To be sold by retail or prescription of the Oncologist only

1. Generic Name

Capecitabine Tablets IP 500 mg

2. Brand Name

CAPEGARD 500 Tablets

3. Black Box Warning

Capecitabine-Warfarin Interaction Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (International Normalized Ratio [INR] 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.

4. Qualitative and Quantitative Composition

CAPEGARD 500 Tablets

Each film coated tablet contains:

Capecitabine IP……………….... 500 mg

5. Dosage Form(S) And Strength(S)

Oral tablet: 500 mg

6. Clinical Particulars

6.1 Therapeutic Indications

• Treatment of metastatic breast cancer after failure of paclitaxel and anthracycline containing chemotherapy regimen
• First-line treatment in patients with metastatic colorectal cancer.

6.2 Posology and Method of Administration

Important Administration Instructions

CAPEGARD 500 Tablets should be swallowed whole with water within 30 minutes after a meal. Capecitabine is a cytotoxic drug. Follow applicable special handling and disposal procedures. If Capecitabine tablets must be cut or crushed, this should be done by a professional trained in safe handling of cytotoxic drugs using appropriate equipment and safety procedures. The dose of CAPEGARD 500 Tablets is calculated according to the body surface area.

Standard Starting Dose

Monotherapy (Metastatic 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).

Dose Level: 1,250 mg/m2 Twice a Day		Number of Tablets to be Taken at Each Dose (Morning and Evening)
Surface Area (m2)	Total Daily Dose* (mg)	500 mg tablet
≤1.25	3,000	3
1.26–1.37	3,300	3
1.38–1.51	3,600	3
1.52–1.65	4,000	4
1.66–1.77	4,300	4
1.78–1.91	4,600	4
1.92–2.05	5,000	5
2.06–2.17	5,300	5
≥2.18	5,600	5

In Combination With Docetaxel (Metastatic Breast Cancer)

In combination with docetaxel, the recommended dose of capecitabine 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, according to the docetaxel labelling, should be started prior to docetaxel administration for patients receiving the capecitabine plus docetaxel combination. Table 1 displays the total daily dose of CAPEGARD 500 Tablets by body surface area and the number of tablets to be taken at each dose.

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.

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, Metastatic Breast Cancer)

The CAPEGARD 500 Tablets dose modification scheme as described below (see Table 2) is recommended for the management of adverse reactions.

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.

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 [Cockcroft and Gault] 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.

Elderly

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.

Paediatric

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

6.3 Contraindications

• History of severe and unexpected reactions to fluoropyrimidine therapy.
• Hypersensitivity to capecitabine or to any of its components or fluorouracil.
• Known complete dihydropyrimidine dehydrogenase (DPD) deficiency.
• During pregnancy and lactation.
• In patients with severe leukopenia, neutropenia or thrombocytopenia.
• In patients with severe hepatic impairment.
• In patients with severe renal impairment (creatinine clearance <30 ml/min).
• Recent or concomitant treatment with brivudine If contraindications exist to any of the medicinal products in the combination regimen, that medicinal product should not be used.

6.4 Special Warnings and Precautions for Use

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

Capecitabine can induce diarrhea, sometimes severe. Patients with severe diarrhoea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. In 875 patients with either metastatic breast or colorectal cancer who received Capecitabine monotherapy, the median time to first occurrence of grade 2 to 4 diarrhea was 34 days (range from 1 to 369 days). The median duration of grade 3 to 4 diarrhea was 5 days. 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. Necrotizing enterocolitis (typhlitis) has been reported.

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

The cardiotoxicity observed with capecitabine includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrhythmias (including ventricular fibrillation, torsade de pointes, and bradycardia), cardiac arrest, cardiac failure, sudden death, cardiogenic shock, electrocardiographic changes (including very rare cases of QT prolongation), and cardiomyopathy. These adverse reactions may be more common in patients with a prior history of coronary artery disease. Caution must be exercised in patients with history of significant cardiac disease, arrhythmias and angina pectoris.

DPD Deficiency

DPD activity is rate limiting in the catabolism of 5-fluorouracil. Patients with DPD deficiency are therefore at increased risk of fluoropyrimidines-related toxicity, including for example stomatitis, diarrhoea, mucosal inflammation, neutropenia and neurotoxicity.

DPD-deficiency related toxicity usually occurs during the first cycle of treatment or after dose increase.

Complete DPD Deficiency

Complete DPD deficiency is rare (0.01-0.5% of Caucasians). Based on postmarketing reports, patients with certain homozygous or certain compound heterozygous mutations in the DPD gene that result in complete or near complete absence of DPD activity are at increased risk for acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions caused by capecitabine (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity).

Withhold or permanently discontinue capecitabine based on clinical assessment of the onset, duration and severity of the observed toxicities in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of DPD activity. No capecitabine dose has been proven safe for patients with complete absence of DPD activity.

Partial DPD Deficiency

Partial DPD deficiency is estimated to affect 3-9% of the Caucasian population. Patients with partial DPD activity may also have increased risk of severe, life-threatening, or fatal adverse reactions caused by capecitabine.

A reduced starting dose should be considered to limit this toxicity. DPD deficiency should be considered as a parameter to be taken into account in conjunction with other routine measures for dose reduction. Initial dose reduction may impact the efficacy of treatment. In the absence of serious toxicity, subsequent doses may be increased with careful monitoring.

Testing for DPD Deficiency

Phenotype and/or genotype testing prior to the initiation of treatment with Capecitabine is recommended despite uncertainties regarding optimal pre-treatment testing methodologies. Consideration should be given to applicable clinical guidelines.

Genotypic Characterisation of DPD Deficiency

Pre-treatment testing for rare mutations of the DPYD gene can identify patients with DPD deficiency.

The four DPYD variants c.1905+1G>A [also known as DPYD*2A], c.1679T>G [DPYD*13], c.2846A>T and c.1236G>A/HapB3 can cause complete absence or reduction of DPD enzymatic activity. Other rare variants may also be associated with an increased risk of severe or life-threatening toxicity.

Certain homozygous and compound heterozygous mutations in the DPYD gene locus (e.g. combinations of the four variants with at least one allele of c.1905+1G>A or c.1679T>G) are known to cause complete or near complete absence of DPD enzymatic activity.

Patients with certain heterozygous DPYD variants (including c.1905+1G>A, c.1679T>G, c.2846A>T and c.1236G>A/HapB3 variants) have increased risk of severe toxicity when treated with fluoropyrimidines.

The frequency of the heterozygous c.1905+1G>A genotype in the DPYD gene in Caucasian patients is around 1%, 1.1% for c.2846A>T, 2.6-6.3% for c.1236G>A/HapB3 variants and 0.07 to 0.1% for c.1679T>G.

Data on the frequency of the four DPYD variants in other populations than Caucasian is limited. At the present, the four DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T and c.1236G>A/HapB3) are considered virtually absent in populations of African (-American) or Asian origin.

Phenotypic Characterisation of DPD Deficiency

For phenotypic characterisation of DPD deficiency, the measurement of pre-therapeutic blood levels of the endogenous DPD substrate uracil (U) in plasma is recommended.

Elevated pre-treatment uracil concentrations are associated with an increased risk of toxicity. Despite uncertainties on uracil thresholds defining complete and partial DPD deficiency, a blood uracil level ≥ 16 ng/ml and < 150 ng/ml should be considered indicative of partial DPD deficiency and associated with an increased risk for fluoropyrimidine toxicity. A blood uracil level ≥ 150 ng/ml should be considered indicative of complete DPD deficiency and associated with a risk for life-threatening or fatal fluoropyrimidine toxicity.

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.

Mucocutaneous and Dermatologic Toxicity

Severe mucocutaneous reactions, some with fatal outcome, such as Stevens-Johnson syndrome and Toxic Epidermal Necrolysis (TEN) can occur in patients treated with capecitabine. Capecitabine should be permanently discontinued in patients who experience a severe mucocutaneous reaction possibly attributable to capecitabine treatment.

Hand-and-foot syndrome (palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema) is a cutaneous toxicity. Median time to onset was 79 days (range from 11 to 360 days) with a severity range of grades 1 to 3 for patients receiving capecitabine monotherapy in the metastatic setting. Grade 1 is characterized by any of the following: numbness, dysesthesia/paresthesia, tingling, painless swelling or erythema of the hands and/or feet and/or discomfort which does not disrupt normal activities. Grade 2 hand-and-foot syndrome is defined as painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patient's activities of daily living. Grade 3 hand-and-foot syndrome is defined as moist desquamation, ulceration, blistering or 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. Persistent or severe hand-and-foot syndrome (grade 2 and above) can eventually lead to loss of fingerprints which could impact patient identification. If grade 2 or 3 hand-and-foot syndrome occurs, administration of capecitabine should be interrupted until the event resolves or decreases in intensity to grade 1. Following grade 3 hand-and-foot syndrome, subsequent doses of capecitabine should be decreased

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 × upper limit of normal [ULN]) hyperbilirubinaemia occurred in 15.2% (n=133) of patients and grade 4 (>3 × 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 µm/L at baseline to 13 µm/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 × ULN) hyperbilirubinaemia occurred in 7% (n=17) and grade 4 (>3 × 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 × 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.

Brivudine

Brivudine must not be administered concomitantly with capecitabine. Fatal cases have been reported following this drug interaction. There must be at least a 4-week waiting period between end of treatment with brivudine and start of capecitabine therapy. Treatment with brivudine can be started 24 hours after the last dose of capecitabine. In the event of accidental administration of brivudine to patients being treated with capecitabine, effective measures should be taken to reduce the toxicity of capecitabine. Immediate admission to hospital is recommended. All measures should be initiated to prevent systemic infections and dehydration.

Severe Skin Reactions

Capecitabine can induce severe skin reactions such as Stevens-Johnson syndrome and Toxic Epidermal Necrolysis. Capecitabine should be permanently discontinued in patients who experience a severe skin reaction during treatment.

Embryo-Fetal Toxicity

Based on findings from animal reproduction studies and its mechanism of action, capecitabine may cause fetal harm when given to a pregnant woman. Limited available data are not sufficient to inform use of capecitabine in pregnant women. In animal reproduction studies, administration of capecitabine to pregnant animals during the period of organogenesis caused embryolethality and teratogenicity in mice and embryolethality in monkeys at 0.2 and 0.6 times the exposure (AUC) in patients receiving the recommended dose respectively. Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of capecitabine.

Coumarin-derivative Anticoagulation

In an 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 receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored closely and the anticoagulant dose adjusted accordingly.

Dehydration and Renal Failure

Dehydration has been observed and may cause acute renal failure which can be fatal. Patients with pre-existing compromised renal function or who are receiving concomitant capecitabine with known nephrotoxic agents are at higher risk. Patients with anorexia, asthenia, nausea, vomiting or diarrhea may rapidly become dehydrated. Monitor patients when capecitabine is administered to prevent and correct dehydration at the onset. 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 should be applied for the precipitating adverse event as necessary.

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 to 4 adverse event.

Renal Impairment

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.

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.

6.5 Drug Interactions

Interaction studies have only been performed in adults.

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 and phenytoin dose may need to be reduced. Formal drug-drug interaction studies with phenytoin have not been conducted, but the mechanism of interaction is presumed to be inhibition of the CYP2C9 isoenzyme by capecitabine and/or its metabolites.

Folinic Acid/ Folic acid/ Leucovorin

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 (MTD) of capecitabine alone using the intermittent regimen is 3000 mg/m² per day whereas it is only 2000 mg/m² per day when capecitabine was combined with folinic acid (30 mg orally bid). The enhanced toxicity may be relevant when switching from 5-FU/LV to a capecitabine regimen. This may also be relevant with folic acid supplementation for folate deficiency due to the similarity between folinic acid and folic acid.

Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil.

Brivudine

A clinically significant interaction between brivudine and fluoropyrimidines (e.g. capecitabine, 5-Fluorouracil, tegafur), resulting from the inhibition of dihydropyrimidine dehydrogenase by brivudine, has been described. This interaction, which leads to increased fluoropyrimidine toxicity, is potentially fatal. Therefore, brivudine must not be administered concomitantly with capecitabine (see section 4.3 and 4.4). There must be at least a 4-week waiting period between end of treatment with brivudine and start of capecitabine therapy. Treatment with brivudine can be started 24 hours after the last dose of capecitabine.

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

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

Food was shown to reduce both the rate and extent of absorption of capecitabine. 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.

6.6 Use in Special Population

Patients with Renal Impairment

Patients with moderate (creatinine clearance = 30 to 50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment showed higher exposure for capecitabine, 5- DFUR, and FBAL than in those with normal renal function.

Patients with Hepatic Impairment

Exercise caution when patients with mild to moderate hepatic dysfunction due to liver metastases are treated with capecitabine. The effect of severe hepatic dysfunction on capecitabine is not known.

Pregnant Women

Based on findings in animal reproduction studies and its mechanism of action, capecitabine can cause fetal harm when administered to a pregnant woman. Limited available human data are not sufficient to inform the drug-associated risk during pregnancy. In animal reproduction studies, administration of capecitabine to pregnant animals during the period of organogenesis caused embryo lethality and teratogenicity in mice and embryo lethality in monkeys at 0.2 and 0.6 times the exposure (AUC) in patients receiving the recommended dose respectively.

Apprise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15- 20%, respectively.

Data

Oral administration of capecitabine to pregnant mice during the period of organogenesis at a dose of 198 mg/kg/day caused malformations and embryo lethality. In separate pharmacokinetic studies, this dose in mice produced 5'-DFUR AUC values that were approximately 0.2 times the AUC values in patients administered the recommended daily dose. Malformations in mice included cleft palate, anophthalmia, microphthalmia, oligodactyly, polydactyly, syndactyly, kinky tail and dilation of cerebral ventricles. Oral administration of capecitabine to pregnant monkeys during the period of organogenesis at a dose of 90 mg/kg/day, caused fetal lethality. This dose produced 5'-DFUR AUC values that were approximately 0.6 times the AUC values in patients administered the recommended daily dose.

Lactating Women

There is no information regarding the presence of capecitabine in human milk, or on its effects on milk production or the breast-fed infant. Capecitabine metabolites were present in the milk of lactating mice. Because of the potential for serious adverse reactions from capecitabine exposure in breast-fed infants, advise women not to breastfeed during treatment with capecitabine and for 2 weeks after the final dose.

Data

Lactating mice given a single oral dose of capecitabine excreted significant amounts of capecitabine metabolites into the milk.

Females and Males of Reproductive Potential

Pregnancy Testing

Pregnancy testing is recommended for females of reproductive potential prior to initiating capecitabine.

Contraception

Females

Capecitabine can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the final dose of capecitabine.

Males

Based on genetic toxicity findings, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months following the final dose of capecitabine.

Infertility

Based on animal studies, capecitabine may impair fertility in females and males of reproductive potential.

Pediatric Patients

The safety and effectiveness of capecitabine in pediatric patients have not been established. No clinical benefit was demonstrated in two single arm trials in pediatric patients with newly diagnosed brainstem gliomas and high grade gliomas. In both trials, pediatric patients received an investigational pediatric formulation of capecitabine concomitantly with and following completion of radiation therapy (total dose of 5580 cGy in 180 cGy fractions). The relative bioavailability of the investigational formulation to capecitabine was similar.

The first trial was conducted in 22 pediatric patients (median age 8 years, range 5-17 years) with newly diagnosed non-disseminated intrinsic diffuse brainstem gliomas and high grade gliomas. In the dose-finding portion of the trial, patients received capecitabine with concomitant radiation therapy at doses ranging from 500 mg/m to 850 mg/m every 12 hours for up to 9 weeks. After a 2 week break, patients received 1250 mg/m² capecitabine every 12 hours on Days 1-14 of a 21-day cycle for up to 3 cycles. The maximum tolerated dose (MTD) of capecitabine administered concomitantly with radiation therapy was 650 mg/m² every 12 hours. The major dose limiting toxicities were palmar-plantar erythrodysesthesia and alanine aminotransferase (ALT) elevation.

The second trial was conducted in 34 additional pediatric patients with newly diagnosed non-disseminated intrinsic diffuse brainstem gliomas (median age 7 years, range 3-16 years) and 10 pediatric patients who received the MTD of capecitabine in the dose finding trial and met the eligibility criteria for this trial. All patients received 650 mg/m² capecitabine every 12 hours with concomitant radiation therapy for up to 9 weeks. After a 2 week break, patients received 1250 mg/m² capecitabine every 12 hours on Days 1- 14 of a 21-day cycle for up to 3 cycles.

There was no improvement in one-year progression-free survival rate and one-year overall survival rate in pediatric patients with newly diagnosed intrinsic brainstem gliomas who received capecitabine relative to a similar population of pediatric patients who participated in other clinical trials.

The adverse reaction profile of capecitabine was consistent with the known adverse reaction profile in adults, with the exception of laboratory abnormalities which occurred more commonly in pediatric patients. The most frequently reported laboratory abnormalities (per-patient incidence ≥40%) were increased ALT (75%), lymphocytopenia (73%), leukopenia (73%), hypokalemia (68%), thrombocytopenia (57%), hypoalbuminemia (55%), neutropenia (50%), low hematocrit (50%), hypocalcemia (48%), hypophosphatemia (45%) and hyponatremia (45%).

Geriatric Patients

Physicians should pay particular attention to monitoring the adverse effects of capecitabine in the elderly.

6.7 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.

6.8 Undesirable Effects

The overall safety profile of capecitabine is based on data from over 3000 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, stomatitis), hand-foot syndrome (palmar-plantar erythrodysesthesia), fatigue, asthenia, anorexia, cardiotoxicity, increased renal dysfunction on those with preexisting compromised renal function, and thrombosis/embolism.

Tabulated Summary of Adverse Reactions

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), very rare (<1/10,000). Within each frequency grouping, ADRs are presented in order of decreasing seriousness.

Capecitabine Monotherapy

Table 4 lists ADRs associated with the use of capecitabine monotherapy based on a pooled analysis of safety data from three major studies including over 1900 patients (studies M66001, SO14695, and SO14796). ADRs are added to the appropriate frequency grouping according to the overall incidence from the pooled analysis.

Body System	Very Common All grades	Common All grades	Uncommon Severe and/or Life-threatening (grade 3-4) or considered medically relevant	Rare/Very Rare (Post-Marketing Experience)
Infections and infestations	-	Herpes viral infection, Nasopharyngitis, Lower respiratory tract infection	Sepsis, Urinary tract infection, Cellulitis, Tonsillitis, Pharyngitis, Oral candidiasis, Influenza, Gastroenteritis, Fungal infection, Infection, Tooth abscess, bronchopneumonia, pneumonia
Neoplasm benign, malignant and unspecified	-	-	Lipoma
Blood and lymphatic system disorders	-	Neutropenia, Anaemia	Febrile neutropenia, Pancytopenia, Granulocytopenia, Thrombocytopenia, Leukopenia, Haemolytic anaemia, International Normalised Ratio (INR) increased/Prothrombin time prolonged
Immune system disorders	-	-	Hypersensitivity	Angioedema (rare)
Metabolism and nutrition disorders	Anorexia	Dehydration, Weight decreased	Diabetes, Hypokalaemia, Appetite disorder, Malnutrition, Hypertriglyceridaemia, cachexia, hypomagnesemia
Psychiatric disorders	-	Insomnia, Depression	Confusional state, Panic attack, Depressed mood, Libido decreased
Nervous system disorders	-	Headache, Lethargy Dizziness, Parasthesia Dysgeusia	Aphasia, Memory impairment, Ataxia, Syncope, Balance disorder, Sensory disorder, Neuropathy peripheral, abnormal coordination, dysarthria, loss of consciousness	Toxic leukoencephalopathy (very rare)
Eye disorders	-	Lacrimation increased, Conjunctivitis, Eye irritation	Visual acuity reduced, Diplopia	Lacrimal duct stenosis (rare), Corneal disorders (rare), keratitis (rare), punctate keratitis (rare)
Ear and labyrinth disorders	-	-	Vertigo, Ear pain
Cardiac disorders	-	-	Angina unstable, Angina pectoris, Myocardial ischaemia, Atrial fibrillation, Arrhythmia, Tachycardia, Sinus tachycardia, Palpitations, myocarditis	Ventricular fibrillation (rare), QT prolongation (rare), Torsade de pointes (rare), Bradycardia (rare), Vasospasm (rare), extrasystoles, pericardial effusion
Vascular disorders	-	Thrombophlebitis	Deep vein thrombosis, Hypertension, Petechiae, Hypotension, Hot flush, Peripheral coldness, cerebrovascular accident
Respiratory, thoracic and mediastinal disorders	-	Dyspnoea, Epistaxis, Cough, Rhinorrhoea	Pulmonary embolism, Pneumothorax, Haemoptysis, Asthma, Dyspnoea exertional
Gastrointestinal disorders	Diarrhoea, Vomiting, Nausea, Stomatitis, Abdominal pain	Gastrointestinal haemorrhage, Constipation, Upper abdominal pain, Dyspepsia, Flatulence, Dry mouth, ileus	Intestinal obstruction, Ascites, Enteritis, Gastritis, Dysphagia, Abdominal pain lower, Oesophagitis, Abdominal discomfort, Gastrooesophageal reflux disease, Colitis, Blood in stool, proctalgia, toxic dilation of intestine
Hepatobiliary disorders	-	Hyperbilirubinemia, Liver function test abnormalities	Jaundice	Hepatic failure (rare), Cholestatic hepatitis (rare)
Skin and subcutaneous tissue disorders	Palmar-plantar erythro-dysaesthesia syndrome**	Rash, Alopecia, Erythema, Dry skin, Pruritus, Skin hyper-pigmentation, Rash macular, Skin desquamation, Dermatitis, Pigmentation disorder, Nail disorder	Blister, Skin ulcer, Rash, Urticaria, Photosensitivity reaction, Palmar erythema, Swelling face, Purpura, Radiation recall syndrome, sweating increased	Cutaneous lupus erythematosus (rare), Severe skin reactions such as Stevens-Johnson Syndrome and toxic Epidermal Necrolysis (very rare)
Muskuloskeletal and connective tissue disorders	-	Pain in extremity, Back pain, Arthralgia	Joint swelling, Bone pain, Facial pain, Musculoskeletal stiffness, Muscular weakness
Renal and urinary disorders	-	-	Hydronephrosis, Urinary incontinence, Haematuria, Nocturia, Blood creatinine increased
Reproductive system and breast disorders	-	-	Vaginal haemorrhage
General disorders and administration site conditions	Fatigue, Asthenia	Pyrexia, Oedema peripheral, Malaise, Chest pain, taste disturbance	Oedema, Chills, Influenza like illness, Rigors, Body temperature increased, fibrosis	Difficulty in walking, thirst, chest mass, collapse, sedation

**Based on the post-marketing experience, persistent or severe palmar-plantar erythrodysaesthesia syndrome can eventually lead to loss of fingerprints.

Capecitabine in Combination Therapy

Table 5 lists ADRs associated with the use of capecitabine in combination with different chemotherapy regimens in multiple indications based on safety data from over 3000 patients. ADRs are added to the appropriate frequency grouping (Very common or Common) according to the highest incidence seen in any of the major clinical trials and are 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. 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 can not be excluded.

Body System	Very common All grades	Common All grades	Uncommon/Rare/Very Rare (Post-Marketing Experience)
Infections and infestations	-	Herpes zoster, Urinary tract infection, Oral candidiasis, Upper respiratory tract infection , Rhinitis, Influenza, +Infection, Oral herpes	Neutropenic sepsis, agranulocytosis
Blood and lymphatic system disorders	+Neutropenia, +Leucopenia, +Anaemia, +Neutropenic fever, Thrombocytopenia, lymphocytopenia	Bone marrow depression, +Febrile Neutropenia
Immune system disorders	-	Hypersensitivity
Metabolism and nutrition disorders	Appetite decreased	Hypokalaemia, Hyponatraemia, Hypomagnesaemia, Hypocalcaemia, hypercalcemia, Hyperglycaemia
Psychiatric disorders	-	Sleep disorder, Anxiety
Nervous system disorders	Paraesthesia, Dysaesthesia, Peripheral neuropathy, Peripheral sensory neuropathy, Dysgeusia, Headache	Neurotoxicity, Tremor, Neuralgia, Hypersensitivity reaction, Hypoaesthesia	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
Vascular disorders	Lower limb oedema, Hypertension, +Embolism and thrombosis	Flushing, Hypotension, Hypertensive crisis, Hot flush, Phlebitis, lymphoedema	Venous phlebitis, postural hypotension
Respiratory, thoracic and mediastinal system disorders	Sore throat, Dysaesthesia pharynx	Hiccups, Pharyngolaryngeal pain, Dysphonia, pleural effusion
Gastrointestinal disorders	Constipation, Dyspepsia	Upper gastrointestinal haemorrhage, Mouth ulceration, Gastritis, Abdominal distension, Gastroesophageal reflux disease, Oral pain, Dysphagia, Rectal haemorrhage, Abdominal pain lower, Oral dysaesthesia, Paraesthesia oral, Hypoaesthesia oral, Abdominal discomfort	Necrotizing enterocolitis, hemorrhagic diarrhea
Hepatobiliary disorders	-	Hepatic function abnormal	Hepatic coma, hepatotoxicity
Skin and subcutaneous tissue disorders	Alopecia, Nail disorder	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	Acute renal failure secondary to dehydration (rare)
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

⁺ For each term, the frequency count was based on ADRs of all grades. For terms marked with a “+”, the frequency count was based on grade 3-4 ADRs. ADRs are added according to the highest incidence seen in any of the major combination trials.

Description of Selected Adverse Reactions

Hand-Foot Syndrome

For the capecitabine dose of 1250 mg/m² twice daily on days 1 to 14 every 3 weeks, a frequency of 53% to 60% of all-grades HFS 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 1000 mg/m² twice daily on days 1 to 14 every 3 weeks, a frequency of 22% to 30% of all-grade HFS was observed in capecitabine combination therapy.

A meta-analysis of 14 clinical trials with data from over 4700 patients treated with capecitabine monotherapy or capecitabine in combination with different chemotherapy regimens in multiple indications (colon, colorectal, gastric and breast cancer) showed that HFS (all grades) occurred in 2066 (43%) patients after a median time of 239 [95% CI 201, 288] days after starting treatment with capecitabine. In all studies combined, the following covariates were statistically significantly associated with an increased risk of developing HFS: increasing capecitabine starting dose (gram), decreasing cumulative capecitabine dose (0.1*kg), increasing relative dose intensity in the first six 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 4700 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 (gram), 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 six 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 7 clinical trials including 949 patients (2 phase III and 5 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 7 clinical trials, encephalopathy was also associated with the use of capecitabine monotherapy with an incidence of less than 0.1%.

Exposure To Crushed Or Cut Capecitabine Tablets

In the instance of exposure to crushed or cut capecitabine tablets, the following adverse drug reactions have been reported: eye irritation, eye swelling, skin rash, headache, paresthesia, diarrhea, nausea, gastric irritation, and vomiting.

Special Populations

Elderly Patients

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 4700 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 HFS 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 4700 patients treated with capecitabine showed that in all studies combined, female gender was statistically significantly associated with an increased risk of developing HFS and diarrhoea and with a decreased risk of developing neutropenia.

Patients with Renal Impairment

An analysis of 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, vs. 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%) vs. 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) vs. 5% and 8% in patients with no or mild renal impairment.

Reporting of Suspected Adverse Reactions

If you experience any side effects, talk to your doctor or pharmacist, or write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 18002677779 (Cipla Number) or you can report to PvPI on 1800 180 3024.

By reporting side effects, you can help provide more information on the safety of this product.

6.9 Overdose

The manifestations of acute overdose would include nausea, vomiting, diarrhoea, mucositis, 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.

Single doses of capecitabine were not lethal to mice, rats, and monkeys at doses up to 2000 mg/kg

7. Pharmacological Properties

7.1 Mechanism of Action

Enzymes convert capecitabine to 5-fluorouracil (5-FU) in vivo. Both normal and tumor 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. First, FdUMP and the folate cofactor, N^5-10 -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. Second, 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.

7.2 Pharmacodynamic Properties

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.

There is evidence that the metabolism of 5-FU in the anabolic pathway blocks the methylation reaction of deoxyuridylic acid to thymidylic acid, thereby interfering with the synthesis of deoxyribonucleic acid (DNA). The incorporation of 5-FU also leads to inhibition of RNA 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.

7.3 Pharmacokinetic Properties

Absorption

Following oral administration to cancer patients, capecitabine reached peak blood levels in about 1.5 hours (T_max), 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 C_max and AUC_0-∞ decreased by 60% and 35%, respectively. The C_max and AUC_0-∞ of 5-FU were also reduced by food by 43% and 21%, respectively. Food delayed the T_max of both the parent drug and 5-FU by 1.5 hours.

The pharmacokinetics of capecitabine and its metabolites have been evaluated in about 200 cancer patients over a dosage range of 500 to 3500 mg/m /day. Over this range, the pharmacokinetics of capecitabine and its metabolite, 5'-DFCR were dose proportional and did not change over time. The increases in the AUCs of 5'-DFUR and 5-FU, however, were greater than proportional to the increase in dose and the AUC of 5-FU was 34% higher on day 14 than on day 1. The interpatient variability in the C and AUC of 5-FU was greater than 85%.

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.

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 (t_1/2 in hours) of capecitabine and 5-FU was about 0.75 hour

Combination Therapy

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.

Pharmacokinetics in Special Populations

Gender, 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 (white/Caucasian patients, black patients, and patients of other 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.

Following oral administration of 825 mg/m² capecitabine twice daily for 14 days, the Japanese patients had about 36% lower C_max and 24% lower AUC for capecitabine than the Caucasian patients. The Japanese patients also had about 25% lower C_max 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 AUC_0-∞ and C_max of capecitabine increased by 60% in patients with hepatic dysfunction compared to patients with normal hepatic function. The AUC_0-∞ and C_max 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 <30 mL/min) renal impairment showed 85% and 258% higher systemic exposure, respectively, to FBAL on day 1 compared to normal renal function patients (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. 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.

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 C_max 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 (C_max and AUC) and docetaxel has no effect on the pharmacokinetics of capecitabine and the 5-FU precursor, 5'-DFUR.

Effect of Allopurinol on Capecitabine

Published literature reported that concomitant use with allopurinol may decrease conversion of capecitabine to the active metabolites, FdUMP and FUTP; however, the clinical significance was not fully characterized.

8. Non-clinical Properties

8.1 Animal Toxicology or Pharmacology

Carcinogenesis, Mutagenesis, Impairment of Fertility and Preclinical Safety Data

Adequate studies investigating the carcinogenic potential of capecitabine have not been conducted. Capecitabine was not mutagenic in vitro to bacteria (Ames test) or mammalian cells (Chinese hamster V79/HPRT gene mutation assay). Capecitabine was clastogenic in vitro to human peripheral blood lymphocytes but not clastogenic in vivo to mouse bone marrow (micronucleus test). Fluorouracil causes mutations in bacteria and yeast. Fluorouracil also causes chromosomal abnormalities in the mouse micronucleus test in vivo.

In studies of fertility and general reproductive performance in female mice, oral capecitabine doses of 760 mg/kg/day (about 2300 mg/m²/day) disturbed estrus and consequently caused a decrease in fertility. In mice that became pregnant, no fetuses survived this dose. The disturbance in estrus was reversible. In males, this dose caused degenerative changes in the testes, including decreases in the number of spermatocytes and spermatids. In separate pharmacokinetic studies, this dose in mice roduced 5'-DFUR AUC values about 0.7 times the corresponding values in patients administered the recommended daily dose.

A two-year mouse carcinogenicity study produced no evidence of carcinogenicity by capecitabine.

In embryotoxicity and teratogenicity studies in mice, dose-related increases in foetal resorption and teratogenicity were observed. In monkeys, abortion and embryolethality were observed at high doses, but there was no evidence of teratogenicity.

In repeat-dose toxicity studies, daily oral administration of capecitabine to cynomolgus monkeys and mice produced toxic effects on the gastrointestinal, lymphoid and haemopoietic systems, typical for fluoropyrimidines. These toxicities were reversible. Skin toxicity, characterised by degenerative/regressive changes, was observed with capecitabine. Capecitabine was devoid of hepatic and CNS toxicities. Cardiovascular toxicity (e.g. PR- and QT-interval prolongation) was detectable in cynomolgus monkeys after intravenous administration (100 mg/kg) but not after repeated oral dosing (1379 mg/m²/day).

9. Description

Capecitabine is a fluoropyrimidine carbamate with antineoplastic activity. It is an orally administered systemic prodrug of 5'-deoxy-5-fluorouridine (5'-DFUR) which is converted to 5-fluorouracil.

The chemical name for capecitabine is 5'-deoxy-5-fluoro-N-[(pentyloxy) carbonyl]-cytidine and has a molecular weight of 359.35. Capecitabine has the following structural formula:

10. Pharmaceutical Particulars

10.1 Incompatibilities

Not applicable

10.2 Shelf-Life

2 years

10.3 Packaging Information

CAPEGARD 500 Tablets..................... Blister pack of 10 tablets

10.4 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. Procedures for the proper handling and disposal of anticancer drugs should be considered.

11. Patient counselling Information

1 What Capecitabine is and what it is used for

Capecitabine belongs to the group of medicines called “cytostatic medicines”, which stop the growth of cancer cells. Capecitabine contains capecitabine, which itself is not a cytostatic medicine. Only after being absorbed by the body it is changed into an active anti-cancer medicine (more in tumour tissue than in normal tissue).

Capecitabine is used in the treatment of colon, rectal, gastric, or breast cancers.

Furthermore, Capecitabine is used to prevent new occurrence of colon cancer after complete removal of the tumour by surgery.

Capecitabine may be used either alone or in combination with other medicines.

2. What you need to know before you take Capecitabine

Do not Take Capecitabine:

• if you are allergic to capecitabine or any of the other ingredients of this medicine. You must inform your doctor if you know that you have an allergy or over-reaction to this medicine,
• if you previously have had severe reactions to fluoropyrimidine therapy (a group of anticancer medicines such as fluorouracil),
• if you are pregnant or breastfeeding,
• if you have severely low levels of white cells or platelets in the blood (leucopenia, neutropenia or thrombocytopenia),
• if you have severe liver or kidney problems,
• if you know that you do not have any activity of the enzyme dihydropyrimidine dehydrogenase (DPD) (complete DPD deficiency),
• if you are being treated now or have been treated in the last 4 weeks with brivudine as part of herpes zoster (chickenpox or shingles) therapy.

Warnings and Precautions

Talk to your doctor or pharmacist before taking Capecitabine

• if you know that you have a partial deficiency in the activity of the enzyme dihydropyrimidine dehydrogenase (DPD)
• if you have a family member who has partial or complete deficiency of the enzyme dihydropyrimidine dehydrogenase (DPD)
• if you have liver or kidney diseases
• if you have or had heart problems (for example an irregular heartbeat or pains to the chest, jaw and back brought on by physical effort and due to problems with the blood flow to the heart)
• if you have brain diseases (for example, cancer that has spread to the brain, or nerve damage (neuropathy)
• if you have calcium imbalances (seen in blood tests)
• if you have diabetes
• if you cannot keep food or water in your body because of severe nausea and vomiting
• if you have diarrhoea
• if you are or become dehydrated
• if you have imbalances of ions in your blood (electrolyte imbalances, seen in tests)
• if you have a history of eye problems as you may need extra monitoring of your eyes
• if you have a severe skin reaction.

DPD Deficiency

DPD deficiency is a genetic condition that is not usually associated with health problems unless you receive certain medicines. If you have DPD deficiency and take Capecitabine, you are at an increased risk of severe side effects (listed under section 4 Possible side effects). It is recommended to test you for DPD deficiency before start of treatment. If you have no activity of the enzyme you should not take Capecitabine. If you have a reduced enzyme activity (partial deficiency) your doctor might prescribe a reduced dose. If you have negative test results for DPD deficiency, severe and life-threatening side effects may still occur.

Children and Adolescents

Capecitabine is not indicated in children and adolescents. Do not give Capecitabine to children and adolescents.

Other Medicines and Capecitabine

Before starting treatment, tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This is extremely important, as taking more than one medicine at the same time can strengthen or weaken the effect of the medicines.

You must not take brivudine (an anti-viral medicines for treatment of shingles or chickenpox) at the same time as capecitabine treatment (including during any rest periods when you are not taking any capecitabine tablets).

If you have taken brivudine you must wait for at least 4 weeks after stoping brivudine before starting to take capecitabine.

Also, you need to be particularly careful if you are taking any of the following:

• gout medicines (allopurinol),
• blood-thinning medicines (coumarin, warfarin),
• medicines for seizures or tremors (phenytoin),
• interferon alpha
• radiotherapy and certain medicines used to treat cancer (folinic acid, oxaliplatin, bevacizumab, cisplatin, irinotecan)
• medicines used to treat folic acid deficiency

Capecitabine with Food and Drink

You should take Capecitabine no later than 30 minutes after meals.

Pregnancy and Breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. You must not take Capecitabine if you are pregnant or think you might be.

You must not breast-feed if you are taking Capecitabine and for 2 weeks after the last dose. If you are a woman who could become pregnant you should use effective contraception during treatment with Capecitabine and for 6 months after the last dose. If you are a male patient and your female partner could become pregnant, you should use effective contraception during treatment with Capecitabine and for 3 months after the last dose.

Driving and Using Machines

Capecitabine may make you feel dizzy, nauseous or tired. It is therefore possible that Capecitabine could affect your ability to drive a car or operate machines.

Capecitabine Contains Anhydrous Lactose

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

3. How to Take Capecitabine

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

Capecitabine should only be prescribed by a doctor experienced in the use of anticancer medicines.

Your doctor will prescribe a dose and treatment regimen that is right for you. The dose of Capecitabine is based on your body surface area. This is calculated from your height and weight. The usual dose for adults is 1250 mg/m² of body surface area taken two times daily (morning and evening).

Your doctor will tell you what dose you need to take, when to take it and for how long you need to take it.

• Take the tablets morning and evening as prescribed by your doctor.
• Take the tablets within 30 minutes after the end of a meal (breakfast and dinner) and swallow whole with water. Do not crush or cut tablets. If you cannot swallow Capecitabine tablets whole, tell your healthcare provider.
• It is important that you take all your medicine as prescribed by your doctor.

Capecitabine tablets are usually taken for 14 days followed by a 7 day rest period (when no tablets are taken). This 21 day period is one treatment cycle.

In combination with other medicines the usual dose for adults may be less than 1250 mg/m² of body surface area, and you may need to take the tablets over a different time period (e.g. every day, with no rest period).

If You Take More Capecitabine than You Should

If you take more Capecitabine than you should, contact your doctor as soon as possible before taking the next dose.

You might get the following side effects if you take a lot more capecitabine than you should: feeling or being sick, diarrhoea, inflammation or ulceration of the gut or mouth, pain or bleeding from the intestine or stomach, or bone marrow depression (reduction in certain kinds of blood cells). Tell your doctor immediately if you experience any of these symptoms.

If You Forget to Take Capecitabine

Do not take the missed dose at all. Do not take a double dose to make up for a forgotten dose. Instead, continue your regular dosing schedule and check with your doctor.

If You Stop Taking Capecitabine

Although there are no side effects caused by stopping treatment with capecitabine, you should not stop taking these tablets or change the dose, unless your doctor has told you to. If you are taking coumarin anticoagulants (containing e.g. phenprocoumon), your doctor will need to check your dose of this medicine and change it if necessary when you stop taking capecitabine.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible Side Effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

STOP taking Capecitabine immediately and contact your doctor if any of these symptoms occur:

• Diarrhoea: if you have an increase of 4 or more bowel movements compared to your normal bowel movements each day or any diarrhoea at night.
• Vomiting: if you vomit more than once in a 24-hour time period.
• Nausea: if you lose your appetite, and the amount of food you eat each day is much less than usual.
• Stomatitis: if you have pain, redness, swelling or sores in your mouth and/or throat.
• Hand-and-foot skin-reaction: if you have pain, swelling, redness or tingling of hands and/or feet.
• Fever: if you have a temperature of 38°C or greater.
• Infection: if you experience signs of infection caused by bacteria or virus, or other organisms.
• Chest pain: if you experience pain localised to the centre of the chest, especially if it occurs during exercise.
• Steven-Johnson syndrome: if you experience painful red or purplish rash that spreads and blisters and/or other lesions begin to appear in the mucous membrane (e.g. mouth and lips), in particular if you had before light sensitivity, infections of the respiratory system (e.g. bronchitis) and/or fever.
• Angioedema: Seek medical attention straight away if you notice any of the following symptoms you may need urgent medical treatment: swelling mainly of the face, lips, tongue or throat which makes it difficult to swallow or breathe, itching and rashes. This could be a sign of angioedema.

If caught early, these side effects usually improve within 2 to 3 days after treatment discontinuation. If these side effects continue, however, contact your doctor immediately. Your doctor may instruct you to restart treatment at a lower dose.

If severe stomatitis (sores in your mouth and/or throat), mucosal inflammation, diarrhoea, neutropenia (increased risk for infections), or neurotoxicity occurs during the first cycle of treatment, a DPD deficiency may be involved (see Section 2: Warning and precautions).

Hand and foot skin-reaction can lead to loss of fingerprint, which could impact your identification by fingerprint scan.

In addition to the above, when capecitabine is used alone, very common side effects, which may affect more than 1 in 10 people are:

• abdominal pain
• rash, dry or itchy skin
• tiredness
• loss of appetite (anorexia)

These side effects can become severe; therefore, it is important that you always contact your doctor immediately when you start to experience a side effect. Your doctor may instruct you to decrease the dose and/or temporarily discontinue treatment with Capecitabine. This will help reduce the likelihood that the side effect continues or becomes severe.

Other side effects are:

Common side effects (may affect up to 1 in 10 people) include:

• decreases in the number of white blood cells or red blood cells (seen in tests)
• dehydration, weight loss
• sleeplessness (insomnia), depression
• headache, sleepiness, dizziness, abnormal sensation in the skin (numbness or tingling sensation), taste changes
• eye irritation, increased tears, eye redness (conjunctivitis)
• inflammation of the veins (thrombophlebitis)
• shortness of breath, nose bleeds, cough, runny nose
• cold sores or other herpes infections
• infections of the lungs or respiratory system (e.g. pneumonia or bronchitis)
• bleeding from the gut, constipation, pain in upper abdomen, indigestion, excess wind, dry mouth
• skin rash, hair loss (alopecia), skin reddening, dry skin, itching (pruritus), skin discolouration, skin loss, skin inflammation, nail disorder
• pain in the joints, or in the limbs (extremities), chest or back
• fever, swelling in the limbs, feeling ill
• problems with liver function (seen in blood tests) and increased blood bilirubin (excreted by the liver)

Uncommon side effects (may affect up to 1 in 100 people) include:

• blood infection, urinary tract infection, infection of the skin, infections in the nose and throat, fungal infections (including those of the mouth), influenza, gastroenteritis, tooth abscess
• lumps under the skin (lipoma)
• decreases in blood cells including platelets, thinning of blood (seen in tests)
• allergy
• diabetes, decrease in blood potassium, malnutrition, increased blood triglycerides
• confusional state, panic attacks, depressed mood, decreased libido
• difficulty speaking, impaired memory, loss of movement coordination, balance disorder, fainting, nerve damage (neuropathy) and problems with sensation
• blurred or double vision
• vertigo, ear pain
• irregular heartbeat and palpitations (arrhythmias), chest pain and heart attack (infarction)
• blood clots in the deep veins, high or low blood pressure, hot flushes, cold limbs (extremities), purple spots on the skin
• blood clots in the veins in the lung (pulmonary embolism), collapsed lung, coughing up blood, asthma, shortness of breath on exertion
• bowel obstruction, collection of fluid in the abdomen, inflammation of the small or large intestine, the stomach or the oesophagus, pain in the lower abdomen, abdominal discomfort, heartburn (reflux of food from the stomach), blood in the stool
• jaundice (yellowing of skin and eyes)
• skin ulcer and blister, reaction of the skin with sunlight, reddening of palms, swelling or pain of the face
• joint swelling or stiffness, bone pain, muscle weakness or stiffness
• fluid collection in the kidneys, increased frequency of urination during the night, incontinence, blood in the urine, increase in blood creatinine (sign of kidney dysfunction)
• unusual bleeding from the vagina
• swelling (oedema), chills and rigors

Some of these side effects are more common when capecitabine is used with other medicines for the treatment of cancer. Other side-effects seen in this setting are the following:

Common side effects (may affect up to 1 in 10 people) include:

• Decrease in blood sodium, magnesium or calcium, increase in blood sugar
• nerve pain
• ringing or buzzing in the ears (tinnitus), loss of hearing
• vein inflammation
• hiccups, change in voice
• pain or altered/abnormal sensation in the mouth, pain in the jaw
• sweating, night sweats
• muscle spasm
• difficulty in urination, blood or protein in the urine
• bruising or reaction at the injection site (caused by medicines given by injection at the same time)

Rare side effects (may affect up to 1 in 1,000 people) include:

• narrowing or blockage of tear duct (lacrimal duct stenosis)
• liver failure
• inflammation leading to dysfunction or obstruction in bile secretion (cholestatic hepatitis)
• specific changes in the electrocardiogram (QT prolongation)
• certain types of arrhythmia (including ventricular fibrillation, torsade de pointes, and bradycardia)
• eye inflammation causing eye pain and possibly eyesight problems
• inflammation of the skin causing red scaly patches due to an immune system illness
• angioedema (swelling mainly of the face, lip, tongue or throat, itching and rashes)

Very rare side effects (may affect up to 1 in 10,000 people) include:

• severe skin reaction such as skin rash, ulceration and blistering which may involve ulcers of the mouth, nose, genitalia, hands, feet and eyes (red and swollen eyes).

Reporting of Side Effects

If you experience any side effects, talk to your doctor or pharmacist, or write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 18002677779 (Cipla Number) or you can report to PvPI on 1800 180 3024.

By reporting side effects, you can help provide more information on the safety of this product.

5. How to Store Capecitabine

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. Procedures for the proper handling and disposal of anticancer drugs should be considered.

12. Details of Manufacturer

Mfd. by CIPLA LTD.

Registered Office: Cipla House, Peninsula Business Park, Ganpatrao Kadam Marg,

Lower Parel, Mumbai - 400 013, INDIA

13. Details of Permission or License Number with Date

789/(70)/MFG/DFDA/2010/11088 dated 14.01.2011

14. Date of Revision

20/06/2022