitabine can be handled by referring to the following tables (see Tables 3 and 4).
Table 3. Dose adjustment regimen for capecitabine in combination with docetaxel chemotherapy
NCIC
Toxicity grading* Grade 2 Grade 3 Grade 4 When first occurring within 14 days of capecitabine treatment.
Suspend capecitabine therapy until the adverse reaction resolves to grade 0 to 1. Continue treatment at the original capecitabine dose for the duration of the course, with no additional capecitabine dose missed during the course. Adjuvant measures may be used to prevent adverse reactions when available.
If Grade 2 adverse reactions persist until the next course of capecitabine/docetaxel should be administered.
Delay treatment until the adverse reaction resolves to Grade 0 to 1, then continue treatment with the original dose of capecitabine and docetaxel. Adjuvant measures may be used to prevent adverse reactions when available. When occurring within 14 days of capecitabine treatment.
Suspend capecitabine therapy until the adverse reaction resolves to grade 0 to 1. Continue therapy at 75% of the original capecitabine dose for the duration of the course of treatment, with no supplementation of any capecitabine dose missed during the course of treatment. Adjuvant measures may be used to prevent adverse reactions when available.
If Grade 3 adverse reactions persist until the next course of capecitabine/docetaxel should be administered.
Delay treatment until the adverse reaction resolves to grade 0 to 1.
For patients with Grade 3 adverse reactions at any time during the course of therapy, continue subsequent courses of therapy at 75% of the original capecitabine dose and docetaxel 55 mg/m2 when the adverse reactions have resolved to Grade 0 to 1. Adjuvant measures may be used to prevent adverse reactions when available. Discontinue treatment unless the physician in charge believes it is in the patient’s best interest to continue treatment at 50% of the original capecitabine dose. The same adverse reaction
When reoccurring within 14 days of capecitabine treatment.
Suspend capecitabine therapy until the adverse reaction resolves to grade 0 to 1. Continue therapy at 75% of the original capecitabine dose for the duration of the course of treatment, with no additional capecitabine dose missed during the course of treatment. Adjuvant measures may be used to prevent adverse reactions when available.
If Grade 2 adverse reactions persist until the next course of capecitabine/docetaxel should be administered.
Delay treatment until the adverse reaction resolves to Grade 0 to 1.
For patients who experience a recurrence of Grade 2 adverse reactions at any time during the course of therapy, continue subsequent courses of therapy at 75% of the original capecitabine dose and docetaxel 55 mg/m2 when the adverse reactions have resolved to Grade 0 to 1. Adjuvant measures may be used to prevent adverse reactions when available. When occurring within 14 days of capecitabine treatment.
Suspend capecitabine therapy until the adverse reaction resolves to Grade 0 to 1. Continue therapy at 50% of the original capecitabine dose for the duration of the course, with no additional capecitabine dose missed during the course of therapy. Adjuvant measures may be used to prevent adverse reactions when available.
If Grade 3 adverse reactions persist until the next course of capecitabine/docetaxel should be administered.
Delay treatment until the adverse reaction resolves to grade 0 to 1.
For patients who experience a Grade 3 adverse reaction at any time during the course of therapy, continue subsequent courses of therapy at 50% of the original capecitabine dose and discontinue docetaxel when the adverse reaction has resolved to Grade 0 to 1. Use adjunctive measures to prevent adverse reactions when available. Discontinue treatment. The same adverse reaction
Third occurrence within 14 days of capecitabine treatment When occurring.
Suspend capecitabine therapy until the adverse reaction resolves to Grade 0 to 1; continue therapy at 50% of the original capecitabine dose for the duration of the course, with no additional capecitabine dose missed during the course of therapy. Adjuvant measures may be used to prevent adverse reactions when available.
If Grade 2 adverse reactions persist until the next course of capecitabine/docetaxel should be administered.
Delay treatment until the adverse reaction has resolved to Grade 0 to 1.
For patients who experience a Grade 2 adverse reaction for the third time at any time during the course of therapy, continue subsequent courses of therapy at 50% of the original capecitabine dose and discontinue docetaxel when the adverse reaction has resolved to Grade 0 to 1. Ancillary measures may be used to prevent adverse reactions when available. Discontinue treatment. Same adverse reaction
Discontinue treatment on the fourth occurrence. *Use the Common Toxic Reaction Classification Criteria (CTC) developed by the National Cancer Institute (NCIC), Canadian Clinical Trials Group, except for hand-foot syndrome and hyperbilirubinemia (see [Precautions]).
The dose adjustment regimen for capecitabine monotherapy is shown in Table 4.
Table 4. Dose adjustment regimen for capecitabine monotherapy
NCIC adverse reaction grading* Dose adjustment for next course of therapy
(% starting dose) – Grade 1 Maintain original dose Maintain original dose – Grade 2 – First occurrence of dose suspension until return to grade 0~1 100% – Second occurrence of dose suspension until return to grade 0~1 75% – Third occurrence of dose suspension until return to grade 0~1 50% – Fourth occurrence of permanent termination of treatment NA – Grade 3 – First occurrence of dose suspension until return to grade 0~1 75% – second occurrence of suspension until recovery to level 0~1 50% – third occurrence of permanent termination of treatment NA-4 – first occurrence of permanent termination of treatment
OR
If the physician believes it is in the patient’s best interest to continue treatment, suspend dosing until remission to Grade 0~1 and then continue treatment. 50%-Second occurrence of permanent discontinuation of treatment NA* Except for hand-foot syndrome and hyperbilirubinemia, use the common toxicity reaction grading criteria developed by the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) (see [Precautions]).
In the event of a Grade 1 adverse reaction, no dose adjustment is recommended. In the event of a grade 2 or 3 adverse reaction, capecitabine treatment should be suspended. Once the adverse reaction resolves or decreases in severity to grade 1, treatment may be restarted with the original dose of capecitabine or at the dose adjusted according to the table above. In case of Grade 4 adverse reactions, treatment should be discontinued or suspended until the adverse reaction disappears or its severity is reduced to Grade 1, and then restarted at 50% of the original dose. Doses of capecitabine missed due to toxic reactions will not be replenished or restored and the patient will instead continue the planned course of treatment.
Adjustment of starting dose for special populations.
Hepatic impairment: No adjustment of the starting dose is necessary for patients with mild to moderate hepatic dysfunction caused by liver metastases, but patients should be monitored closely. No studies have been conducted in patients with severe hepatic dysfunction.
Renal impairment: No adjustment of the starting dose of capecitabine is recommended in patients with mild renal impairment (creatinine clearance = 51-80 ml/min [Cockroft and Gault, see below for details of the calculation formula]). In patients with moderate renal impairment (baseline creatinine clearance = 30-50 ml/min), a reduction in the starting dose of capecitabine to 75% of the standard dose (from 1250 mg/m2 twice daily to 950 mg/m2 twice daily) is recommended when used for single agent chemotherapy or in combination with docetaxel (see [Pharmacokinetics]: Special Populations). Corresponding dose adjustments in patients following Grade 2 to Grade 4 adverse reactions (see [Precautions]) are recommended in accordance with Tables 3 and 4. Recommendations for starting dose adjustment in patients with moderately impaired renal function can be applied both to capecitabine monotherapy and to the combination of capecitabine and docetaxel.
Cockroft and Gault equation.
Creatinine clearance in men = (140 – age [years]) (weight [kg]) (72) (serum creatinine [mg/dl]) Creatinine clearance in women = 0.85 × creatinine clearance in men
Elderly patients: no adjustment of starting dose is required for capecitabine monotherapy. Capecitabine has a relatively higher incidence of grade 3 or 4 drug-related adverse reactions in older patients (> 60 years) compared to younger patients. When capecitabine was used in combination with oxaliplatin, more grade 3 to 4 adverse reactions and adverse reactions leading to discontinuation occurred in older patients (≥65 years of age) compared with younger patients. Physicians should closely monitor the effects of capecitabine in older patients.
When capecitabine is used in combination with docetaxel, an increased incidence of grade 3 or 4 drug-related adverse reactions can be observed in patients 60 years of age and older. Therefore, for patients aged 60 years and older receiving capecitabine plus docetaxel in combination, it is recommended that the starting dose of capecitabine be reduced to 75%.
When used in combination with cisplatin, the recommended dose of capecitabine is 1000 mg/m2 twice daily, with 1 week of discontinuation after 2 weeks of treatment. The cisplatin dose of 80 mg/m2 is administered intravenously over 2 hours on day 1 of each 3-week course. The first dose of capecitabine was given in the evening on day 1 and the last dose was given in the morning of day 15.
Patients receiving capecitabine in combination with cisplatin need to be given adequate hydration and antiemetic therapy according to the product instructions for cisplatin before cisplatin is given.
In combination with cisplatin, toxicities that are not considered serious or life-threatening by the treating physician, such as: hair loss, appetite changes, nail discoloration, etc., may be continued at the starting dose without dose reduction or interruption. For further information on cisplatin, please consult the cisplatin insert.
For hematotoxic dose adjustments.
If the patient’s absolute neutrophil count (ANC) is greater than 1,500 × 106/l and platelet count is greater than 100,000 × 106/l at the start of the course of treatment, a new 3-week course of treatment may be started. Otherwise, treatment needs to be delayed until the hematologic parameters have recovered. Detailed guidance on dose adjustment for hematologic toxicity is provided in Table 5.
Table 5. Dose adjustment regimen for capecitabine (X) in combination with cisplatin (P) during planned treatment based on hematologic toxicity
Absolute neutrophil ANC count (× 106/l) Platelet count (× 106/l) Dose adjustment for capecitabine and cisplatin at treatment restart ≥1500 and ≥100,000X: 100% starting dose without delay
P: 100% starting dose without delay
≥1000 and < 1500 and ≥100,000X: 75% starting dose without delay
P: 75% starting dose without delay
< 1000 and/or < 100,000X: Delayed until ANC ≥1000 and platelets ≥100,000, then 75% of starting dose when ANC ≥1000 to < 1500 and 100% of starting dose when ANC ≥1500
P: Delayed until ANC ≥ 1000 and platelets ≥ 100,000, then 75% of the original dose when ANC ≥ 1000 to < 1500 and 100% of the starting dose when ANC ≥ 1500
If an unscheduled assessment during treatment reveals dose-limiting toxicity, the administration of capecitabine must be interrupted for this course and capecitabine and cisplatin should be reduced for the subsequent course, as shown in Table 6.
Table 6. Dose adjustment regimen in case of hematologic toxicity during capecitabine (X) in combination with cisplatin (P) therapy
Dose limiting toxicity Capecitabine with cisplatin dose adjustment Grade 4 neutropenia over 5 days* X: 75% starting dose
P: 75% starting dose Grade 4 thrombocytopenia*X: 50% starting dose
P: 50% starting dose neutropenic fever, neutropenic sepsis, neutropenic infection X: Interrupt therapy unless the physician believes it is in the patient’s best interest to continue treatment at the 50% starting dose after hematologic toxicity has returned to grade 0 to 1
P: Interrupt therapy unless the physician believes it is in the patient’s best interest to continue treatment at 50% of the starting dose after hematologic toxicity has returned to grade 0 to 1 *According to NCIC classification criteria.
Dose adjustment in case of non-hematologic toxicity: Capecitabine
Capecitabine dose adjustment recommendations apply to toxicities associated with capecitabine rather than with cisplatin or combination therapy. For example, neurotoxicity or ototoxicity do not require a dose reduction of capecitabine. Capecitabine therapy must be interrupted or discontinued immediately if a grade 2, 3 or 4 non-hematologic toxic reaction occurs, see Table 3 (also see Section I, Precautions). Interruption of capecitabine therapy should be counted as a missed treatment period and the missed dose will not be compensated. The original treatment regimen should be maintained. Capecitabine therapy should be discontinued if the creatinine clearance calculated during treatment is less than 30 ml/min. Table 7 summarizes capecitabine and cisplatin dose adjustments based on creatinine clearance.
Dose adjustment for non-hematologic toxicity: cisplatin
The recommendations for cisplatin dose adjustment apply to toxicities associated with cisplatin therapy rather than those associated with capecitabine or coadministration. Cisplatin dose adjustments are described in the cisplatin instructional information.
Nephrotoxicity: Creatinine clearance should be greater than 60 ml/min prior to treatment and should also be calculated prior to each course of treatment according to the Cockroft-Gault formula. After the 1st course, if the creatinine clearance <60ml/min, it must be recalculated after 24 hours of hydration.
In patients with impaired renal function, cisplatin dose adjustment must be consistent with the guidance in the cisplatin instructional information.
In clinical studies applying capecitabine and cisplatin, cisplatin dose adjustments are shown in Table 7.
Table 7. Dose adjustment regimens for cisplatin and capecitabine based on creatinine clearance
Creatinine clearance cisplatin dose capecitabine dose ³ 60 ml/min full dose full dose 41-59 ml/min cisplatin dose mg/m2 the same value as the creatinine clearance ml/min value. For example, if creatinine clearance is 45 ml/min , cisplatin dose is 45 mg/m2 full dose £ 40 ml/min Permanent discontinuation of cisplatin full dose * £ 30 ml/min Permanent discontinuation of capecitabine * When creatinine clearance is less than or equal to 40 ml/min, treatment with capecitabine alone may be continued if creatinine clearance is greater than 30 ml/min.
Nausea or vomiting: For grade 3 or 4 nausea or vomiting, cisplatin should be reduced to 60 mg/m2 in subsequent courses despite adequate prophylaxis.
Ototoxicity: The presence of hearing loss, new tinnitus or new audiogram with significant loss of high frequency hearing should discontinue cisplatin, but continue capecitabine.
Neurotoxicity: Patients who develop grade 2 NCI – CTC neurotoxicity should discontinue cisplatin but continue capecitabine.
[Adverse Reactions].
The investigators concluded that adverse reactions may occur both when capecitabine is administered as monotherapy for different indications (adjuvant colon cancer treatment, metastatic colorectal cancer and metastatic breast cancer treatment) and when combination chemotherapy regimens are administered. Based on the highest incidence rates derived from the pooled analysis of seven clinical trials, the various adverse reactions were grouped into the corresponding categories in the following tables. The adverse reactions are listed in each frequency classification in order of severity from most to least severe. Frequencies were categorized as very common (³ 1/10), common (³ 5/100 – < 1/10), and occasional (³ 1/1000 – < 1/100).
Capecitabine Monotherapy – Information on the safety of capecitabine monotherapy was obtained from reports of patients treated for adjuvant colon cancer and metastatic breast cancer or metastatic colorectal cancer. Safety information includes information from 1 phase III trial of adjuvant therapy for colon cancer (995 patients treated with capecitabine and 974 patients treated with 5-FU/LV intravenous infusion), 4 phase II trials in women with breast cancer (N=319) and 3 (1 phase II, 2 phase III) colorectal cancer trials (N=630). The safety of capecitabine monotherapy was similar in patients treated for adjuvant colon cancer as in patients treated for metastatic breast cancer or metastatic colorectal cancer. The intensity grading of adverse reactions was based on the NCIC CTC grading system for toxicity grading.
Table 8: Summary of adverse reactions reported in patients with ≥ 5% of patients on capecitabine monotherapy
Summary of adverse reactions reported by ≥ 5% of patients
Body system
Adverse reactions were very common
(≥ 10%) Common
(≥ 5% – < 10%) Metabolic and nutritional anorexia (G3/4:1%)
Dehydration (G3/4: 3%)
Low appetite (G3/4:< 1%) Neurological Sensory abnormalities,.
Taste disturbances (G3/4:<1%),.
headache (G3/4:<1%).
Dizziness (other than vertigo) (G3/4:<1%) Eye Increased tearing
Conjunctivitis (G3/4:<1%)
Gastrointestinal diarrhea (G3/4: 13%)
Vomiting (G3/4: 4%)
Nausea (G3/4: 4%)
Stomatitis (all)* (G3/4/4%)
Abdominal pain (G3/4: 3%) Constipation (G3/4:<1%)
Epigastric pain (G3/4: 1%)
dyspepsia (G3/4:<1%), the
Hepatobiliary hyperbilirubinemia (G3/4:1%) Cutaneous and subcutaneous tissue hand-foot syndrome** (G3/4:17%).
dermatitis (G3/4:<1%) rash, the
alopecia.
Erythema (G3/4:<1%).
Dry skin (G3/4:<1%), general and administration site fatigue (G3/4: 3%), and
Sleepiness (G3/4:<1%) Fever (G3/4:<1%).
Weakness (G3/4:<1%).
Weakness (G3/4:<1%)* Stomatitis, mucosal inflammation, mucosal ulcers, oral ulcers
**Based on post-marketing experience, persistent or severe hand-foot syndrome may eventually lead to loss of fingerprints (see [Caution])
Data from seven completed clinical trials suggest that less than 2% of patients develop skin cracking that may be associated with treatment with capecitabine (N=949).
The following known toxicities of fluoropyrimidine therapy were 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, flatulence, mucosal inflammation/ulceration such as esophagitis, gastritis, duodenitis, colitis and gastrointestinal bleeding
Cardiac disorders: lower extremity edema, cardiogenic chest pain (e.g., angina), cardiomyopathy, myocardial ischemia/infarction, heart failure, sudden death, tachycardia, arrhythmias (e.g., atrial fibrillation, premature ventricular contractions)
Neurological disorders: insomnia, confusion, encephalopathy, cerebellar dysfunction (e.g., ataxia, dysphonia, balance dysfunction, abnormal ataxia)
Infectious and invasive diseases: diseases associated with myelosuppression, immune system compromise and/or mucosal barrier compromise, such as local and fatal systemic infections (including bacterial, viral, fungal), and sepsis
Hematologic and lymphatic disorders: anemia, myelosuppression, pancytopenia
Skin and subcutaneous tissue disorders: pruritus, localized epidermal peeling, skin pigmentation, nail lesions, photosensitivity reactions, radiation therapy recall syndrome
Systemic conditions and administration sites: limb pain, chest pain (non-cardiogenic chest pain)
Eye: eye irritation
Respiratory: dyspnea, cough
Musculoskeletal: back pain, myalgia, arthralgia
Mental disorders: depression
Hepatic failure and biliary depressive hepatitis have been reported during the clinical trial phase and post-marketing dosing experience. A causal relationship between these two disorders and capecitabine use cannot yet be given.
Capecitabine combination therapy
Table 9 lists the adverse reactions that occurred, and/or occurred more frequently, when capecitabine was combined with multiple chemotherapy regimens for various indications, excluding adverse drug reactions observed with capecitabine monotherapy. The safety profile was similar across indications and combination regimen groups. The incidence of these adverse reactions was ≥5% when capecitabine was combined with other chemotherapy treatments. Based on the highest incidence in each clinical trial, adverse reactions were grouped into the categories of events in the table below. Some adverse reactions were common with chemotherapy (e.g., peripheral sensory neuropathy with docetaxel or oxaliplatin treatment) or with bevacizumab treatment (e.g., hypertension); however, the possibility that capecitabine treatment exacerbated these adverse reactions cannot be excluded.
Table 9. Adverse reactions that are very common or common with capecitabine in combination with different chemotherapy regimens
(in addition to the adverse reactions observed with capecitabine monotherapy)
Body system
Adverse reactions very common
≥10% common
≥5% – <10% Infection and infestation Infection+
Oral candidiasis Blood and lymphatic system Neutropenia+
Leukopenia+
Febrile neutropenia+
Thrombocytopenia+
Anemia+ Metabolic and nutritional hypophagia Hypokalemia
Weight loss Mental illness Insomnia Neurological peripheral neuropathy
Peripheral sensory neuropathy
Neuropathy
Sensory abnormalities
Taste disorders
Dullness of sensation
Headache Hyperalgesia Increased eye tearing Vascular thrombosis/embolism
Hypertension
Lower extremity edema Respiratory, thoracic and mediastinal pharyngeal hypesthesia
Sore throat Epistaxis
Difficulty in vocalization
Nasal leakage
Breathing difficulties Gastrointestinal constipation
Indigestion Dry mouth Skin and subcutaneous tissue Hair loss
Nail disorders Musculoskeletal system Joint pain
Myalgia
Limb pain jaw pain
Back pain systemic and administration site
Fever
Weakness
weakness
Cold and heat intolerance Fever+
Pain
The frequency of all adverse reactions was based on all graded adverse reactions, except for the frequency of + marked adverse reactions which were based on grade 3/4 adverse reactions.
Hypersensitivity reactions (2%) and myocardial ischemia/myocardial infarction events (3%) were commonly reported with capecitabine in combination with chemotherapy, but their incidence was less than 5%.
The rare or occasional adverse reactions reported with capecitabine in combination with other chemotherapy were consistent with those reported with capecitabine alone or with monotherapy with the combined chemotherapeutic agents (see Prescribing Information for Combination Therapy Drugs).
Laboratory Abnormalities
The following table lists the laboratory abnormalities observed in 995 patients with colon cancer (adjuvant therapy) and 949 patients with metastatic breast and colorectal cancer treated with capecitabine (whether or not related to capecitabine).
Table 10. Laboratory abnormalities: capecitabine monotherapy for colon (adjuvant), metastatic breast, and colorectal cancers
Parameters a
Capecitabine 1250 mg/m2 administered intermittently twice daily Grade 3/4 Laboratory abnormalities (%) Alanine aminotransferase (ALT) elevation 1.6 Aspartate aminotransferase (AST) elevation 1.1 Alkaline phosphatase elevation 3.5 Hypercalcemia 1.1 Hypocalcemia 2.3 Granulocytopenia 0.3 Hemoglobin reduction 3.1 Lymphopenia 44.4 Neutropenia 3.6 Neutrophil /granulocytopenia2.4 thrombocytopenia2.0 hypokalemia0.3 elevated serum creatinine0.5 hyponatremia0.4 elevated bilirubin20 hyperglycemia4.4a Laboratory abnormalities were graded with reference to the NCIC CTC grading system.
The following table shows the laboratory abnormalities that occurred in 302 patients with gastric cancer treated with capecitabine in combination with cisplatin (whether or not these abnormalities were treatment related).
Table 11: Laboratory abnormalities: Capecitabine in combination with cisplatin in first-line treatment of advanced or metastatic gastric cancer
Capecitabine 1000 mg/m2
twice daily for 2 weeks.
Cisplatin 80 mg/m2 , day 1, for 3 weeks
(N=156) 5-FU 800 mg/m2/d,
days 1 to 5.
Cisplatin 80 mg/m2 , day 1, 3 weeks
(N=155) Occurrence of grade 3/4
Toxic patients (%) Occurrence of grade 4
Toxic patients (%) occurring grade 3/4
Toxic patients (%) occurring grade 4
Toxic patients (%) Hemoglobinopenia 23.13.219.48.4 Neutropenia 23.12.621.98.4 Neutropenia/granulocytopenia 26.93.225.28.4 Thrombocytopenia 5.10.63.91.9 Sodium decreased 9.60.66.51.3 Potassium decreased 7.11.35.81.3 Bilirubin increased 3.81.32.61.3 Alkaline phosphatase elevated1.90.64.50.6 ALT (SGPT) elevated0.00.03.20.6 AST (SGOT) elevated0.00.03.21.3 Albumin decreased5.20.03.90.0 Creatinine elevated0.60.01.30.0 Fasting glucose elevated4.50.61.90.0 Granulocytopenia 4.50.63.20.0 Leukopenia (WBC) 8.31.3112.6
Immunogenicity: not applicable
Post-marketing reports
Based on spontaneous case reports and literature cases, the following adverse reactions were identified from post-marketing dosing experience with capecitabine. Adverse drug reactions were listed according to the systemic organ classification in MedDRA, and the corresponding frequency category estimates for adverse drug reactions were determined based on the following rules: very common (≥ 1/10); common (≥ 5/100 to <1/10); occasional (≥ 1/1,000 to <1/100); rare (≥ 1/10,000 to <1/1,000 ); very rare (≥ 1/100,000 to < 1/10,000); unknown (could not be estimated using available data).
Table 12 . Adverse drug reactions (ADRs) in postmarketing drug use experience
System Organ Classification (SOC) ADR(s) Frequency of Occurrence Renal and Urologic Disorders Acute Renal Failure Secondary to Dehydration (see [Caution]) Rare Neurologic Disorders Toxic Cerebral Leukoaraiosis Unknown Hepatobiliary Disorders Hepatic Failure, Cholestatic Hepatitis Very Rare Metabolic and Nutritional Disorders Hypertriglyceridemia Unknown Skin and Subcutaneous Tissue Disorders Cutaneous Lupus Erythematosus, Severe Skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis relaxation (TEN), (see [Precautions]) Very rare ocular organ disease Lacrimal duct stenosis NOS. corneal disease, including keratitis Very rare NOS: not specified
Exposure to crushing or cutting capecitabine tablets.
The following adverse reactions (ADRs) have been reported with exposure to crushed or cut capecitabine tablets: eye irritation, eye swelling, rash, headache, sensory confusion, diarrhea, nausea, gastric irritation, and vomiting.
Contraindications]
Known hypersensitivity to capecitabine or any of its excipients is contraindicated.
Capecitabine is contraindicated in patients with a previous severe, unintended reaction to fluoropyrimidine or known hypersensitivity to fluoropyrimidine.
Capecitabine is contraindicated in patients with known complete deficiency of dihydropyrimidine dehydrogenase (DPD) activity (see [Precautions]).
Capecitabine should not be administered concomitantly with solifudine or its analogs (e.g., brodifacoum) (see [Drug Interactions]).
Capecitabine is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 ml/min).
Combination chemotherapy should be avoided if there is a contraindication associated with either combination drug.
Contraindications to cisplatin also apply to the combination of capecitabine and cisplatin.
[Precautions].
Diarrhea: Capecitabine can cause diarrhea, sometimes more severe. Patients who develop severe diarrhea should be closely monitored, and if they begin to become dehydrated, fluids and electrolytes should be replenished immediately. Where appropriate, standard antidiarrheal therapy medications (e.g., loperamide) should be started early. A lower dose should be administered if necessary (see [Dosage]).
Dehydration: Dehydration must be prevented and corrected promptly when it occurs. Dehydration can occur early in the course of a patient’s anorexia, weakness, nausea, vomiting, or diarrhea. Dehydration may lead to acute renal failure, especially in patients with renal insufficiency or in patients on nephrotoxic drugs in combination with capecitabine. Renal failure leading to death has been reported in these cases. When symptoms of Grade 2 (or higher) dehydration develop, treatment with this product must be discontinued immediately while the dehydration is corrected. Treatment with this product should not be restarted until the patient’s symptoms of dehydration have resolved and the immediate cause of the dehydration has been corrected and controlled. Dose adjustment of the administered dose is necessary to address this adverse reaction.
Cardiotoxicity similar to that of fluoropyrimidine drugs has been observed with capecitabine, including myocardial infarction, angina pectoris, arrhythmias, cardiac arrest, cardiac failure, and electrocardiographic changes. These adverse reactions may be more common in patients with a prior history of coronary artery disease.
Dihydropyrimidine dehydrogenase (DPD) deficiency: Rare unintended severe toxicities associated with 5-FU (e.g., stomatitis, diarrhea, mucosal inflammation, neutropenia, and neurotoxicity) have been attributed to a deficiency in DPD (an enzyme involved in the degradation of fluorouracil) activity. Patients with some pure or some compound heterozygous mutation at the DPYD locus result in complete or near complete deficiency of DPD activity and are at highest risk for severe, life-threatening or lethal adverse reactions due to fluoropyrimidines. Therefore, such patients should not be treated with capecitabine. No safe dose has been established for patients with complete deficiency of DPD activity (see [Contraindications]). Patients carrying a certain heterozygous DPYD mutation that can cause partial DPD deficiency (e.g., DPYD*2A mutation) show an increased risk of severe toxicity when treated with capecitabine. For patients with partial DPD deficiency in whom the benefit of this product outweighs the risk (given the suitability of alternative non-fluoropyrimidine-based chemotherapy regimens), treatment must be administered with extreme caution, starting with a substantially lower dose, followed by frequent monitoring and dose adjustment based on toxicity.
DPD deficiency testing should be performed based on local accessibility and current guidelines.
Life-threatening toxicity manifesting as acute drug overdose may occur in patients treated with capecitabine who fail to confirm DPD deficiency and in patients who test negative for specific DPYD variants. In the event of grade 2-4 acute toxicity, treatment must be discontinued immediately. Permanent discontinuation should be considered based on clinical assessment of the time of onset, duration and severity of observed toxicity.
Capecitabine can cause severe skin reactions such as Stevens-Johnson syndrome and toxic epidermolysis bullosa (TEN). Capecitabine should be permanently discontinued in patients who may have a serious skin reaction as a result of treatment with capecitabine.
Capecitabine can cause hand-foot syndrome (painful palm-foot erythema or chemotherapy-induced erythema of the extremities), a skin toxicity. Persistent or severe hand-foot syndrome (grade 2 and above) can eventually lead to loss of fingerprints, which in turn may affect patient identification. Patients with metastatic tumors treated with capecitabine monotherapy had a median time to onset of hand-foot syndrome of 79 days (range from 11 to 360 days) and a severity of grade 1 to 3.
Grade 1 hand-foot syndrome was defined as the presence of any of the following: numbness, dullness/abnormal sensation, tingling sensation, erythema and/or discomfort not interfering with normal activities in the hands and/or feet. grade 2 hand-foot syndrome was defined as painful erythema and swelling of the hands and/or feet and/or discomfort that interfered with the patient’s daily activities. grade 3 hand-foot syndrome was defined as wet flaking, ulceration, blistering or severe pain in the hands and/or feet and/or or severe discomfort that prevents the patient from working or performing daily activities.
Capecitabine should be withheld in the presence of Grade 2 or 3 hand-foot syndrome until normalization or reduction in severity to Grade 1. After the development of Grade 3 hand-foot syndrome, the dose should be reduced when capecitabine is used again (see [DOSAGE]). Vitamin B6 (pyridoxine) is not recommended for symptomatic improvement or secondary prevention of hand-foot syndrome when capecitabine is combined with cisplatin because it has been reported that vitamin B6 may reduce the efficacy of cisplatin. There is evidence that dextro-panthenol is effective in helping to prevent hand-foot syndrome in patients treated with capecitabine.
Capecitabine can cause hyperbilirubinemia. Capecitabine should be suspended immediately if drug-related bilirubin is elevated >3.0 × ULN or hepatic transaminases (ALT, AST) are elevated >2.5 × ULN. Capecitabine may be resumed when bilirubin decreases to ≤3.0 × ULN or hepatic transaminases ≤2.5 × ULN.
Special caution must be exercised when using capecitabine concomitantly with drugs that are metabolized by cytochrome P450 2C9 (e.g., warfarin or phenytoin). Patients on combined anticoagulation therapy with capecitabine and oral coumarin derivatives should be closely monitored for anticoagulant response (INR or prothrombin time) and the anticoagulant dose should be adjusted accordingly. Phenytoin plasma concentrations should be routinely monitored in patients receiving phenytoin in combination with capecitabine administration. (See [Drug Interactions]). Toxic reactions to capecitabine therapy should be closely monitored. Most adverse reactions are reversible and do not require discontinuation of the drug, although dose may need to be limited or reduced (see [DOSAGE]).
Renal Impairment
Caution should be exercised when capecitabine is used in patients with renal impairment. As with 5-fluorouracil, patients with moderate renal impairment (creatinine clearance of 30 to 50 mL/min [Cockroft and Gault]) have a higher incidence of treatment-related Grade 3 or 4 adverse events. In patients with moderate renal impairment (creatinine clearance of 30-50 mL/min [Cockroft and Gault]), it is recommended that the starting 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 patients experience grade 2 to 4 adverse events, close monitoring and immediate suspension of dosing should be performed, and subsequent dose adjustments can be made by referring to the appropriate dose adjustment tables.
Hepatic Impairment
Capecitabine should be monitored closely when used in patients with hepatic impairment. The effect of non-hepatic metastasis-induced liver injury or severe liver injury on the in vivo distribution of capecitabine is not known (see Pharmacokinetics and Special Dosage Guidelines for Special Populations).
Effects on the ability to drive and operate machinery
Capecitabine has a moderate effect on the ability to drive and operate machinery. Patients should be advised to use caution when driving or operating machinery if they experience adverse reactions (e.g., dizziness, fatigue, and or nausea) during capecitabine treatment (see [ADVERSE REACTIONS]).
Special Instructions for Use, Handling and Disposal
Disposal of unused/expired drugs
The discharge of drugs into the environment should be minimized. Drugs should not be disposed of through wastewater and should not be disposed of as household waste. If your location has a defined “collection system”, please use these.
Because Siroda is a cytotoxic drug, special handling should be performed with appropriate equipment and disposal procedures. Any unused drug or waste material should be disposed of in accordance with local regulations.
[Females and males with fertility].
Fertility: Based on evidence from animal studies, capecitabine may impair fertility in fertile males and females (see [Pharmacologic Toxicology])
Contraception
Women: Women of childbearing potential should be advised to avoid pregnancy while on capecitabine treatment. An effective method of contraception should be used during treatment and for at least 6 months after the last dose of capecitabine. If a patient becomes pregnant while on capecitabine treatment, the potential harm to the fetus must be explained.
Men: Based on genotoxicity results, male patients and female partners of childbearing potential should use an effective method of contraception during treatment and for 3 months after the last dose of capecitabine.
[Pregnant and lactating women use].
Pregnancy: No studies have been conducted on the use of capecitabine in pregnant women. Based on the pharmacological and toxicological properties of capecitabine, it can be inferred that capecitabine use in pregnant women may cause fetal damage. In animal reproductive toxicity studies, capecitabine caused embryonic death and malformation. These findings are within the range of expected effects of fluoropyrimidine derivatives. Capecitabine may be a human teratogen. Capecitabine is contraindicated during pregnancy (see [Pharmacology and Toxicology]). If capecitabine is used during pregnancy, or if the patient becomes pregnant while on the drug, the patient should be informed of the potential risk of the drug to the fetus.
Lactation: It is not known whether capecitabine can be secreted into human milk. No studies designed to assess the effect of capecitabine on lactation or the presence of capecitabine in human milk have been conducted. A single dose of capecitabine administered orally to lactating mice resulted in significant amounts of capecitabine metabolites in milk. Because the potential for harm to nursing infants is not known, nursing should be discontinued during capecitabine treatment and for 2 weeks after the last dose.
Pediatric Use]
The safety and efficacy of capecitabine in patients under 18 years of age have not been demonstrated.
Geriatric use]
The incidence of gastrointestinal toxicity in patients aged 60-79 years with metastatic colorectal cancer treated with capecitabine monotherapy is similar to that of the overall population. Reversible grade 3 or 4 gastrointestinal adverse reactions, such as diarrhea, nausea, and vomiting, occur at a higher rate in patients over 80 years of age (see Special Dosage Guidelines). When capecitabine is combined with other antineoplastic agents, grade 3 and 4 and adverse reactions leading to discontinuation occur more frequently in older patients (≥65 years of age) compared to younger patients. Safety analysis of capecitabine in combination with docetaxel in patients over 60 years of age showed a higher incidence of treatment-related grade 3 and 4 adverse reactions, treatment-related serious adverse reactions, and early withdrawal from treatment due to adverse reactions than in the group of patients under 60 years of age.
[Drug Interactions].
Coumarin-based anticoagulants: Changes in coagulation parameters and/or bleeding have been reported in patients treated with capecitabine and concomitantly with coumarin-derived anticoagulants such as warfarin and phenprocoumarin. These occurred within days to months of capecitabine treatment, with some patients presenting within 1 month of capecitabine discontinuation. In a drug interaction study, a single dose of 20 mg warfarin followed by capecitabine treatment resulted in a 57% increase in mean AUC and a 91% increase in INR for S-warfarin. These results suggest the existence of an interaction, which is likely due to the inhibitory effect of capecitabine on the cytochrome P450 2C9 isoenzyme system. Patients on capecitabine with oral anticoagulants of coumarin derivatives should be routinely monitored for anticoagulation parameters (INR or PT) and the dose of anticoagulant adjusted accordingly.
Cytochrome P-450 2C9 substrates: Interactions between capecitabine and other drugs known to be metabolized by cytochrome P-450 2C9 have not been formally studied. Capecitabine should be used with caution with these drugs.
Phenytoin: Concomitant administration of capecitabine and phenytoin has been reported to increase the plasma concentration of phenytoin. Formal studies of the interaction between capecitabine and phenytoin have not been performed, but it is speculated that the mechanism of interaction may be inhibition of the CYP2C9 isoenzyme by capecitabine (see coumarin anticoagulants). Plasma concentrations of phenytoin should be routinely monitored in patients taking capecitabine concomitantly with phenytoin.
Drug-food interactions: In all clinical trials, patients were instructed to take capecitabine within 30 minutes of a meal. The available safety and efficacy data are based on administration with food and therefore 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 has been studied in patients with malignancies. Plasma concentrations of capecitabine and one of its metabolites (5′-DFCR) were slightly increased; there was no effect on the three major metabolites (5′-DFUR, 5-FU and FBAL).
Formyltetrahydrofolate (folinic acid): The effect of formyltetrahydrofolate on the pharmacokinetics of capecitabine was studied in patients with malignancies and showed no effect on the pharmacokinetics of capecitabine and its metabolites. However, formyltetrahydrofolate has an effect on the pharmacodynamics of capecitabine and may increase the toxicity of capecitabine.
Solifudine and its analogs: The literature shows a clinically significant interaction between solifudine and 5-fluorouracil drugs due to the inhibition of dihydropyrimidine dehydrogenase by solifudine. This interaction results in elevated fluoropyrimidine toxicity with the potential for lethality. Therefore, capecitabine should not be administered concomitantly with solifudine and its analogs such as brodifacoum (see [Contraindications]). There must be a waiting period of at least 4 weeks between the end of treatment with solifudine and its analogs (e.g., brodifacoum) and the start of capecitabine therapy.
Oxaliplatin: There is no clinically significant difference in exposure to capecitabine or its metabolites, free platinum or total platinum when oxaliplatin is administered in combination with capecitabine (with or without bevacizumab).
Bevacizumab: There were no clinically significant effects of bevacizumab on the pharmacokinetic parameters of capecitabine or its metabolites.
[Drug overdose].
Acute drug overdose is manifested by nausea, vomiting, diarrhea, mucositis, gastrointestinal irritation and bleeding, and bone marrow suppression.
Medical management of drug overdose should include: conventional treatment, supportive treatment (aimed at correcting clinical manifestations) and prevention of complications.
Pharmacology and Toxicology
Pharmacological effects
In vivo capecitabine is converted to 5-fluorouracil (5-FU) by enzymatic action. Both normal and tumor cells metabolize 5-FU into 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites cause cellular damage through two different mechanisms. First, FdUMP and the folate co-factor N5,10-methylenetetrahydrofolate bind to thymidylate synthase (TS) to form a covalently bound triple complex. This binding inhibits the formation of thymidine from 2′-deoxyuridine [pyrimidine nucleotide]. Thymidine nucleotides are essential precursors for thymidine nucleoside triphosphate, which is required for DNA synthesis, and thus deficiency of this compound inhibits cell division. Second, nuclear transcriptase may incorrectly program FUTP at the site of uridine triphosphate (UTP) during RNA synthesis. this metabolic error will interfere with RNA processing and protein synthesis.
Toxicological studies
Genotoxicity
Capecitabine was not mutagenic in bacterial (Ames test) or mammalian cells (Chinese hamster V79/HPRT gene mutation test) in in vitro assays. Capecitabine was chromosome disrupting in human lymphocytes in vitro but not in mouse bone marrow in vivo (micronucleus test). 5-Fluorouracil was mutagenic in bacteria and yeast in vitro and caused chromosomal abnormalities in mice in vivo in the micronucleus test.
Reproductive toxicity
In a mouse fertility study, oral administration of capecitabine at 760 mg/kg/day to pregnant mice showed estrus disturbance and decreased fertility. In pregnant mice, no embryos survived at this dose. The estrous disturbance was reversible. This dose induced degenerative changes in males in this assay, including a decrease in spermatocyte and sperm cell numbers. Independent pharmacokinetic studies showed that mice at this dose produced 5′-DFUR AUC approximately 0.7 times the AUC of patients receiving the recommended daily dose.
During organogenesis, oral administration of capecitabine 198 mg/kg/day to pregnant mice resulted in malformations and embryonic lethality. In independent pharmacokinetic studies, mice at this dose produced a 5′- DFUR AUC approximately 0.2 times the AUC of patients receiving the recommended daily dose. Fetal malformations in mice included cleft lip, anophthalmia, microphthalmia, oligophthalmia, polydactyly, syndactyly, caudal malformation, and ventricular dilatation. During organogenesis, oral administration of capecitabine at 90 mg/kg/day to pregnant monkeys resulted in fetal mortality. This dose produced a 5′-DFUR AUC approximately 0.6 times the AUC of patients receiving the recommended daily dose.
A single oral administration of capecitabine to lactating mice resulted in detectable amounts of capecitabine metabolites in milk.
Carcinogenicity
No information is available on the potential carcinogenicity of capecitabine.
Pharmacokinetics]
Capecitabine is relatively non-cytotoxic in vitro. In vivo the drug is converted to 5-fluorouracil (5-FU) by the action of enzymes.
Biotransformation.
Capecitabine is readily absorbed from the gastrointestinal tract. In the liver, a 60-kD carboxylesterase enzyme hydrolyzes most of capecitabine to 5′-deoxy-5-fluorocytidine (5′-DFCR). 5′-DFCR is then converted to 5′-deoxy-5-fluorouridine (5′-DFUR ) by cytidine deaminase, which is present in most tissues, including tumor tissue. Thymidine phosphorylase (dThdPase) then hydrolyzes 5′-DFUR to 5-FU. many human tissues express thymidine phosphorylase, and some human tumors express this enzyme at higher concentrations than surrounding normal tissue.
Metabolic pathway of capecitabine to 5-FU.
Pharmacokinetics in colorectal tumors and adjacent healthy tissues: The median ratio of 5-FU concentrations in colorectal tumors relative to adjacent tissues was 2.9 (from 0.9 to 8.0) after 7 days of oral capecitabine prior to surgery in patients with colorectal cancer. These ratios have not been evaluated in breast cancer patients and have not been compared with 5-FU drip.
Human Pharmacokinetics.
Pharmacokinetic data for capecitabine and its metabolites were evaluated in approximately 200 patients with malignancies in the dose range of 500-3500 mg/m2/day. In this dose range, the pharmacokinetics of capecitabine and its metabolite 5′-DFCR were dose proportional and did not vary over time. However, the proportional increase in the area under the curve (AUC) of 5′-DFUR and 5-FU drug-time was greater than the proportional increase in dose, with the AUC of 5-FU on day 14 being 34% higher than on day 1. The elimination half-life of both parental capecitabine and 5-FU was approximately 3/4 h. The maximum blood concentration and AUC of 5-FU showed greater than 85% inter-patient variability.
Absorption, Distribution, Metabolism and Excretion.
Capecitabine reaches peak blood concentrations approximately 1.5 hours after oral administration (Tmax), and 5-FU reaches peak concentrations later (2 hours). Food decreases the absorption rate and extent of absorption of capecitabine, with mean Cmax and AUC0-∝ decreasing by 60% and 35%, respectively. Food also reduced the Cmax and AUC0-∝ of 5-FU by 43% and 21%, respectively. Food also delayed the Tmax of capecitabine and 5-FU by 1.5 hours (see [Precautions] and [Dosage]).
Plasma protein binding of capecitabine and its metabolites is less than 60%, independent of concentration. Capecitabine is primarily bound to human albumin (approximately 35%).
Capecitabine is metabolized in large amounts to 5-FU by enzymes. dihydropyrimidine dehydrogenase hydrogenates the capecitabine metabolite 5-FU to the much less toxic 5-fluoro-5,6-dihydrofluorouracil (FUH2). Dihydropyrimidinase then cleaves the pyrimidine ring to produce 5-fluoroureidopropionic acid (FUPA). Finally β-ureidopropionic acidase cleaves FUPA to α-fluoro-β-alanine (FBAL) for removal from the urine.
Capecitabine and its metabolites are mostly excreted in the urine. 95.5% of administered capecitabine appears in the urine. Very little (2.6%) is excreted from the feces. The major metabolite excreted in the urine was FBAL, accounting for 57% of the dose used. About 3% of the drug was excreted from the urine in its original form.
A phase I clinical study was conducted in 26 patients with solid tumors to assess the effect of capecitabine on the pharmacokinetics of docetaxel and the effect of docetaxel on the pharmacokinetics of capecitabine. The results showed no effect of capecitabine on the pharmacokinetics (Cmax and AUC) of docetaxel, and no effect of docetaxel on the pharmacokinetics of capecitabine and the 5-FU precursor 5′-DFUR.
Special Populations.
Two large controlled studies enrolled 505 patients with colorectal cancer on capecitabine 1250 mg/m2 twice a day. Analysis of the combined patient populations revealed no effect of gender (202 women and 303 men) and race (455 white/Caucasian, 22 black, and 28 patients of other races) on the pharmacokinetics of 5′-DFUR, 5-FU, and FBAL. In the range of 27 to 86 years, age had no significant effect on the pharmacokinetics of 5′-DFUR and 5-FU. In contrast, for FBAL, a 20% increase in age resulted in a 15% increase in its AUC (see [Precautions] and [Dosage]).
Hepatic insufficiency.
In 13 patients with mild to moderate hepatic dysfunction (as determined by combined bilirubin, AST/ALT, and alkaline phosphatase scores) due to liver metastases, a single dose of capecitabine 1255 mg/m2 was administered and evaluated. The AUC0-∝ and Cmax of capecitabine were increased by 60% in patients with hepatic dysfunction compared with patients with normal liver function (n=14), whereas the AUC0-∝ and Cmax of 5-FU were unaffected. Caution is required when using capecitabine in patients with mild to moderate hepatic dysfunction due to liver metastases (see [Precautions] and [Dosage]).
Formal pharmacokinetic studies have not been performed in patients with severe hepatic impairment and no population pharmacokinetic data have been collected.
Renal Insufficiency.
After oral administration of capecitabine 1250 mg/m2 twice daily in patients with malignancies with varying degrees of renal impairment, patients with moderate (creatinine clearance = 30-50 ml/min) and severe (creatinine clearance <30 ml/min) renal impairment had higher day one organismal FBAL levels than patients with normal renal function (creatinine clearance >80 ml/min) by 85% and 258%. Body 5′-DFUR levels were 42% and 71% higher in patients with moderate and severe renal impairment, respectively, than in normal patients. Capecitabine levels in patients with moderate and severe renal impairment were approximately 25% higher than normal (see [Contraindications], [Precautions] and [Dosage]).
Storage
Store under 30℃ in a sealed container.
Packaging
Polytrifluoroethylene/polyvinyl chloride solid pharmaceutical laminate and pharmaceutical aluminum foil, 12 tablets/plate x 1 plate/box, 12 tablets/plate x 5 plates/box.
【Expiration date】.
24 months
【Execution standard
【Approval number】
【Drug marketing license holder
Unit name: Chengdu Yuan Dong Biopharmaceutical Co.
Registered address: No. 8 Xiyuan Avenue, Chengdu High-tech Zone
Quality complaint phone number: 028-87827168
Consultation number: 028-67585099
Fax number: 028-87826048
Postal Code: 611731
Web address: www.eastonpharma.cn
Adverse reaction report mailbox: [email protected]
Manufacturer
Company name: Chengdu Yuandong Biopharmaceutical Co.
Production Address: No. 8, Xiyuan Avenue, Chengdu High-tech Zone
Contact：028-87827168
Fax: 028-87826048
Postal Code: 611731
Web address: www.eastonpharma.cn