CAPEGARD 500 Tablets (Capecitabine)

Table of Content

Black Box Warning: CAPECITABINE-WARFARIN INTERACTION

Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (International Normalized Ratio or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly. A clinically important capecitabine-warfarin drug interaction was demonstrated in a clinical pharmacology trial. Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking capecitabine concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. Postmarketing reports have shown clinically significant increases in the prothrombin time and INR in patients who were stabilized on anticoagulants at the time capecitabine was introduced. 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. These events occurred in patients with and without liver metastases. Age greater than 60 years and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy.

Composition

CAPEGARD 500 Tablets
Each tablet contains:
Capecitabine …............ 500 mg

Dosage Form

Oral tablet

Pharmacology

Pharmacodynamics

Capecitabine is a non-cytotoxic fluoropyrimidine carbamate, which functions as an orally administered precursor of the cytotoxic moiety 5-fluorouracil (5-FU). Capecitabine is activated via several enzymatic steps. The enzyme involved in the final conversion to 5-FU, thymidine phosphorylase, is found in tumour tissues, but also in normal tissues, albeit usually at lower levels. 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.

Enzymes convert capecitabine to 5-FU in vivo. Both normal and tumour cells metabolize 5-FU to 5-fluoro-2'-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites cause cell injury by two different mechanisms. Firstly, FdUMP and the folate cofactor, N5-10-methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a covalently-bound ternary complex. This binding inhibits the formation of thymidylate from 2'-deoxyuridylate. Thymidylate is the necessary precursor of thymidine triphosphate, which is essential for the synthesis of DNA, so that a deficiency of this compound can inhibit cell division. Secondly, nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during the synthesis of RNA. This metabolic error can interfere with RNA processing and protein synthesis. Since DNA and RNA are essential for cell division and growth, the effect of 5-FU may be to create a thymidine deficiency that provokes unbalanced growth and death of a cell. The effects of DNA and RNA deprivation are most marked on those cells that proliferate more rapidly and metabolize 5-FU at a more rapid rate.

Pharmacokinetics

Absorption
Following oral administration to cancer patients, capecitabine reached peak blood levels in about 1.5 hours (Tmax), with peak 5-FU levels occurring slightly later at 2 hours. Food reduced both the rate and extent of absorption of capecitabine, with the mean Cmax and AUC0-∞ decreased by 60% and 35%, respectively. The Cmax and AUC0-∞ of 5-FU were also reduced by food by 43% and 21%, respectively. Food delayed the Tmax of both the parent drug and 5-FU by 1.5 hours.

After oral administration, capecitabine is rapidly and extensively absorbed, followed by extensive conversion to the metabolites, 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5-fluorouridine (5'-DFUR). Administration with food decreases the rate of capecitabine absorption, but only results in a minor effect on the AUC of 5'-DFUR, and on the AUC of the subsequent metabolite, 5-FU. At the dose of 1,250 mg/m2 on day 14 with administration after food intake, the peak plasma concentrations (Cmax in μg/ml) for capecitabine , 5'-DFCR, 5'-DFUR, 5-FU and α-fluoro-β-alanine (FBAL) were 4.67, 3.05, 12.1, 0.95 and 5.46, respectively. The time to peak plasma concentrations (Tmax in hours) were 1.50, 2.00, 2.00, 2.00 and 3.34, respectively. The AUC0-∞ values in μg-h/ml were 7.75, 7.24, 24.6, 2.03 and 36.3, respectively.

Distribution
Plasma protein binding of capecitabine and its metabolites is less than 60% and is not concentration-dependent. Capecitabine was primarily bound to human albumin. Capecitabine has a low potential for pharmacokinetic interactions related to plasma protein binding. In vitro human plasma studies have determined that capecitabine, 5'-DFCR, 5'-DFUR and 5-FU are 54%, 10%, 62% and 10% protein-bound, mainly to albumin, respectively.

Bioactivation and Metabolism
Capecitabine is extensively metabolized enzymatically to 5-FU. In the liver, a 60 kDa carboxylesterase hydrolyses much of the compound to 5'-DFCR. Cytidine deaminase, an enzyme found in most tissues, including tumours, subsequently converts 5'-DFCR to 5'-DFUR. The enzyme, thymidine phosphorylase, then hydrolyses 5'-DFUR to the active drug, 5-FU. Many tissues throughout the body express thymidine phosphorylase. Some human carcinomas express this enzyme in higher concentrations than the surrounding normal tissues. Following oral administration of capecitabine, 7 days before surgery, in patients with colorectal cancer, the median ratio of 5-FU concentration in colorectal tumours to adjacent tissues was 2.9 (range from 0.9 to 8.0). These ratios have not been evaluated in breast cancer patients or compared to 5-FU infusion.

Metabolic Pathway of Capecitabine to 5-FU

The enzyme, dihydropyrimidine dehydrogenase (DPD), 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 FBAL, which is cleared in the urine.

In vitro enzymatic studies with human liver microsomes indicated that capecitabine and its metabolites (5'-DFUR, 5'-DFCR, 5-FU and FBAL) did not inhibit the metabolism of test substrates by cytochrome (CY) P450 isoenzymes, 1A2, 2A6, 3A4, 2C19, 2D6 and 2E1.

Excretion
Capecitabine and its metabolites are predominantly excreted in the urine; 95.5% of the administered capecitabine dose is recovered in the urine. Faecal excretion is minimal (2.6%). The major metabolite excreted in urine is FBAL, which represents 57% of the administered dose. About 3% of the administered dose is excreted in the urine as unchanged drug. The elimination half-life (t1/2 in hours) of capecitabine, 5'-DFCR, 5'-DFUR, 5-FU and FBAL were 0.85, 1.11, 0.66, 0.76 and 3.23, respectively.

Special Populations
Presence or absence of liver metastasis at baseline, Karnofsky Performance Status, total bilirubin, serum albumin, aspartate amino transferase (ASAT) and alanine amino transferase (ALAT) had no statistically significant effect on the pharmacokinetics of 5'-DFUR, 5-FU and FBAL.

Effect of Age, Gender and Race on the Pharmacokinetics of Capecitabine
Gender and race have no influence on the pharmacokinetics of 5'-DFUR, 5-FU and FBAL. Age has no significant influence on the pharmacokinetics of 5'-DFUR and 5-FU over the range of 27 to 86 years. A 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.

Following oral administration of 825 mg/m2 capecitabine twice daily for 14 days, the Japanese patients had about 36% lower Cmax and 24% lower AUC for capecitabine than the Caucasian patients. The Japanese patients also had about 25% lower Cmax and 34% lower AUC for FBAL than the Caucasian patients. The clinical significance of these differences is unknown. No significant differences occurred in the exposure to other metabolites (5'-DFCR, 5'-DFUR and 5-FU).

Effect of Hepatic Impairment
Capecitabine has been evaluated in 13 patients with mild-to-moderate hepatic dysfunction due to liver metastases defined by a composite score, including bilirubin, AST/ALT and alkaline phosphatase following a single dose of capecitabine. Both the AUC0-∞ and Cmax of capecitabine increased by 60% in patients with hepatic dysfunction compared to patients with normal hepatic function. The AUC0-∞ and Cmax of 5-FU were not affected. In patients with mild-to-moderate hepatic dysfunction due to liver metastases, caution should be exercised when capecitabine is administered. The effect of severe hepatic dysfunction on capecitabine is not known.

Effect of Renal Impairment
Following oral administration of 1,250 mg/m2 capecitabine twice a day to cancer patients with varying degrees of renal impairment, patients with moderate (creatinine clearance = 30-50 mL/min) and severe (creatinine clearance 80 mL/min). FBAL is a metabolite without antiproliferative activity. Systemic exposure to 5'-DFUR was 42% and 71% greater in moderately and severely renal impaired patients, respectively, than in normal patients. Systemic exposure to capecitabine was about 25% greater in both moderately and severely renal impaired patients.

Effect of Capecitabine on the Pharmacokinetics of Warfarin
In patients with cancer, chronic administration of capecitabine (1,250 mg/m2 b.i.d.) with a single 20 mg dose of warfarin increased the mean AUC of S-warfarin by 57% and decreased its clearance by 37%. Baseline-corrected AUC of INR in these patients increased by 2.8-fold, and the maximum observed mean INR value was increased by 91%.

Effect of Antacids on the Pharmacokinetics of Capecitabine
When an aluminium hydroxide- and magnesium hydroxide-containing antacid, was administered immediately after capecitabine (1,250 mg/m2), the AUC and Cmax increased by 16% and 35%, respectively, for capecitabine and by 18% and 22%, respectively, for 5'-DFCR. No effect was observed on the other three major metabolites (5'-DFUR, 5-FU, FBAL) of capecitabine.

Effect of Capecitabine on the Pharmacokinetics of Docetaxel and Vice Versa
Capecitabine was found to have no effect on the pharmacokinetics of docetaxel (Cmax and AUC) and docetaxel has no effect on the pharmacokinetics of capecitabine and the 5-FU precursor, 5'-DFUR.

Indications

Colorectal Cancer

  • CAPEGARD 500 Tablets are indicated as a single agent for adjuvant treatment in patients with Dukes' C colon cancer who have undergone complete resection of the primary tumour when treatment with fluoropyrimidine therapy alone is preferred. CAPEGARD 500 Tablets were non-inferior to 5-FU and leucovorin (5-FU/LV) for disease-free survival.
  • CAPEGARD 500 Tablets are indicated for the first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred. Combination chemotherapy has shown a survival benefit compared to 5-FU/LV alone. A survival benefit over 5-FU/LV has not been demonstrated with CAPEGARD 500 Tablets monotherapy. Use of CAPEGARD 500 Tablets instead of 5-FU/LV in combinations has not been adequately studied to assure safety or preservation of the survival advantage.

Breast Cancer

  • CAPEGARD 500 Tablets in combination with docetaxel are indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.
  • CAPEGARD 500 Tablets monotherapy is also indicated for the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy is not indicated (e.g. patients who have received cumulative doses of 400 mg/m2 of doxorubicin or doxorubicin equivalents).

Gastric Cancer

  • CAPEGARD 500 Tablets are indicated for the first-line treatment of advanced gastric cancer in combination with a platinum-based regimen.

Dosage and Administration

CAPEGARD 500 Tablets should be swallowed whole with water within 30 minutes after a meal. The dose of CAPEGARD 500 Tablets is calculated according to the body surface area.

Standard Starting Dose

Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer)
The recommended dose of CAPEGARD 500 Tablets is 1,250 mg/m2 administered orally twice daily (morning and evening; equivalent to 2,500 mg/m2 total daily dose) for 2 weeks followed by a 1-week rest period; the tablets are given as 3-week cycles (see Table 1).

Adjuvant treatment in patients with Dukes' C colon cancer is recommended for a total of 6 months .

Table 1: CAPEGARD 500 Tablets Dose Calculation According to Body Surface Area
Dose Level: 1,250 mg/m2
Twice a Day
Surface Area (m2)
Total Daily Dose* (mg)
≤1.25
3,000
1.26-1.37
3,300
1.38-1.51
3,600
1.52-1.65
4,000
Dose Level: 1,250 mg/m2
Twice a Day
Surface Area (m2)
Total Daily Dose* (mg)
1.66-1.77
4,300
1.78-1.91
4,600
1.92-2.05
5,000
2.06-2.17
5,300
≥2.18
5,600
* Total Daily Dose divided by 2 to allow equal morning and evening doses

Combination Therapy (Colon, Colorectal and Gastric Cancer)
In combination treatment, the recommended starting dose of CAPEGARD 500 Tablets should be reduced to 800-1,000 mg/m2 when administered twice daily for 14 days followed by a 7-day rest period, or to 625 mg/m2 twice daily when administered continuously. The inclusion of biological medicinal products in a combination regimen has no effect on the starting dose of CAPEGARD 500 Tablets. Premedication to maintain adequate hydration and anti-emesis according to the cisplatin summary of product characteristics should be started prior to cisplatin administration for patients receiving the CAPEGARD 500 Tablets plus cisplatin combination. Premedication with anti-emetics according to the oxaliplatin summary of product characteristics is recommended for patients receiving the CAPEGARD 500 Tablets plus oxaliplatin combination. Adjuvant treatment in patients with stage III colon cancer is recommended for duration of 6 months.

Breast Cancer
In combination with docetaxel, the recommended dose of CAPEGARD 500 Tablets is 1,250 mg/m2 twice daily for 2 weeks followed by a 1-week rest period, combined with docetaxel at 75 mg/m2 as a 1-hour intravenous infusion every 3 weeks. Pre-medication with an oral corticosteroid such as dexamethasone, according to the docetaxel labelling, should be started prior to docetaxel administration for patients receiving the CAPEGARD 500 Tablets plus docetaxel combination. Table 1 displays the total daily dose of CAPEGARD 500 Tablets by body surface area.

Dose Management Guidelines

General
CAPEGARD 500 Tablets dosage may need to be individualized to optimize patient management. Patients should be carefully monitored for toxicity and doses of CAPEGARD 500 Tablets should be modified as necessary to accommodate individual patient tolerance to treatment. Toxicity due to CAPEGARD 500 Tablets administration may be managed by symptomatic treatment, dose interruptions and adjustment of the CAPEGARD 500 Tablets dose. Once the dose has been reduced, it should not be increased at a later time. Doses of CAPEGARD 500 Tablets omitted for toxicity should not be replaced or restored; instead the patient should resume the planned treatment cycles. For those toxicities considered by the treating doctor to be 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.

The dose of phenytoin and the dose of coumarin-derivative anticoagulants may need to be reduced when either drug is administered concomitantly with CAPEGARD 500 Tablets.

Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer)
The CAPEGARD 500 Tablets dose modification scheme as described below (see Table 2) is recommended for the management of adverse reactions.

Table 2: Recommended Dose Modifications for CAPEGARD 500 Tablets
Toxicity NCIC
Grades*
During a Course of Therapy
Dose Adjustment for Next
Treatment (% of Starting Dose)
Grade 1
Maintain Dose Level
Maintain Dose Level
Grade 2
1st appearance
Interrupt until resolved to grade
0-1
100%
2nd appearance
75%
3rd appearance
50%
4th appearance
Discontinue treatment
permanently
-
Grade 3
1st appearance
Interrupt until resolved to grade
0-1
75%
2nd appearance
50%
3rd appearance
Discontinue treatment
permanently
-
Grade 4
1st appearance
Discontinue permanently
OR
If the physician deems it to be in
the patient's best interest to
continue, interrupt until resolved
to grade 0-1
50%
* National Cancer Institute of Canada Common Toxicity Criteria were used
except for the hand-and-foot syndrome

In Combination with Docetaxel (Metastatic Breast Cancer)
Dose modifications of CAPEGARD 500 Tablets for toxicity should be made according to Table 2 above. At the beginning of a treatment cycle, if a treatment delay is indicated for either CAPEGARD 500 Tablets or docetaxel, then administration of both agents should be delayed until the requirements for restarting both drugs are met.

The dose reduction schedule for docetaxel when used in combination with CAPEGARD 500 Tablets for the treatment of metastatic breast cancer is shown in Table 3.

Table 3: Docetaxel Dose Reduction Schedule in Combination with CAPEGARD 500 Tablets
Toxicity NCIC
Grades*
Grade 2
Grade 3
Grade 4
1st appearance
Delay treatment until resolved
to grade 0-1; Resume
treatment with original dose of
75 mg/m2 docetaxel
Delay treatment until
resolved to grade
0-1;
Resume treatment
with 55 mg/m2 of
docetaxel.
Discontinue
treatment
with
docetaxel
2nd appearance
Delay treatment until resolved
to grade 0-1; Resume
treatment with 55 mg/m2 of
docetaxel.
Discontinue
treatment with
docetaxel
-
3rd appearance
Discontinue treatment with
docetaxel
-
-
* National Cancer Institute of Canada Common Toxicity Criteria were used
except for hand-and-foot syndrome

Haematology
Patients with baseline neutrophil counts of <1.5 × 109/L and/or thrombocyte counts of <100 × 109/L should not be treated with CAPEGARD 500 Tablets. If unscheduled laboratory assessments during a treatment cycle show that the neutrophil count drops below 1.0 × 109/L or that the platelet count drops below 75 × 109/L, treatment with CAPEGARD 500 Tablets should be interrupted. 

Dose Modifications for Toxicity When CAPEGARD 500 Tablets Are Used As a 3-Weekly Cycle in Combination with Other Medicinal Products
Dose modifications for toxicity when CAPEGARD 500 Tablets is used as a 3 weekly cycle in combination with other medicinal products should be made according to table 2 above for CAPEGARD 500 Tablets and according to the appropriate summary of product characteristics for the other medicinal product(s).

At the beginning of a treatment cycle, if a treatment delay is indicated for either CAPEGARD 500 Tablets or the other medicinal product(s), then administration of all therapy should be delayed until the requirements for restarting all medicinal products are met.

During a treatment cycle for those toxicities considered by the treating doctor not to be related to CAPEGARD 500 Tablets, CAPEGARD 500 Tablets should be continued and the dose of the other medicinal product should be adjusted according to the appropriate Prescribing Information.

If the other medicinal product(s) have to be discontinued permanently, CAPEGARD 500 Tablets treatment can be resumed when the requirements for restarting CAPEGARD 500 Tablets are met.

This advice is applicable to all indications and to all special populations.

Dose Modifications for Toxicity When CAPEGARD 500 Tablets Are Used Continuously in Combination with Other Medicinal Products
Dose modifications for toxicity when CAPEGARD 500 Tablets are used continuously in combination with other medicinal products should be made according to Table 2 above for capecitabine and according to the appropriate summary of product characteristics for the other medicinal product(s).

Dose Adjustments for Special Populations
Hepatic Impairment
Insufficient safety and efficacy data are available in patients with hepatic impairment to provide a dose adjustment recommendation. No information is available on hepatic impairment due to cirrhosis or hepatitis.

Renal Impairment
CAPEGARD 500 Tablets are contraindicated in patients with severe renal impairment (creatinine clearance <30 ml/min at baseline). The incidence of grade 3 or 4 adverse reactions in patients with moderate renal impairment (creatinine clearance: 30–50 ml/min at baseline) is increased, compared to the overall population. In patients with moderate renal impairment at baseline, a dose reduction to 75% for a starting dose of 1,250 mg/m2 is recommended. In patients with moderate renal impairment at baseline, no dose reduction is required for a starting dose of 1,000 mg/m2. In patients with mild renal impairment (creatinine clearance: 51–80 ml/min at baseline), no adjustment of the starting dose is recommended. Careful monitoring and prompt treatment interruption is recommended if the patient develops a grade 2, 3 or 4 adverse events during treatment and subsequent dose adjustment as outlined in Table 2 above. If the calculated creatinine clearance decreases during treatment to a value <30 ml/min, CAPEGARD 500 Tablets should be discontinued. These dose adjustment recommendations for renal impairment apply both to monotherapy and combination use.

Geriatric
During CAPEGARD 500 Tablets monotherapy, no adjustment of the starting dose is needed. However, grade 3 or 4 treatment-related adverse reactions were more frequent in patients who were ≥60 years of age compared to younger patients.

When CAPEGARD 500 Tablets were used in combination with other medicinal products, elderly patients (aged ≥65 years) experienced more grade 3 and grade 4 adverse drug reactions, including those leading to discontinuation, compared to younger patients. Careful monitoring of patients ≥60 years of age is advisable.

In Combination with Docetaxel
An increased incidence of grade 3 or 4 treatment-related adverse reactions and treatment-related serious adverse reactions were observed in patients ≥60 years of age. For patients ≥60 years of age, a starting dose reduction of CAPEGARD 500 Tablets to 75% (950 mg/m2 twice daily) is recommended. If no toxicity is observed in patients ≥60 years of age treated with a reduced CAPEGARD 500 Tablets starting dose in combination with docetaxel, the dose of CAPEGARD 500 Tablets may be cautiously escalated to 1,250 mg/m2 twice daily.

In Combination with Irinotecan
For patients ≥65 years of age, a starting dose reduction of CAPEGARD 500 Tablets to 800 mg/m2 twice daily is recommended.

Paediatric
There is no relevant use of CAPEGARD 500 Tablets in the paediatric population for the indications of colon, colorectal, gastric and breast cancer.

Contraindications

  • History of severe and unexpected reactions to fluoropyrimidine therapy.
  • In patients with a known hypersensitivity to CAPEGARD 500 Tablets or to any of its components. CAPEGARD 500 Tablets are contraindicated in patients who have a known hypersensitivity to 5-FU.
  • In patients with known DPD deficiency.
  • During pregnancy and lactation.
  • In patients with severe leucopenia, neutropenia or thrombocytopenia.
  • In patients with severe hepatic impairment.
  • In patients with severe renal impairment (creatinine clearance
  • Treatment with sorivudine or its chemically related analogues, such as brivudine.
  • If contraindications exist to any of the medicinal products in the combination regimen, that medicinal product should not be used.

Warnings and Precautions

Drug Interactions

Interaction studies have only been performed in adults.

Interactions with Other Medicinal Products
CYP450 2C9 Substrates
Other than warfarin, no formal drug-drug interaction studies between capecitabine and other CYP2C9 substrates have been conducted. Care should be exercised when capecitabine is co-administered with 2C9 substrates (e.g. phenytoin).

Coumarin-derivative Anticoagulants
Altered coagulation parameters and/or bleeding have been reported in patients taking capecitabine concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. These reactions 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 pharmacokinetic 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 the INR value. Since metabolism of R-warfarin was not affected, these results indicate that capecitabine down-regulates isozyme 2C9, but has no effect on isozymes 1A2 and 3A4. Patients taking coumarin-derivative anticoagulants concomitantly with capecitabine should be monitored regularly for alterations in their coagulation parameters (INR or prothrombin time) and the anti-coagulant dose adjusted accordingly.

Phenytoin
Increased phenytoin plasma concentrations resulting in symptoms of phenytoin intoxication in single cases have been reported during concomitant use of capecitabine with phenytoin. Patients taking phenytoin concomitantly with capecitabine should be regularly monitored for increased phenytoin plasma concentrations.

Folinic Acid
A combination study with capecitabine and folinic acid indicated that folinic acid has no major effect on the pharmacokinetics of capecitabine and its metabolites. However, folinic acid has an effect on the pharmacodynamics of capecitabine and its toxicity may be enhanced by folinic acid: the maximum tolerated dose of capecitabine alone using the intermittent regimen is 3,000 mg/m2 per day whereas it is only 2,000 mg/m2 per day when capecitabine was combined with folinic acid (30 mg orally b.i.d.).

Sorivudine and Analogues
A clinically significant drug-drug interaction between sorivudine and 5-FU, resulting from the inhibition of DPD by sorivudine, has been described. This interaction, which leads to increased fluoropyrimidine toxicity, is potentially fatal. Therefore, capecitabine must not be administered concomitantly with sorivudine or its chemically related analogues, such as brivudine. There must be at least a 4-week waiting period between end of treatment with sorivudine or its chemically related analogues such as brivudine and the start of capecitabine therapy.

Antacid
The effect of an aluminium hydroxide- and magnesium hydroxide-containing antacid on the pharmacokinetics of capecitabine was investigated. There was a small increase in plasma concentrations of capecitabine and one metabolite (5'-DFCR); there was no effect on the three major metabolites (5'-DFUR, 5-FU and FBAL).

Allopurinol
Interactions with allopurinol have been observed for 5-FU, with, possibly, decreased efficacy of 5-FU. Concomitant use of allopurinol with capecitabine should be avoided.

Interferon Alpha-2a
The maximum tolerated dose of capecitabine was 2,000 mg/m2 per day when combined with interferon alpha-2a (3 MIU/m2 per day) compared to 3,000 mg/m2 per day when capecitabine was used alone.

Radiotherapy
The maximum tolerated dose of capecitabine alone using the intermittent regimen is 3,000 mg/m2 per day, whereas, when combined with radiotherapy for rectal cancer, the maximum tolerated dose of capecitabine is 2,000 mg/m2 per day using either a continuous schedule, or given daily Monday through Friday during a 6-week course of radiotherapy.

Oxaliplatin
No clinically significant differences in exposure to capecitabine or its metabolites, and free platinum or total platinum occurred when capecitabine was administered in combination with oxaliplatin or in combination with oxaliplatin and bevacizumab.

Bevacizumab
There was no clinically significant effect of bevacizumab on the pharmacokinetic parameters of capecitabine or its metabolites in the presence of oxaliplatin.

Food Interaction

In all clinical trials, patients were instructed to take capecitabine within 30 minutes after a meal. Since current safety and efficacy data are based upon administration with food, it is recommended that capecitabine be administered with food. Administration with food decreases the rate of capecitabine absorption.

General

Patients receiving therapy with capecitabine should be monitored by a doctor. Most adverse reactions are reversible and do not need to result in discontinuation, although doses may need to be withheld or reduced.

Dose-limiting Toxicities

Dose limiting toxicities include diarrhoea, abdominal pain, nausea, stomatitis and hand-foot syndrome (hand-foot skin reaction, Palmar-Plantar erythrodysaesthesia). Most adverse reactions are reversible and do not require permanent discontinuation of therapy, although doses may need to be withheld or reduced.

Diarrhoea

Patients with severe diarrhoea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. Standard anti-diarrhoeal treatments (e.g. loperamide) may be used. NCIC-CTC grade 2 diarrhoea is defined as an increase of 4-6 stools/day or nocturnal stools, and grade 3 diarrhoea as an increase of 7-9 stools/day or incontinence and malabsorption. Grade 4 diarrhoea is an increase of ≥10 stools/day or grossly bloody diarrhoea or the need for parenteral support. If grade 2, 3 or 4 diarrhoea occurs, administration of capecitabine should be immediately interrupted until the diarrhoea resolves or decreases in intensity to grade 1. Following a reoccurrence of grade 2 diarrhoea or occurrence of any grade 3 or 4 diarrhoea, subsequent doses of capecitabine should be decreased.

Necrotizing enterocolitis (typhlitis) has been reported.

Dehydration

Dehydration should be prevented or corrected at the onset. Patients with anorexia, asthenia, nausea, vomiting or diarrhoea 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 applied for the precipitating adverse event as necessary.

Hypocalcaemia or Hypercalcaemia

Hypocalcaemia or hypercalcaemia has been reported during capecitabine treatment. Caution must be exercised in patients with pre-existing hypocalcaemia or hypercalcaemia.

Central or Peripheral Nervous System Disease

Caution must be exercised in patients with central or peripheral nervous system disease, e.g. brain metastasis or neuropathy.

Diabetes Mellitus or Electrolyte Disturbances

Caution must be exercised in patients with diabetes mellitus or electrolyte disturbances, as these may be aggravated during capecitabine treatment.

Coagulopathy

Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored closely with great frequency and the anticoagulant dose should be adjusted accordingly.

Cardiotoxicity

Cardiotoxicity has been associated with fluoropyrimidine therapy, including myocardial infarction, angina, dysrhythmias, cardiogenic shock, sudden death and electrocardiographic changes (including very rare cases of QT prolongation). These adverse reactions may be more common in patients with a prior history of coronary artery disease. Cardiac arrhythmias (including ventricular fibrillation, torsades de pointes, and bradycardia), angina pectoris, myocardial infarction, heart failure and cardiomyopathy have been reported in patients receiving capecitabine. Caution must be exercised in patients with history of significant cardiac disease, arrhythmias and angina pectoris.

DPD Deficiency

Rarely, unexpected, severe toxicity (e.g., stomatitis, diarrhoea, neutropenia and neurotoxicity) associated with 5-FU has been attributed to a deficiency of DPD activity. A link between decreased levels of DPD and increased, potentially fatal toxic effects of 5-FU, therefore, cannot be excluded.

In patients with unrecognized DPD deficiency treated with capecitabine, life-threatening toxicities manifesting as acute overdose may occur. In the event of grade 2-4 acute toxicity, treatment must be discontinued immediately until observed toxicity resolves. Permanent discontinuation should be considered based on clinical assessment of the onset, duration and severity of the observed toxicities.

Ophthalmologic Complications

Patients should be carefully monitored for ophthalmologic complications such as keratitis and corneal disorders, especially if they have a prior history of eye disorders. Treatment of eye disorders should be initiated as clinically appropriate.

Lactose

As this medicinal product contains anhydrous lactose as an excipient, patients with rare hereditary problems of galactose intolerance, the Lapp-lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Hand-Foot Syndrome

Hand-foot syndrome (also known as hand-foot skin reaction or Palmar-Plantar erythrodysaesthesia or chemotherapy-induced acral erythema).

  • Grade 1 hand- foot syndrome is defined as numbness, dysaesthesia/ paraesthesia, tingling, painless swelling or erythema of the hands and/or feet and/or discomfort, which does not disrupt the patient's normal activities.
  • Grade 2 hand-foot syndrome is painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patient's activities of daily living.
  • Grade 3 hand-foot syndrome is moist desquamation, ulceration, blistering and severe pain of the hands and/or feet and/or severe discomfort that causes the patient to be unable to work or perform activities of daily living.

If grade 2 or 3 hand-foot syndrome occurs, administration of capecitabine should be interrupted until the event resolves or decreases in intensity to grade 1. Following grade 3 hand-foot syndrome, subsequent doses of capecitabine should be decreased. When capecitabine and cisplatin are used in combination, the use of vitamin B6 (pyridoxine) is not advised for symptomatic or secondary prophylactic treatment of hand-foot syndrome, because of published reports that it may decrease the efficacy of cisplatin.

Hyperbilirubinaemia

  • In 875 patients with either metastatic breast or colorectal cancer who received at least one dose of capecitabine 1,250 mg/m2 twice daily as monotherapy for 2 weeks followed by a 1-week rest period, grade 3 (1.5-3 x upper limit of normal ) hyperbilirubinaemia occurred in 15.2% (n=133) of patients and grade 4 (>3 x ULN) hyperbilirubinaemia occurred in 3.9% (n=34) of patients. Of 566 patients who had hepatic metastases at baseline and 309 patients without hepatic metastases at baseline, grade 3 or 4 hyperbilirubinaemia occurred in 22.8% and 12.3%, respectively. Of the 167 patients with grade 3 or 4 hyperbilirubinaemia, 18.6% (n=31) also had post-baseline elevations (grades 1 to 4, without elevations at baseline) in alkaline phosphatase and 27.5% (n=46) had post-baseline elevations in transaminases at any time (not necessarily concurrent). The majority of these patients, i.e. 64.5% (n=20) and 71.7% (n=33), had liver metastases at baseline. In addition, 57.5% (n=96) and 35.3% (n=59) of the 167 patients had elevations (grades 1 to 4) at both pre-baseline and post-baseline in alkaline phosphatase or transaminases, respectively. Only 7.8% (n=13) and 3.0% (n=5) had grade 3 or 4 elevations in alkaline phosphatase or transaminases.
  • In the 596 patients treated with capecitabine as first-line therapy for metastatic colorectal cancer, the incidence of grade 3 or 4 hyperbilirubinaemia was similar to the overall clinical trial safety database of capecitabine monotherapy. The median time to onset for grade 3 or 4 hyperbilirubinaemia in the colorectal cancer population was 64 days and median total bilirubin increased from 8 -m/L at baseline to 13 -m/L during treatment with capecitabine. Of the 136 colorectal cancer patients with grade 3 or 4 hyperbilirubinaemia, 49 patients had grade 3 or 4 hyperbilirubinaemia as their last measured value, of which 46 had liver metastases at baseline.
  • In 251 patients with metastatic breast cancer who received a combination of capecitabine and docetaxel, grade 3 (1.5-3 x ULN) hyperbilirubinaemia occurred in 7% (n=17) and grade 4 (>3 x ULN) hyperbilirubinaemia occurred in 2% (n=5).
  • If drug-related grade 3 to 4 elevations in bilirubin occur, administration of capecitabine should be immediately interrupted until the hyperbilirubinaemia decreases to ≤3.0 x ULN.

Haematologic

  • In 875 patients with either metastatic breast or colorectal cancer who received a dose of 1,250 mg/m2 administered twice daily as monotherapy for 2 weeks followed by a 1-week rest period, 3.2%, 1.7%, and 2.4% of patients had grade 3 or 4 neutropenia, thrombocytopenia or decreases in haemoglobin, respectively.
  • In 251 patients with metastatic breast cancer who received a dose of 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 anaemia.
  • Patients with baseline neutrophil counts of <1.5 × 109/L and/or thrombocyte counts of <100 × 109/L should not be treated with capecitabine. If unscheduled laboratory assessments during a treatment cycle show grade 3 or 4 haematologic toxicity, treatment with capecitabine should be interrupted.

Combination with Other Drugs

Use of capecitabine in combination with irinotecan has not been adequately studied.

Renal Impairment

Patients with moderate renal impairment at baseline require dose reduction. Patients with mild and moderate renal impairment at baseline should be carefully monitored for adverse reactions. Prompt interruption of therapy with subsequent dose adjustments is recommended if a patient develops a grade 2-4 adverse event as outlined in Table 2. The incidence of grade 3 or 4 adverse reactions in patients with moderate renal impairment (creatinine clearance: 30-50 ml/min) is increased compared to the overall population.

Hepatic Impairment

In the absence of safety and efficacy data in patients with hepatic impairment, capecitabine use should be carefully monitored in patients with mild-to-moderate liver dysfunction, regardless of the presence or absence of liver metastasis. Administration of capecitabine should be interrupted if treatment-related elevations in bilirubin of >3.0 x ULN or treatment-related elevations in hepatic aminotransferases (ALT, AST) of >2.5 x ULN occur. Treatment with capecitabine monotherapy may be resumed when bilirubin decreases to ≤3.0 x ULN or hepatic aminotransferases decrease to ≤ 2.5 x ULN. The effect of severe hepatic dysfunction on the disposition of capecitabine is not known

In animal studies effects on fertility were observed.

Pregnancy

Pregnancy Category D
There are no studies in pregnant women using capecitabine; however, it should be assumed that capecitabine may cause foetal harm if administered to pregnant women. In reproductive toxicity studies in animals, capecitabine administration caused embryo-lethality and teratogenicity. These findings are expected effects of fluoropyrimidine derivatives. Capecitabine is contraindicated during pregnancy.

Women of Childbearing Potential/Contraception in Males and Females
Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with capecitabine. If the patient becomes pregnant while receiving capecitabine, the potential hazard to the foetus must be explained. An effective method of contraception should be used during treatment.

Lactation

It is not known whether capecitabine is excreted in human breast milk. In lactating mice, considerable amounts of capecitabine and its metabolites were found in milk. Breastfeeding should be discontinued while receiving treatment with capecitabine.

Paediatric Use

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

Geriatric Use

Patients ≥80 years of age may experience a greater incidence of grade 3 or 4 adverse reactions. In 875 patients with either metastatic breast or colorectal cancer who received capecitabine monotherapy, 62% of the 21 patients ≥80 years of age treated with capecitabine experienced a treatment-related grade 3 or 4 adverse event as follows: diarrhoea in 6 (28.6%), nausea in 3 (14.3%), hand-foot syndrome in 3 (14.3%), and vomiting in 2 (9.5%) patients. Among the 10 patients ≥70 years of age (no patients were >80 years of age) treated with capecitabine in combination with docetaxel, 30% (3 out of 10) of patients experienced grade 3 or 4 diarrhoea and stomatitis, and 40% (4 out of 10) experienced grade 3 hand-foot syndrome.

Among the 67 patients ≥60 years of age receiving capecitabine in combination with docetaxel, the incidence of grade 3 or 4 treatment-related adverse reactions, and serious adverse reactions, withdrawals due to adverse reactions, treatment discontinuations due to adverse reactions and treatment discontinuations within the first two treatment cycles was higher than in the <60 years of age-patient group.

In 995 patients receiving capecitabine as adjuvant therapy for Dukes' C colon cancer after resection of the primary tumour, 41% of the 398 patients ≥65 years of age treated with capecitabine experienced a treatment-related grade 3 or 4 adverse event as follows: hand-foot syndrome in 75 (18.8%), diarrhoea in 52 (13.1%), stomatitis in 12 (3.0%), neutropenia/granulocytopenia in 11 (2.8%), vomiting in 6 (1.5%), and nausea in 5 (1.3%) patients. In patients ≥65 years of age (all-randomized population; capecitabine, 188 patients; 5-FU/LV, 208 patients) treated for Dukes' C colon cancer after resection of the primary tumour, the hazard ratios for disease-free survival and overall survival for capecitabine, compared to 5-FU/LV, were 1.01 (95% CI: 0.80-1.27) and 1.04 (95% CI: 0.79-1.37), respectively.

Fertility

There is no data on capecitabine and its impact on fertility. The capecitabine pivotal studies included females of childbearing potential and males only if they agreed to use an acceptable method of birth control to avoid pregnancy for the duration of the study and for a reasonable period thereafter.

Effects on the Ability to Drive and Use Machines

Capecitabine has minor or moderate influence on the ability to drive and use machines. Capecitabine may cause dizziness, fatigue and nausea.

Undesirable Effects

Summary of the Safety Profile

The overall safety profile of capecitabine is based on data from over 3,000 patients treated with capecitabine as monotherapy or capecitabine in combination with different chemotherapy regimens in multiple indications. The safety profiles of capecitabine monotherapy for the metastatic breast cancer, metastatic colorectal cancer and adjuvant colon cancer populations are comparable.

The most commonly reported and/or clinically relevant treatment-related adverse drug reactions (ADRs) were gastrointestinal disorders (especially diarrhoea, nausea, vomiting, abdominal pain, and stomatitis), hand-foot syndrome (Palmar-Plantar erythrodysaesthesia), fatigue, asthenia, anorexia, cardiotoxicity, increased renal dysfunction in those with pre-existing compromised renal function, and thrombosis/embolism.

Tabulated Summary of ADRs

ADRs considered by the investigator to be possibly, probably, or remotely related to the administration of capecitabine are listed in Table 4 for capecitabine given as monotherapy and in Table 5 for capecitabine given in combination with different chemotherapy regimens in multiple indications. The following headings are used to rank the ADRs by frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), and very rare (<1/10,000). Within each frequency grouping, the ADRs are presented in order of decreasing seriousness.

Capecitabine Monotherapy
Table 4 lists the ADRs associated with the use of capecitabine monotherapy, based on a pooled analysis of safety data from three major studies, including over 1,900 patients (Studies M66001, SO14695 and SO14796). The ADRs are added to the appropriate frequency grouping according to the overall incidence from the pooled analysis.

Table 4: Summary of Related ADRs Reported in Patients Treated with Capecitabine Monotherapy
Body System
Very Common
All Grades
Common
All Grades
Uncommon,Severe and/or Life-
threatening (Grade 3-4) or Considered
Medically Relevant
Infections and infestations
-
Herpes viral infection,Nasopharyngitis
Lower respiratory tract infection
Sepsis, urinary tract infection,
cellulitis, tonsillitis, pharyngitis,
laryngitis, bronchitis,oral
candidiasis, influenza, gastroenteritis,
fungal infection, infection,
tooth abscess, pneumonia,
bronchopneumonia, keratoconjunctivitis,
fungal infections
(including candidiasis)
Neoplasm benign,
malignant and unspecified
-
-
Lipoma
Blood and lymphatic
system disorders
-
Neutropenia, Anaemia
Febrile neutropenia, Pancytopenia,
Granulocytopenia, Thrombocytopenia,
Leucopenia, Lymphocytopenia,
Haemolytic anaemia, INR
increased/Prothrombin time prolonged,
Coagulation disorder, Bone marrow
depression, Idiopathic
thrombocytopenia purpura
Immune system disorders
-
-
Hypersensitivity
Metabolism and nutrition
disorders
Anorexia
Dehydration, , Weight decreased
or increased, Cachexia
Diabetes, hypokalaemia, appetite
disorder, malnutrition,
hypertriglyceridaemia,
hypomagnesemia
Psychiatric disorders
-
Insomnia, depression,
taste disturbance
Confusional state, panic attack,
depressed mood, libido
decreased, mood alteration
Nervous system disorders
-
Headache, Lethargy Dizziness,
Paraesthesia Dysgeusia
Aphasia, memory impairment,
ataxia, syncope, balance disorder,
sensory disorder, neuropathy
peripheral, tremor, dysphasia,
encephalopathy, abnormal coordination,
dysarthria, loss of consciousness,
impaired balance
Eye disorders
-
Lacrimation increased,
Conjunctivitis,Eye irritation
Visual acuity reduced,
Diplopia
Ear and labyrinth
disorders
-
-
Vertigo,Ear pain
Cardiac disorders
-
-
Angina unstable, angina
pectoris, myocardial ischaemia,
atrial fibrillation,
arrhythmia, tachycardia, bradycardia,
sinus tachycardia, palpitations,
ventricular extrasystoles ,
extrasystoles, myocarditis,
pericardial effusion
Vascular disorders
-
Thrombophlebitis
Deep vein thrombosis,
hypertension, petechiae,
hypotension, hot flush,
peripheral coldness, lymphoedema,
pulmonary embolism,
cerebrovascular accident
Respiratory, thoracic and
mediastinal disorders
-
Dyspnoea, epistaxis, cough,
rhinorrhoea, pharyngeal disorder,
pleural effusion
Pulmonary embolism,
pneumothorax, haemoptysis,
asthma, dyspnoea exertional ,
respiratory distress
Gastrointestinal disorders
Diarrhoea, vomiting, nausea,
stomatitis, abdominal pain
Gastrointestinal haemorrhage,
constipation, upper abdominal
pain, dyspepsia, flatulence,
dry mouth
Intestinal obstruction,
Ascites, enteritis, gastritis,
dysphagia, abdominal pain
lower, abdominal distension
oesophagitis, abdominal
discomfort, proctalgia, ascites,
ileus, toxic dilation of
intestine, gastroenteritis, gastric
ulcers, gastro-oesophageal
reflux disease, colitis,
blood in stool
Hepatobiliary disorders
-
Hyperbilirubinaemia, Liver function
test abnormalities
Jaundice, hepatic fibrosis,
hepatitis, abnormal liver
function tests
Skin and subcutaneous
tissue disorders
Palmar-Plantar
erythrodysaesthesia syndrome
Rash, alopecia, erythema,
dry skin, pruritus, skin
hyper-pigmentation, rash
macular, skin desquamation,
dermatitis, pigmentation disorder,
nail disorder, sweating
increased, photosensitivity reaction
Blister, skin ulcer, rash,
urticaria, photosensitivity reaction,
Palmar erythema, swelling
of face, purpura, radiation
recall syndrome, skin
ulceration
Muskuloskeletal and connective
tissue disorders
-
Pain in extremity, Back
pain, Arthralgia
Joint swelling, bone pain,
facial pain, musculoskeletal
stiffness, muscular
weakness , myalgia,
arthritis
Renal and urinary
disorders
-
-
Hydronephrosis, urinary incontinence,
haematuria, nocturia, blood
creatinine increased,
renal impairment
Reproductive system and
breast disorders
-
-
Vaginal haemorrhage
General disorders and
administration site
conditions
Fatigue, asthenia
Pyrexia, oedema peripheral,
malaise, chest pain
Oedema, chills, influenza
like illness, rigors, body
temperature increased, pain,
hot flushes, hoarseness,
irritability, difficulty in
walking, thirst, chest
mass, collapse, fibrosis,
haemorrhage, sedation

Capecitabine in Combination Therapy
Table 5 lists the ADRs associated with the use of capecitabine in combination with different chemotherapy regimens in multiple indications, based on safety data from over 3,000 patients. The ADRs were added to the appropriate frequency grouping (very common or common) according to the highest incidence seen in any of the major clinical trials and were only added when they were seen in addition to those seen with capecitabine monotherapy or seen at a higher frequency grouping compared to capecitabine monotherapy (see Table 4). Uncommon ADRs reported for capecitabine in combination therapy are consistent with the ADRs reported for capecitabine monotherapy or reported for monotherapy with the combination medicinal product (in literature and/or respective summary of product characteristics).

Some of the ADRs are reactions commonly seen with the combination medicinal product (e.g. peripheral sensory neuropathy with docetaxel or oxaliplatin, hypertension seen with bevacizumab); however, an exacerbation by capecitabine therapy cannot be excluded.

Table 5: Summary of Related ADRs Reported in Patients Treated with Capecitabine in Combination Treatment in Addition to Those Seen with Capecitabine Monotherapy or Seen at a Higher Frequency Grouping Compared to Capecitabine Monotherapy
Body System
Very Common
All Grades
Common
All Grades
Infections and infestations
-
Herpes zoster, urinary tract infection,
oral candidiasis, upper respiratory
tract infection, rhinitis,
influenza, infection +,
oral herpes, neutropenic sepsis, sepsis,
bronchopneumonia
Blood and lymphatic system
disorders
Neutropenia +, leucopenia +,
anaemia +, neutropenic fever +,
thrombocytopenia
Bone marrow depression, febrile
neutropenia +, agranulocytosis,
prothrombin decreased
Immune system disorders
-
Hypersensitivity
Metabolism and nutrition
disorders
Appetite decreased
Hypokalaemia, Hyponatraemia, Hypomagnesaemia,
Hypocalcaemia, Hyperglycaemia
Psychiatric disorders
-
Sleep disorder, anxiety
Nervous system disorders
Paraesthesia, dysaesthesia, peripheral
neuropathy, peripheral sensory
neuropathy, dysgeusia, headache
Neurotoxicity, tremor, neuralgia,
hypersensitivity reaction, hypoaesthesia,
taste loss, polyneuropathy,
migraine
Eye disorders
Lacrimation increased
Visual disorders, dry eye, eye
pain, visual impairment,
vision blurred
Ear and labyrinth
disorders
-
Tinnitus, hypoacusis
Cardiac disorders
-
Atrial fibrillation, cardiac
ischaemia/infarction, supraventricular
tachycardia
Vascular disorders
Lower limb oedema, hypertension,
embolism + and
thrombosis
Flushing, hypotension, hypertensive
crisis, hot flush, phlebitis,
lymphoedema, venous phlebitis
and thrombophlebitis, postural
hypotension
Respiratory, thoracic and
mediastinal system disorders
Sore throat, dysaesthesia
pharynx
Hiccups, Pharyngolaryngeal
pain, Dysphonia
Gastrointestinal disorders
Constipation, dyspepsia
Upper gastrointestinal haemorrhage,
mouth ulceration, gastritis,
abdominal distension, gastro-
oesophageal reflux disease,
oral pain, dysphagia, rectal
haemorrhage, abdominal pain lower,
oral dysaesthesia, paraesthesia
oral, hypoaesthesia oral, abdominal
discomfort, necrotizing enterocolitis,
oesophageal ulcer, haemorrhagic
diarrhoea
Hepatobiliary disorders
-
Hepatic function abnormal, hepatic
failure, hepatic coma, hepatotoxicity
Skin and subcutaneous
tissue disorders
Alopecia, nail disorder,
onycholysis
Hyperhidrosis, rash erythematous,
urticaria, night sweats
Musculoskeletal and connective
tissue disorders
Myalgia, arthralgia,
pain in extremity
Pain in jaw, muscle spasms,
trismus, muscular weakness
Renal and urinary
disorder
-
Haematuria, proteinuria, creatinine
renal clearance decreased, dysuria,
renal failure
General disorders
and administration site
conditions
Pyrexia, weakness, lethargy +,
temperature intolerance
Mucosal inflammation, pain in limb,
pain, chills, chest pain, influenza-
like illness, fever +, infusion-related
reaction, injection site reaction,
infusion site pain, injection
site pain
Injury, poisoning and
procedural complications
-
Contusion

Postmarketing Experience

The following additional serious adverse reactions have been identified during postmarketing exposure:

Table 6: Summary of Events Reported with Capecitabine in the Postmarketing Setting
Body System
Rare
Eye disorders
Lacrimal duct stenosis
Cardiac disorders
Ventricular fibrillation, QT prolongation,
torsades de pointes, bradycardia,
vasospasm
Hepatobiliary disorders
Hepatic failure, cholestatic hepatitis
Table 7: Percent Incidence of Grade 3/4 Laboratory Abnormalities reported in ≥1% of Patients receiving Capecitabine Monotherapy for Adjuvant Treatment of Colon Cancer (Safety Population)
Adverse Event
Capecitabine
(n=995)
Grade 3/4 %
Intravenous 5-FU/LV
(n=974)
Grade 3/4 %
 
Increased ALAT (SGPT)
1.6
0.6
Increased calcium
1.1
0.7
Decreased calcium
2.3
2.2
Decreased haemoglobin
1.0
1.2
Decreased lymphocytes
13.0
13.0
Decreased neutrophils*
2.2
26.2
Decreased neutrophils/granulocytes
2.4
26.4
Decreased platelets
1.0
0.7
Increased bilirubin†
20
6.3

Description of Selected Adverse Reactions

Hand-Foot Syndrome
For the capecitabine dose of 1,250 mg/m2 twice daily on days 1-14 every 3 weeks, a frequency of 53-60% of all-grades hand-foot syndrome was observed in capecitabine monotherapy trials (comprising studies in adjuvant therapy in colon cancer, treatment of metastatic colorectal cancer, and treatment of breast cancer) and a frequency of 63% was observed in the capecitabine- docetaxel arm for the treatment of metastatic breast cancer. For the capecitabine dose of 1,000 mg/m2 twice daily on days 1-14 every 3 weeks, a frequency of 22-30% of all-grade hand-foot syndrome was observed in capecitabine combination therapy

A meta-analysis of 14 clinical trials with data from over 4,700 patients treated with capecitabine monotherapy or capecitabine in combination with different chemotherapy regimens in multiple indications (colon, colorectal, gastric and breast cancer) showed that hand-foot syndrome (all grades) occurred in 2,066 (43%) patients after a median time of 239 days after starting treatment with capecitabine. In all studies combined, the following covariates were statistically significantly associated with an increased risk of developing hand-foot syndrome: increasing capecitabine starting dose (gram), decreasing cumulative capecitabine dose (0.1kg*), increasing relative dose intensity in the first 6 weeks, increasing duration of study treatment (weeks), increasing age (by 10-year increments), female gender, and good ECOG performance status at baseline (0 versus ≥1).

Diarrhoea
Capecitabine can induce the occurrence of diarrhoea, which has been observed in up to 50% of patients.

The results of a meta-analysis of 14 clinical trials with data from over 4,700 patients treated with capecitabine showed that in all studies combined, the following covariates were statistically significantly associated with an increased risk of developing diarrhoea: increasing capecitabine starting dose (grams), increasing duration of study treatment (weeks), increasing age (by 10-year increments), and female gender. The following covariates were statistically significantly associated with a decreased risk of developing diarrhoea: increasing cumulative capecitabine dose (0.1*kg) and increasing relative dose intensity in the first 6 weeks.

Cardiotoxicity
In addition to the ADRs described in Tables 4 and 5, the following ADRs with an incidence of less than 0.1% were associated with the use of capecitabine monotherapy, based on a pooled analysis from clinical safety data from seven clinical trials, including 949 patients (two Phase III and five Phase II clinical trials in metastatic colorectal cancer and metastatic breast cancer):

cardiomyopathy, cardiac failure, sudden death, and ventricular extrasystoles.

Encephalopathy
In addition to the ADRs described in Tables 4 and 5, and based on the above pooled analysis from clinical safety data from seven clinical trials, encephalopathy was also associated with the use of capecitabine monotherapy, with an incidence of less than 0.1%.

Special Populations

Geriatric
An analysis of safety data in patients ≥60 years of age treated with capecitabine monotherapy and an analysis of patients treated with capecitabine plus docetaxel combination therapy showed an increase in the incidence of treatment-related grade 3 and 4 adverse reactions and treatment-related serious adverse reactions compared to patients <60 years of age. Patients ≥60 years of age treated with capecitabine plus docetaxel also had more early withdrawals from treatment due to adverse reactions compared to patients <60 years of age.

The results of a meta-analysis of 14 clinical trials with data from over 4,700 patients treated with capecitabine showed that in all studies combined, increasing age (by 10-year increments) was statistically significantly associated with an increased risk of developing hand-foot syndrome and diarrhoea and with a decreased risk of developing neutropenia.

Gender
The results of a meta-analysis of 14 clinical trials with data from over 4,700 patients treated with capecitabine showed that in all studies combined, female gender was statistically significantly associated with an increased risk of developing hand-foot syndrome and diarrhoea and with a decreased risk of developing neutropenia.

Patients with Renal Impairment
An analysis of the safety data in patients treated with capecitabine monotherapy (colorectal cancer) with baseline renal impairment showed an increase in the incidence of treatment-related grade 3 and 4 adverse reactions compared to patients with normal renal function (36% in patients without renal impairment n=268, versus 41% in mild n=257 and 54% in moderate n=59, respectively). Patients with moderately impaired renal function show an increased rate of dose reduction (44%) versus 33% and 32% in patients with no or mild renal impairment and an increase in early withdrawals from treatment (21% withdrawals during the first two cycles) versus 5% and 8% in patients with no or mild renal impairment.

Overdosage

The manifestations of acute overdose would include nausea, vomiting, diarrhoea, gastrointestinal irritation and bleeding, and bone marrow depression.

Medical management of overdose should include customary supportive medical interventions aimed at correcting the presenting clinical manifestations. Although no clinical experience using dialysis as a treatment for capecitabine overdose has been reported, dialysis may be of benefit in reducing circulating concentrations of 5'-DFUR, a low-molecular-weight metabolite of the parent compound.

Shelf-life

2 years

Storage and Handling Instructions

Store in cool dry place. Protect from light.

Care should be exercised in the handling of capecitabine. Capecitabine tablets should not be cut or crushed. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the tablets. If powder from broken capecitabine tablets contacts the skin, wash the skin immediately and thoroughly with soap and water. If capecitabine contacts the mucous membranes, flush thoroughly with water.

Packaging Information

CAPEGARD 500 Tablets: Blister pack of 10 tablets