Xeloda

Capecitabine reached peak blood levels in about 1.5 hours (T_max) with peak 5-FU blood levels occurring slightly later, at 2 hours. Administration with food decreases the rate of capecitabine absorption but only results in a minor decrease in the AUC's of 5'-DFUR and 5-FU (see Precautions and Dosage). Plasma protein binding of capecitabine and its metabolites is low (less than 60%) and is not concentration dependent. Capecitabine was primarily bound to human albumin (approximately 35%). Capecitabine is extensively metabolized to 5-FU. The enzyme dihydropyrimidine dehydrogenase hydrogenates 5-FU, the product of capecitabine metabolism, to the much less toxic, 5-fluoro-5,6-dihydro-fluorouracil (FUH₂). Dihydropyrimidinase cleaves the pyrimidine ring to yield 5-fluoro-ureido-propionic acid (FUPA). Finally, β-ureido-propionase cleaves FUPA to α-fluoro-β-alanine (FBAL) which is cleared in the urine. Over 70% of the administered capecitabine dose is recovered in urine as drug-related material, about 50% of it as FBAL.

Phase I studies evaluating the effect of capecitabine on the pharmacokinetics of either docetaxel or paclitaxel and vice versa showed no effect by capecitabine on the pharmacokinetics of docetaxel or paclitaxel (C_max and AUC) and no effect by docetaxel or paclitaxel on the pharmacokinetics of 5'-DFUR (the most important metabolite of capecitabine).

Based on the population pharmacokinetic analysis which included patients with a wide range of ages (27 to 86 years) and included 234 (46%) patients greater or equal to 65, age has no influence on the pharmacokinetics of 5'-DFUR and 5-FU. The AUC of FBAL increased with age (20% increase in age results in a 15% increase in the AUC of FBAL). This increase is likely due to a change in renal function (see Renal Insufficiency). However, the elderly may be pharmacodynamically more sensitive to the toxic effects of 5-FU (see Warnings, Geriatrics and Dosage).

Capecitabine has been evaluated in patients with mild to moderate hepatic dysfunction due to liver metastases. Both C_max and AUC_0-∞ of capecitabine, 5'-DFUR and 5-FU were increased by 49%, 33% and 28% and by 48%, 20% and 15%, respectively. Conversely, C_max and AUC of 5'-DFCR decreased by 29% and 35%, respectively. Therefore, bioactivation of capecitabine is not affected. There are no pharmacokinetic data on patients with severe hepatic impairment (see Warnings and Dosage).

Within normal and tumor cells, 5-FU is further metabolized to 5-fluoro-2'-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP) which cause cell injury by both DNA and RNA-derived mechanisms.

A population pharmacokinetic analysis was carried out after capecitabine treatment of 505 patients with metastatic colorectal cancer dosed at 2500 mg/m²/day. Gender, race, presence or absence of liver metastasis at baseline, Karnofsky Performance Status, total bilirubin, serum albumin, AST and ALT had no statistically significant effect on the pharmacokinetics of 5'-DFUR, 5-FU and FBAL.

Following oral administration of capecitabine (1255 mg/m² b.i.d. 5 to 7 days) in patients with colorectal cancer, concentrations of 5-FU were significantly greater in primary tumor than in adjacent healthy tissue (geometric mean ratio 2.5; CI: 1.5 to 4.1) and in plasma (geometric mean ratio 14).

Capecitabine is absorbed unchanged from the gastrointestinal tract, metabolized primarily in the liver by the 60kDa carboxylesterase to 5'-Deoxy-5-fluorocytidine (5'-DFCR) which is then converted to 5'-DFUR by cytidine deaminase, principally located in the liver and tumor tissue. Further metabolism of 5'-DFUR to the pharmacologically-active agent 5-FU occurs mainly at the site of the tumor by thymidine phosphorylase (dThdPase), which has levels considerably higher in tumor tissues compared to normal tissues. Healthy liver tissues also contain a relatively high activity of dThdPase. In human cancer xenograft models, capecitabine demonstrated a synergistic effect in combination with docetaxel which may be related to the upregulation of thymidine phosphorylase by docetaxel.

Based on a pharmacokinetic study in cancer patients with mild to severe renal impairment, there is no evidence for an effect of creatinine clearance on the pharmacokinetics of intact drug and 5-FU. Creatinine clearance was found to influence the systemic exposure to 5'-DFUR (35% increase in AUC when creatinine clearance decreases by 50%) and to FBAL (114% increase in AUC when creatinine clearance decreases by 50%). FBAL is a metabolite without antiproliferative activity; 5'-DFUR is the direct precursor of 5-FU.

As seen with 5-FU, the incidence of related grade 3 or 4 adverse events is higher in patients with moderate renal impairment (creatinine clearance 30 to 50 mL/min) (see Contraindications, Warnings and Dosage).

Data from one open-label, multicenter, randomized, controlled, non-inferiority, phase III clinical trial in patients with stage III (Dukes C) colon cancer supports the use of XELODA for the adjuvant treatment of patients with stage III colon cancer (X-ACT Study: M66001). In this trial, 1987 patients were randomized to treatment with monotherapy XELODA (1250 mg/m² twice daily for 2 weeks followed by a 1-week rest period and given as 3-week cycles for 24 weeks) (N=1004) or 5 FU and leucovorin (Mayo regimen: 20 mg/m² leucovorin i.v. followed by 425 mg/m² i.v. bolus 5 FU, on days 1 to 5, every 28 days for 24 weeks) (N=983). Although this trial used bolus 5-FU in the control arm, infusional 5-FU has been shown to be superior to bolus 5-FU.

The primary efficacy endpoint was disease-free survival. The original conditional approval was based on primary analysis at a median follow-up time of 3.8 years which showed XELODA was at least equivalent to i.v. 5-FU/LV in disease-free survival (p=0.0001, non-inferiority margin 1.2) with a trend towards superiority in disease-free survival. The full approval was based on an updated analysis at a median follow-up time of 6.9 years which confirmed XELODA to be at least equivalent to 5-FU/LV in disease-free survival although there was no longer a trend toward superiority in disease-free survival (p=0.06). A summary of the results is provided in Table 1. Compared with 5-FU/LV, XELODA was associated with lower incidence of stomatitis, neutropenia and febrile neutropenia but with a considerably higher incidence of hand-and-foot syndrome and hyperbilirubinemia in the adjuvant treatment of patients with Dukes Stage C colon cancer. See Figure 1.

Based on population pharmacokinetic analysis of 455 white patients (90.1%), 22 black patients (4.4%) and 28 patients of other race or ethnicity (5.5%), the pharmacokinetics of black patients were not different compared to white patients. For the other minority groups the numbers were too small to draw a conclusion.

Capecitabine has been evaluated in breast cancer clinical trials in combination with docetaxel and as monotherapy. Table 3 summarizes data from a pivotal combination trial as well as from 1 pivotal and 2 supportive monotherapy phase II clinical trials.

Combination Therapy: Capecitabine in combination with docetaxel is indicated for the treatment of patients with advanced or metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.

Monotherapy: Capecitabine is also indicated for the treatment of advanced or metastatic breast cancer after failure of standard therapy including a taxane, unless therapy with a taxane is clinically contraindicated.

Capecitabine is indicated for the adjuvant treatment of patients with stage III (Dukes' stage C) colon cancer based on the promising clinical evidence that it may be useful in the treatment of patients with this serious disease.

Capecitabine is indicated for first-line treatment of patients with metastatic colorectal cancer.

Patients experiencing grade 2 vomiting (2 to 5 episodes in a 24-hour period) or greater should be instructed to stop taking capecitabine immediately. Standard antiemetic agents should be prescribed for symptom control (see Dosage).

Increased phenytoin plasma concentrations have been reported during concomitant use of capecitabine with phenytoin, suggesting a potential interaction. Formal drug-drug interaction studies with phenytoin have not been conducted, but the mechanism of interaction is presumed to be inhibition of the CYP 2C9 isoenzyme system by capecitabine (see subsection below, Cytochrome P450 2C9 Substrates). Patients taking phenytoin or fosphenytoin concomitantly with capecitabine should be regularly monitored for increased phenytoin plasma concentrations and associated clinical symptoms.

Altered coagulation parameters and/or bleeding have been reported in patients taking capecitabine concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. These events occurred within several days and up to several months after initiating capecitabine therapy and, in a few cases, within 1 month after stopping capecitabine. In a clinical interaction study, after a single 20 mg dose of warfarin, capecitabine treatment increased the AUC of S-warfarin by 57% with a 91% increase in INR value. Patients taking coumarin-derivative anticoagulants concomitantly with capecitabine should be monitored regularly for alterations in their coagulation parameters (PT or INR) and the anticoagulant dose adjusted accordingly.

Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with capecitabine (see Warnings) and be provided with appropriate counselling if not currently using contraceptives.

No formal drug-drug interaction studies with capecitabine and other drugs known to be metabolized by the cytochrome P450 2C9 isoenzyme have been conducted. Care should be exercised when capecitabine is coadministered with these drugs.

In 251 patients with metastatic breast cancer who received a combination of capecitabine and docetaxel, grade 3 and 4 hyperbilirubinemia occurred in 6.8% (n=17) and 2% (n=5), respectively.

In 875 patients with either metastatic breast or colorectal cancer treated with capecitabine monotherapy, grade 3 hyperbilirubinemia occurred in 133 (15.2%) and grade 4 hyperbilirubinemia occurred in 34 (3.9%) patients with either metastatic breast or colorectal cancer. If drug-related grade 2, 3 or 4{§NCIC grade 2 hyperbilirubinemia is defined as 1.5×normal, grade 3 hyperbilirubinemia as 1.5 to 3×normal and grade 4 hyperbilirubinemia as >3×normal.} elevations in bilirubin occur, administration of capecitabine should be immediately interrupted until the hyperbilirubinemia resolves or decreases in intensity to grade 1. Following grade 3 or 4 hyperbilirubinemia, subsequent doses of capecitabine should be decreased (see Dosage).

A phase I study evaluating the effect of leucovorin on the pharmacokinetics of capecitabine was conducted in 22 cancer patients. Leucovorin has no effect on the pharmacokinetics of capecitabine and its metabolites; however, the toxicity of capecitabine may be enhanced by leucovorin.

See Warnings and Dosage.

In 251 patients with metastatic breast cancer who received capecitabine in combination with docetaxel, 68% had grade 3 or 4 neutropenia, 2.8% had grade 3 or 4 thrombocytopenia and 9.6% had grade 3 or 4 anemia.

In 875 patients with either metastatic breast or colorectal cancer who received capecitabine monotherapy, 3.2%, 1.7%, and 2.4% of patients had grade 3/4 neutropenia, thrombocytopenia and decreases in hemoglobin, respectively.

The effect of food on the pharmacokinetics of capecitabine was investigated in 11 cancer patients. The rate and extent of absorption of capecitabine is decreased when administered with food. The effect on AUC_0-∞ of the 3 main metabolites in plasma (5'DFUR, 5-FU, FBAL) is minor. In all clinical trials, patients were instructed to take capecitabine within 30 minutes after a meal. Therefore, since current safety and efficacy data are based upon administration with food, it is recommended that capecitabine be administered with food.

The effect of an aluminum hydroxide and magnesium hydroxide-containing antacid (Maalox) on the pharmacokinetics of capecitabine was investigated in 12 cancer patients. There was a small increase in plasma concentrations of capecitabine and 1 metabolite (5'DFCR); there was no effect on the 3 major metabolites (5'DFUR, 5-FU and FBAL).

Patients experiencing grade 2 stomatitis or greater (painful erythema, edema or ulcers, but are able to eat) should be instructed to stop taking capecitabine immediately. Symptomatic treatment should be prescribed (see Dosage).

Patients experiencing grade 2 nausea (food intake significantly decreased but able to eat intermittently) or greater should be instructed to stop taking capecitabine immediately. Standard anti-nausea agents should be prescribed for symptom control (see Dosage).

Patients experiencing grade 2 hand-and-foot syndrome (painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patients' activities of daily living) or greater should be instructed to stop taking capecitabine immediately.

The spectrum of cardiotoxicity observed with capecitabine is similar to that of other fluorinated pyrimidines. This includes myocardial infarction, angina, dysrhythmias, cardiac arrest, cardiac failure, and electrocardiograph changes. These adverse events may be more common in patients with a prior history of coronary artery disease. A thorough QT interval prolongation assessment study of XELODA has never been conducted.

Patients experiencing grade 2 diarrhea (an increase of 4 to 6 stools/day or nocturnal stools) or greater should be instructed to stop taking capecitabine immediately. Standard antidiarrheal agents (e.g., loperamide) should be prescribed for symptom control (see Dosage).

Patients and patients' caregivers should be informed of the expected adverse effects of capecitabine, particularly of diarrhea, nausea, vomiting, and hand-and-foot syndrome and stomatitis. The frequent oral administration of capecitabine allows patient specific dose adaptations during therapy (see Dosage). Patients should be taught to recognize and report the common grade 2 toxicities associated with capecitabine treatment (see Information for the Patient).

If capecitabine is prescribed in combination with docetaxel, patients and patients' caregivers should be informed of the expected adverse effects of the combination of capecitabine and docetaxel (see Table 7).

Each peach-colored, biconvex, film-coated, oblong shaped tablet with “XELODA” engraved on one side and “500” on the reverse, contains: capecitabine 500 mg. Nonmedicinal ingredients: croscarmellose sodium, hydroxypropyl methylcellulose, lactose anhydrous, magnesium stearate, microcrystalline cellulose, synthetic red iron oxide, synthetic yellow iron oxide, talc and titanium dioxide. HDPE bottles of 120. Store between 15 and 30°C.

Each light peach-colored, biconvex, film-coated, oblong shaped tablet with “XELODA” engraved on one side and “150” on the reverse, contains: capecitabine 150 mg. Nonmedicinal ingredients: croscarmellose sodium, hydroxypropyl methylcellulose, lactose anhydrous, magnesium stearate, microcrystalline cellulose, synthetic red iron oxide, synthetic yellow iron oxide, talc and titanium dioxide. HDPE bottles of 60. Store between 15 and 30°C.

Patients with hepatic impairment should be carefully monitored when capecitabine is administered. However, the effect of hepatic impairment not due to liver metastases or of severe hepatic impairment on the disposition of capecitabine is not known.

Dehydration should be prevented or corrected at the onset. Patients with anorexia, asthenia, nausea, vomiting or diarrhea may rapidly become dehydrated. If Grade 2 (or higher) dehydration occurs, XELODA treatment should be immediately interrupted and the dehydration corrected.{†NCIC grade 2 dehydration is defined as IV fluids indicated <24 hours, grade 3 dehydration is defined as IV fluids indicated ≥24 hours, grade 4 dehydration is defined as life-threatening consequences (e.g. hemodynamic collapse), and grade 5 dehydration as death.} Treatment should not be restarted until the patient is rehydrated and any precipitating causes have been corrected or controlled. Dose modifications applied should be applied for the precipitating adverse event as necessary (see Dosage).

Altered coagulation parameters and/or bleeding have been reported in patients taking capecitabine concomitantly with coumarin-derived anticoagulants such as warfarin. These events occured within several days and up to several months after initiating capecitabine therapy, and, in a few cases, within 1 month after stopping capecitabine. These events occured in patients with and without liver metastases. In a drug interaction study with single-dose warfarin administration, there was a significant increase in the mean AUC (+57%) of S-warfarin. These results suggest an interaction, probably due to an inhibition of the cytochrome P450 2C9 isoenzyme system by capecitabine. Patients taking coumarin-derivative anticoagulants concomitantly with capecitabine should be monitored regularly for alterations in their coagulation parameters (PT or INR) and the anticoagulant dose adjusted accordingly (see Precautions, Coumarin Anticoagulants).

In a study of single oral administration of capecitabine in lactating mice, it was found that a significant amount of the capecitabine metabolites is transferred to the milk. Because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving capecitabine therapy.

An analysis of safety data in patients equal to or greater than 60 years of age showed an increase in the incidence of treatment-related grade 3 and 4 adverse events, treatment-related serious adverse events and early withdrawals from treatment due to adverse events compared to patients less than 60 years of age. The incidence of grade 3 or 4 stomatitis was greater in the 60- to 70-year-old patient group (30%) than the general population (13%) (see Dosage).

Although there was no evidence for oncogenic potential of capecitabine in a two-year carcinogenicity study in mice, capecitabine was clastogenic in vitro in human lymphocytes (similar to other nucleoside analogues such as 5-FU). There was also a positive trend in the in vivo mouse micronucleus assay. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with XELODA (see Warnings) and be provided with appropriate counselling if not currently using contraceptives. Males are advised not to father a child during treatment.

The safety and effectiveness of capecitabine in persons <18 years of age have not been established.

Patients receiving therapy with capecitabine should be monitored by a physician experienced in the use of cancer chemotherapeutic agents. Most adverse reactions are reversible and do not require discontinuation, although doses may need to be withheld or reduced (see Dosage).

There are no adequate and well-controlled studies in pregnant women using capecitabine. If the drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with capecitabine. Capecitabine was found to be teratogenic and embryolethal in mice and embryolethal in monkeys.

In patients with moderate renal impairment (calculated creatinine clearance 30 to 50 mL/min [Cockroft and Gault])** at baseline, a dose reduction to 75% of the capecitabine starting dose when used as monotherapy or in combination with docetaxel is recommended based upon pharmacokinetic and safety data. Careful monitoring and prompt treatment interruption is recommended if the patient develops a grade 2, 3, or 4 adverse event, with subsequent dose adjustment as outlined in Table 12 and Table 13 in the Dosage section.

Physicians should exercise caution when capecitabine is administered to patients with impaired renal function. As seen with 5-FU, the incidence of treatment-related grade 3 or 4 adverse events was higher in patients with moderate renal impairment (calculated creatinine clearance 30 to 50 mL/min).

Patients ≥80-years-old may experience a greater incidence of gastrointestinal grade 3/4 events.

XELODA very frequently induces diarrhea, which can sometimes be severe. Patients with severe diarrhea should be carefully monitored and, if they become dehydrated, should be given fluid and electrolyte replacement. If grade 2 (or higher) diarrhea occurs, administration of XELODA should be immediately interrupted until diarrhea resolves or decreases in intensity to grade 1.{*National Cancer Institute of Canada (NCIC) grade 1 diarrhea is defined as an increase of <4 stools per day over baseline, mild increase in ostomy output compared to baseline, grade 2 diarrhea is defined as an increase of 4 to 6 stools/day or nocturnal stools, grade 3 diarrhea as an increase of 7 to 9 stools/day or incontinence and malabsorption, grade 4 diarrhea as an increase of 10 stools/day or grossly bloody diarrhea or the need for parenteral support, and grade 5 diarrhea as death.} Standard antidiarrheal agents (e.g. loperamide) should be initiated, as medically appropriate, as early as possible. Dose reduction should be applied as necessary (see Dosage). Necrotizing enterocolitis (typhlitis) has been reported.

dysuria, urinary incontinence, hematuria, hydronephrosis (0.1), nocturia (0.1), urinary tract disorder, urine discoloration, polyuria, renal impairment (0.1), urinary retention.

abdominal distention, esophagitis (0.2), intestinal obstruction (0.3), dysphagia, proctalgia, hemorrhoids, fecal abnormality, tongue disorder, ascites (0.1), gastric ulcer (0.1), gastrointestinal hemorrhage (0.2), ileus (0.3), incisional hernia, rectal disorder, swallowing painful, toxic dilation of intestine, melena, gastroenteritis (0.1).

vision abnormal, cataract.

weight increase, malnutrition (0.2), appetite increased, food intolerance (0.1), hypertriglyceridemia (0.1), hypokalemia, diabetes control impaired (0.1), hypomagnesemia.

food allergy, hypersensitivity (0.1).

lacrimal duct stenosis NOS (very rare).

Adverse events occurring in special patient populations in clinical trials with capecitabine monotherapy in the metastatic setting are summarized below:

cushingoid, hypothyroidism, hirsutism.

herpes simplex, upper respiratory tract infection (0.1), urinary tract infection (0.2), localized infection, sepsis (0.3), bronchitis (0.1), lower respiratory tract infection, cellulitis, fungal infection (0.3), pneumonia (0.1), bronchopneumonia (0.1), herpes zoster, infection (0.1), influenza, keratoconjunctivitis, laryngitis (0.1), superinfection.

In 875 patients with either metastatic breast or colorectal cancer who received at least one dose of capecitabine 2500 mg/m² daily for 2 weeks followed by a 1-week rest period, grade 3 hyperbilirubinemia occurred in 133 (15.2%) and grade 4 hyperbilirubinemia occurred in 34 (3.9%) patients. Grade 3/4 hyperbilirubinemia occurred in 22.8% of the 566 patients with hepatic metastases and in 12.3% of the 309 patients without hepatic metastases at baseline. Of the 167 patients with grade 3 or 4 hyperbilirubinemia, 31 (18.6%) also had postbaseline elevations (grades 1 to 4, without elevations at baseline) in alkaline phosphatase and 46 (27.5%) had postbaseline elevations in transaminases at any time (not necessarily concurrent). The majority of these patients, 20 (64.5%) and 33 (71.7%), had liver metastases at baseline. In addition, 96 (57.5%) and 59 (35.3%) of the 167 patients had elevations (grades 1 to 4) at both pre- and postbaseline in alkaline phosphatase or transaminases, respectively. Only 13 (7.8%) and 5 (3.0%) had grade 3 or 4 elevations in alkaline phosphatase or transaminases.

cough (0.1), epistaxis (0.1), sore throat, chest tightness, rhinitis, increased sputum production, bronchospasm (0.2), hemoptysis, nasal ulcer, pneumothorax, crackles, orthopnea, pharyngeal disorder, pleural disorder, respiratory distress (0.1), sneezing.

intermenstrual bleeding, balanoposthitis, vaginal pain, nipple disorder, premenstrual tension syndrome.

insomnia, ataxia (0.5), sedation, syncope (0.1), tremor, dysphasia, encephalopathy (0.1), coordination abnormal, dysarthria, facial palsy, loss of consciousness (0.2), mental impairment, myoclonic jerks, peroneal nerve palsy (0.1), headache (0.5).

vertigo, earache, deafness, sensation of block in ear.

hepatic failure and cholestatic hepatitis have been reported during clinical trials and post-marketing exposure.

depression, confusion (0.1), amnesia, libido decreased, loss of confidence, mood alteration, personality change, psychogenic disorder.

Among the 21 patients (80 years of age and greater) with either metastatic breast or colorectal cancer who received capecitabine monotherapy (N=875), 6 (28.6%), 3 (14.3%), and 2 (9.5%) patients experienced reversible grade 3/4 diarrhea, nausea and vomiting, respectively. Among the 496 patients aged 60- to 79-years-old, the incidence of gastrointestinal toxicity was similar to that in the overall population. Patients 70- to 79-years-old (22%) had a higher incidence of hand-and-foot syndrome.

leucopenia (0.2), coagulation disorder (0.1), bone marrow depression (0.1), idiopathic thrombocytopenia purpura (1.0), pancytopenia (0.1).

paronychia drainage, postoperative complications, wound drainage increased.

myalgia, back pain, arthralgia (0.1), bone pain (0.1), neck pain, arthritis (0.1), calcaneal spur, muscle weakness.

shivering, chest pain (0.2), influenza-like illness, hot flushes, palmar erythema, hiccups, pain (0.1), hoarseness, fluid retention, irritability, difficulty in walking, thirst, chest mass, collapse, fibrosis (0.1), hemorrhage, neck edema, sedation, sudden death unexplained (0.1), swelling, ulcer (0.1).

hypotension (0.2), hypertension (0.1), flushing, lymphoedema (0.1), hematoma, pulmonary embolism (0.2), cerebrovascular accident (0.1), transient ischemic attack, varicose veins, venous thrombosis (0.8).

tachycardia (0.1), bradycardia, arrhythmia, chest pain (cardiac) (0.2), atrial fibrillation, cardiac failure, cardiomyopathy, extrasystoles, myocardial infarction (0.1), myocarditis (0.1), pericardial effusion.

nail disorder (0.1), sweating increased (0.1), face edema, photosensitivity reaction (0.1), urticaria, skin ulcer, genital pruritus, skin lesion, ecchymoses, hyperkeratosis, intertrigo, leg ulcer (excluding varicose), localized skin reaction, red face, rosacea, scab, foot ulcer (0.1).

radiation recall syndrome (0.1), bruising, overdose, scratch.

Capecitabine Monotherapy Metastatic Breast and Colorectal Cancer: Shown below by body system are the clinical adverse events in <5% of 875 patients (phase III colorectal studies—596 patients, phase II colorectal study—34 patients, phase II breast cancer monotherapy studies—245 patients) reported as related to the administration of capecitabine and that were clinically at least remotely relevant. In parentheses is the incidence of grade 3 or 4 occurrences of each adverse event.

Reports of adverse events in patients taking capecitabine received after market introduction are of similar incidence and severity as reported in the Adverse Effects section.

The following additional adverse events have been identified during post-marketing use of XELODA. Because these events are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to XELODA exposure. The occurrence of these events in individuals receiving XELODA does not establish a casual relationship.

Serious gastro-intestinal disorders have been reported in patients exposed to XELODA and include but are not limited to: necrotizing enterocolitis, ileus paralytic, gastrointestinal perforation and intestinal obstruction.

Thromboembolic events such as deep vein thrombosis, thrombophlebitis and pulmonary embolism have been reported.

The manifestations of acute overdose include: nausea, vomiting, diarrhea, mucositis, gastrointestinal irritation and bleeding, and bone marrow depression.

Management of overdose should include customary therapeutic and supportive medical interventions aimed at correcting the presenting clinical manifestations and preventing their possible complications.

Capecitabine and/or docetaxel dose modifications should be made according to the general dose modification scheme above, if nothing else is stated regarding specific dose adjustments. For those toxicities considered unlikely to become serious or life-threatening, e.g., alopecia, altered taste, nail changes, treatment can be continued at the same dose without reduction or interruption. At the beginning of a treatment cycle, if either a docetaxel or a capecitabine treatment delay is indicated, both docetaxel and capecitabine administration should be delayed until the requirements for restarting both drugs are met. If docetaxel has to be discontinued, capecitabine treatment can be resumed when the requirements for restarting capecitabine are met.

Capecitabine treatment may continue throughout a grade 3 neutropenic episode. However, the patient should be closely monitored and administration of capecitabine should be interrupted if any grade 2 clinical event (e.g. diarrhea, stomatitis, fever) coincides with the grade 3 neutropenic episode. If grade 4 neutropenia occurs treatment with capecitabine should be interrupted until recovery to grade 0-1. Treatment should only be re-administered when the neutrophil count is ≥1.5×10⁹/L (Grade 0-1).

Docetaxel dosage should be reduced from 75 mg/m² to 55 mg/m² in patients with neutropenia <0.5×10⁹/L (Grade 4) for more than 1 week, or febrile (>38°C) neutropenia. Docetaxel should be discontinued if Grade 4 neutropenia or febrile neutropenia occurs at a dose of 55 mg/m² docetaxel.

Patients with baseline neutrophil counts of <1.5×10⁹/L and/or thrombocyte counts of <100×10⁹/L should not be treated with the XELODA/docetaxel combination.

Once the docetaxel dose is reduced for a given cycle, no further dose reduction is recommended for subsequent cycles unless worsening of the parameters is observed. In case of recovery of liver function tests after previous reduction of the docetaxel dose, the docetaxel dose can be re-escalated to the previous dose level.

In patients with moderate renal impairment (calculated creatinine clearance 30 to 50 mL/min [Cockroft and Gault]) at baseline, a dose reduction to 75% from a starting dose of 1250 mg/m² is recommended based upon pharmacokinetic and safety data (see Pharmacology, Pharmacokinetics, Renal Insufficiency and Warnings). In patients with mild renal impairment (calculated creatinine clearance 51 to 80 mL/min) no adjustment in starting dose is recommended. In patients with severe renal impairment, XELODA should not be administered (see Contraindications). Careful monitoring and prompt treatment interruption is recommended if the patient develops a grade 2, 3, or 4 adverse event, with subsequent dose adjustment as outlined in the tables above. If the calculated creatinine clearance decreases during treatment to a value below 30 mL/min, XELODA should be discontinued. The dose adjustment recommendation for patients with moderate renal impairment apply both to monotherapy and combination use. For dosage calculations, see Table 11.

Dehydration should be prevented or corrected at the onset. Patients with anorexia, asthenia, nausea, vomiting or diarrhea may rapidly become dehydrated. If grade 2 (or higher) dehydration occurs, capecitabine treatment should be immediately interrupted and the dehydration corrected. Treatment should not be restarted until the patient is rehydrated and any precipitating causes have been corrected or controlled. Dose modifications applied should be those for the precipitating adverse event in accordance with the above guidelines.

No adjustment of the starting dose is needed for capecitabine. However for capecitabine monotherapy in the metastatic setting, severe grade 3 or 4 treatment-related adverse events were more frequent in patients over 80 years of age compared to younger patients. Careful monitoring of elderly patients is advisable. For treatment with capecitabine in combination with docetaxel, an increased incidence of grade 3 or 4 treatment-related adverse events and treatment-related serious adverse events was observed in patients 60 years of age or more.

Patients who develop severe hypersensitivity reactions (hypotension with a decrease of ≥20 mmHg, or bronchospasm, or generalised rash/erythema) should stop treatment immediately and be given appropriate therapy. These patients should not be rechallenged with the drug suspected to have caused hypersensitivity.

For 1^st appearance of grade 2 toxicity, reduce the docetaxel dose to 55 mg/m². If grade 3 toxicity appears, discontinue docetaxel treatment. In both instances follow the above dose modification scheme for capecitabine.

Severe (grade 3 or 4) toxicity such as pleural effusion, pericardial effusion or ascites which is possibly related to docetaxel should be closely monitored. In case of appearance of such toxicity docetaxel treatment should be discontinued, capecitabine treatment may be continued without dose modification.

Standard and Reduced Dose Calculations According to Body Surface Area for a Starting Dose of XELODA of 1250 mg/m²

Hepatic Impairment: In patients with mild to moderate hepatic dysfunction due to liver metastases, no dose adjustment is necessary; however, such patients should be carefully monitored. Patients with severe hepatic dysfunction have not been studied (see Warnings).

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