Capecitabine

Capecitabine is a fluoropyrimidine carbamate that is not cytotoxic itself. Taken by mouth, it is absorbed intact and converted in several enzymatic steps to the cytotoxic antimetabolite fluorouracil (5-FU). The last step is carried out by thymidine phosphorylase, which is found in tumour tissue and, usually at lower levels, in normal tissue, so 5-FU is generated preferentially in the tumour. The medicine was designed to give 5-FU exposure that resembles an infusion, without the need for a central venous line or a pump.

Mechanism of Action

• Activation in three steps: hepatic carboxylesterase converts capecitabine to 5’-deoxy-5-fluorocytidine (5’-DFCR); cytidine deaminase, mainly in the liver and in tumour tissue, converts this to 5’-deoxy-5-fluorouridine (5’-DFUR); thymidine phosphorylase then releases 5-FU.
• Higher levels in tumour: in patients with colorectal cancer, the 5-FU concentration ratio was 3.2 between tumour and adjacent tissue and 21.4 between tumour and plasma. In colorectal tumours, 5-FU generation appears to take place largely in tumour stromal cells.
• Thymidylate synthase: an active metabolite of 5-FU (FdUMP) binds thymidylate synthase together with a folate cofactor and blocks the conversion of deoxyuridylic acid to thymidylic acid. The resulting thymidine deficiency disturbs DNA synthesis and repair and leads to unbalanced growth and cell death.
• RNA and protein synthesis: incorporation of 5-FU also inhibits RNA and protein synthesis.
• Rapidly dividing cells: the effects of DNA and RNA deprivation are greatest in cells that divide quickly and that metabolise 5-FU quickly.
• Docetaxel: in human cancer xenograft models, capecitabine acted synergistically with docetaxel, which may be related to docetaxel increasing thymidine phosphorylase.
• Breakdown of 5-FU: dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the breakdown of 5-FU, so DPD deficiency leads to higher exposure and toxicity (see Special Instructions).

Pharmacokinetics

• Absorption: capecitabine is rapidly and extensively absorbed and then extensively converted to 5’-DFCR and 5’-DFUR. Food slows the rate of absorption of capecitabine but has only a minor effect on the AUC of 5’-DFUR and of 5-FU, which is why the tablets are taken after a meal. After 1,250 mg/m² on day 14, peak plasma concentrations of capecitabine and 5-FU were reached after about 1.5 and 2 hours. The AUC of 5-FU was 30–35% higher on day 14 than on day 1, and lowering the dose reduces 5-FU exposure more than proportionally because the pharmacokinetics of the active metabolite are not linear.
• Distribution: in laboratory studies, 54% of capecitabine, 10% of 5’-DFCR, 62% of 5’-DFUR and 10% of 5-FU are bound to plasma proteins, mainly albumin.
• Metabolism: the activation steps are described above. 5-FU is then broken down by DPD to 5-fluoro-5,6-dihydro-fluorouracil, then through 5-fluoro-ureido-propionic acid to α-fluoro-β-alanine (FBAL).
• Elimination: the elimination half-lives of capecitabine and 5-FU are about 0.75 hour. After a radiolabelled dose, about 96% was recovered in urine (about 3% as unchanged capecitabine and 57% as FBAL) and about 2.6% in faeces.
• Special populations: because DPD clears 5-FU, DPD deficiency is the most important cause of severe toxicity (see Special Instructions). Dose recommendations for renal and hepatic impairment and for older patients are given under Administration and Dosage.

Capecitabine is indicated for:

• Colon cancer, adjuvant treatment: patients after surgery for stage III (Dukes’ stage C) colon cancer.
• Metastatic colorectal cancer.
• Advanced gastric cancer: first-line treatment, in combination with a platinum-based regimen.
• Breast cancer, with docetaxel: locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy; previous therapy should have included an anthracycline.
• Breast cancer, as monotherapy: locally advanced or metastatic breast cancer after failure of taxanes and an anthracycline-containing chemotherapy regimen, or when further anthracycline therapy is not indicated.

• A history of severe and unexpected reactions to fluoropyrimidine therapy.
• Hypersensitivity to capecitabine, to fluorouracil or to any of the excipients.
• Known complete dihydropyrimidine dehydrogenase (DPD) deficiency.
• Pregnancy and breastfeeding.
• Severe leukopenia, neutropenia or thrombocytopenia.
• Severe hepatic impairment.
• Severe renal impairment (creatinine clearance below 30 mL/min).
• Recent or concomitant treatment with brivudine.
• Any contraindication to a medicine in the combination regimen: that medicine must not be used.

The safety profile is based on data from more than 3,000 patients treated with capecitabine alone or with other chemotherapy in several indications; the monotherapy profiles in metastatic breast cancer, metastatic colorectal cancer and adjuvant colon cancer are comparable. The most commonly reported or clinically important treatment-related reactions are gastrointestinal disorders (especially diarrhoea, nausea, vomiting, abdominal pain and stomatitis), hand-foot syndrome (palmar-plantar erythrodysaesthesia), fatigue, asthenia, anorexia, cardiotoxicity, worsening kidney function in patients with pre-existing renal impairment, and thrombosis or embolism.

The frequencies below are for capecitabine monotherapy, based on pooled data from three studies with over 1,900 patients. Reactions added by combination regimens, which have their own table in the SmPC, are summarised after the monotherapy list. In the Uncommon group the SmPC lists reactions that are serious or life-threatening (grade 3 or 4) or considered medically relevant.

Very common (≥1/10): anorexia; diarrhoea, vomiting, nausea, stomatitis, abdominal pain; palmar-plantar erythrodysaesthesia (hand-foot syndrome); fatigue, asthenia.

Common (≥1/100 to <1/10): herpes viral infection, nasopharyngitis, lower respiratory tract infection; neutropenia, anaemia; dehydration, weight loss; insomnia, depression; headache, lethargy, dizziness, paraesthesia, dysgeusia; increased lacrimation, conjunctivitis, eye irritation; thrombophlebitis; dyspnoea, epistaxis, cough, rhinorrhoea; gastrointestinal haemorrhage, constipation, upper abdominal pain, dyspepsia, flatulence, dry mouth; hyperbilirubinaemia, abnormal liver function tests; rash, alopecia, erythema, dry skin, pruritus, skin hyperpigmentation, macular rash, skin desquamation, dermatitis, pigmentation disorder, nail disorder; pain in extremity, back pain, arthralgia; pyrexia, peripheral oedema, malaise, chest pain.

Uncommon (≥1/1,000 to <1/100): sepsis, urinary tract infection, cellulitis, tonsillitis, pharyngitis, oral candidiasis, influenza, gastroenteritis, fungal infection, infection, dental abscess; lipoma; febrile neutropenia, pancytopenia, granulocytopenia, thrombocytopenia, leukopenia, haemolytic anaemia, increased INR or prolonged prothrombin time; hypersensitivity; diabetes, hypokalaemia, appetite disorder, malnutrition, hypertriglyceridaemia; confusional state, panic attack, depressed mood, decreased libido; aphasia, memory impairment, ataxia, syncope, balance disorder, sensory disorder, peripheral neuropathy; reduced visual acuity, diplopia; vertigo, ear pain; unstable angina, angina pectoris, myocardial ischaemia or infarction, atrial fibrillation, arrhythmia, tachycardia, sinus tachycardia, palpitations; deep vein thrombosis, hypertension, hypotension, petechiae, hot flush, peripheral coldness; pulmonary embolism, pneumothorax, haemoptysis, asthma, exertional dyspnoea; intestinal obstruction, ascites, enteritis, gastritis, dysphagia, lower abdominal pain, oesophagitis, abdominal discomfort, gastro-oesophageal reflux disease, colitis, blood in stool; jaundice; skin blisters, skin ulcer, urticaria, photosensitivity reaction, palmar erythema, facial swelling, purpura, radiation recall syndrome; joint swelling, bone pain, facial pain, musculoskeletal stiffness, muscular weakness; hydronephrosis, urinary incontinence, haematuria, nocturia, increased blood creatinine; vaginal haemorrhage; oedema, chills, influenza-like illness, rigors, raised body temperature.

Rare (≥1/10,000 to <1/1,000), from post-marketing experience: angioedema; lacrimal duct stenosis, corneal disorders, keratitis and punctate keratitis; ventricular fibrillation, QT prolongation, torsade de pointes, bradycardia, vasospasm; hepatic failure, cholestatic hepatitis; cutaneous lupus erythematosus. Toxic leukoencephalopathy and severe skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis are very rare (fewer than 1 in 10,000).

Added by combination regimens: the SmPC’s second table, based on over 3,000 patients, lists reactions seen with capecitabine plus other chemotherapy in addition to the monotherapy profile, or in a higher frequency group than with monotherapy. Some are typical of the partner medicine (for example peripheral sensory neuropathy with docetaxel or oxaliplatin, hypertension with bevacizumab), although capecitabine may add to them. Uncommon reactions in combination match those of monotherapy or of the partner medicine. For neutropenia, leukopenia, anaemia, neutropenic fever, embolism and thrombosis and lethargy (very common) and for infection, febrile neutropenia and fever (common), the SmPC counts grade 3 or 4 reactions only.

Very common in combination (≥1/10): neutropenia, leukopenia, anaemia, neutropenic fever, thrombocytopenia; decreased appetite; paraesthesia, dysaesthesia, peripheral neuropathy, peripheral sensory neuropathy, dysgeusia, headache; increased lacrimation; lower limb oedema, hypertension, embolism and thrombosis; sore throat, pharyngeal dysaesthesia; constipation, dyspepsia; alopecia, nail disorder; myalgia, arthralgia, pain in extremity; pyrexia, weakness, lethargy, temperature intolerance.

Common in combination (≥1/100 to <1/10), in brief: infections (herpes zoster, urinary and upper respiratory tract infection, oral candidiasis, rhinitis, influenza, oral herpes), bone marrow depression, febrile neutropenia; hypersensitivity; hypokalaemia, hyponatraemia, hypomagnesaemia, hypocalcaemia, hyperglycaemia; sleep disorder, anxiety; neurotoxicity, tremor, neuralgia, hypoaesthesia; visual disorders, dry eye, eye pain, blurred vision, tinnitus, hypoacusis; atrial fibrillation, cardiac ischaemia or infarction; flushing, hypotension, hypertensive crisis, hot flush, phlebitis; hiccups, pharyngolaryngeal pain, dysphonia; upper gastrointestinal and rectal haemorrhage, mouth ulceration, gastritis, abdominal distension or discomfort, gastro-oesophageal reflux disease, dysphagia, oral pain and sensory changes; abnormal liver function; hyperhidrosis, erythematous rash, urticaria, night sweats; jaw pain, muscle spasms, trismus, muscular weakness; haematuria, proteinuria, reduced creatinine clearance, dysuria; mucosal inflammation, pain, chills, chest pain, influenza-like illness, fever, infusion-related and injection site reactions; contusion.

Rare in combination (≥1/10,000 to <1/1,000), from post-marketing experience: acute renal failure secondary to dehydration.

Important serious reactions: the dose-limiting toxicities are diarrhoea, abdominal pain, nausea, stomatitis and hand-foot syndrome, and most reactions are reversible. Serious problems to watch for include severe diarrhoea with dehydration and acute renal failure, severe hand-foot syndrome, cardiotoxicity (myocardial infarction, angina, arrhythmias, cardiogenic shock, sudden death), severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis) and, in patients with DPD deficiency, life-threatening or fatal toxicity.

Interaction studies have been performed only in adults.

• Brivudine (contraindicated): brivudine inhibits DPD, which increases fluoropyrimidine toxicity; the interaction is potentially fatal. Brivudine must not be given with capecitabine, and at least 4 weeks must pass between the end of brivudine and the start of capecitabine (see Special Instructions).
• Coumarin-derivative anticoagulants (warfarin, phenprocoumon): altered coagulation values and bleeding have been reported, from a few days to several months after starting capecitabine and, in a few cases, within a month after stopping it. After a single 20 mg dose of warfarin, capecitabine raised the AUC of S-warfarin by 57% and the INR by 91%, probably through inhibition of CYP2C9. Monitor INR or prothrombin time closely and adjust the anticoagulant dose.
• CYP2C9 substrates (for example phenytoin): apart from warfarin, no formal interaction studies were done; take care when combining.
• Phenytoin: raised phenytoin levels with signs of phenytoin toxicity have been reported in single cases; check phenytoin concentrations regularly.
• Folinic acid and folic acid: folinic acid does not change the pharmacokinetics of capecitabine but can increase its toxicity (maximum tolerated dose on the intermittent regimen 3,000 mg/m² per day alone, 2,000 mg/m² per day with oral folinic acid 30 mg twice daily); this may matter when switching from a 5-FU/folinic acid regimen to capecitabine, and possibly with folic acid supplements for folate deficiency.
• Antacids (aluminium hydroxide and magnesium hydroxide): a small rise in plasma levels of capecitabine and of 5’-DFCR, with no effect on 5’-DFUR, 5-FU or FBAL.
• Allopurinol: it has interacted with 5-FU, possibly lowering its efficacy; avoid using it with capecitabine.
• Interferon alfa: the maximum tolerated dose of capecitabine was 2,000 mg/m² per day with interferon alfa-2a (3 MIU/m² per day), against 3,000 mg/m² per day alone.
• Radiotherapy: with radiotherapy for rectal cancer the maximum tolerated dose of capecitabine was 2,000 mg/m² per day (continuous, or daily Monday to Friday over a 6-week course), against 3,000 mg/m² per day alone on the intermittent regimen.
• Oxaliplatin and bevacizumab: no clinically significant difference in exposure to capecitabine or its metabolites, or to free and total platinum, with oxaliplatin alone or with bevacizumab; bevacizumab did not change capecitabine pharmacokinetics in the presence of oxaliplatin.
• Cisplatin and vitamin B6: when capecitabine is given with cisplatin, vitamin B6 (pyridoxine) is not advised for treating or preventing hand-foot syndrome, because reports suggest it may reduce the efficacy of cisplatin.
• Nephrotoxic medicines: dehydration caused by capecitabine can lead to acute renal failure, particularly when nephrotoxic medicines are taken at the same time.
• Food: tablets are taken within 30 minutes after a meal. Food slows the rate of absorption but has only a minor effect on exposure to the active metabolites.
• Other medicines: dose modifications for combination partners follow their own SmPCs.

Capecitabine should be prescribed only by a qualified physician experienced in anti-cancer medicines, and all patients need careful monitoring during the first cycle. The tablets are swallowed whole with water within 30 minutes after a meal, in the morning and in the evening, and must not be crushed or cut. Treatment is stopped for progressive disease or intolerable toxicity. Testing for DPD deficiency before the first dose is recommended (see Special Instructions).

Recommended Dose

The dose is calculated from body surface area. The SmPC gives tables for starting doses of 1,250 mg/m² and 1,000 mg/m², with the number of 150 mg and 500 mg tablets for each body surface area band.

• Monotherapy (adjuvant colon cancer, metastatic colorectal cancer, locally advanced or metastatic breast cancer): 1,250 mg/m² twice daily (morning and evening; 2,500 mg/m² per day) for 14 days, followed by a 7-day rest period. Adjuvant treatment of stage III colon cancer lasts 6 months in total.
• Combination therapy in colon, colorectal and gastric cancer: the starting dose is reduced to 800–1,000 mg/m² twice daily for 14 days followed by a 7-day rest period, or to 625 mg/m² twice daily when given continuously. With irinotecan, the starting dose is 800 mg/m² twice daily for 14 days followed by a 7-day rest period, combined with irinotecan 200 mg/m² on day 1. Adding bevacizumab does not change the capecitabine starting dose. Adjuvant treatment of stage III colon cancer lasts 6 months.
• Premedication in these combinations: hydration and antiemetic premedication as in the cisplatin SmPC before cisplatin; antiemetic premedication as in the oxaliplatin SmPC for the oxaliplatin combination.
• Combination with docetaxel in breast cancer: capecitabine 1,250 mg/m² twice daily for 14 days followed by a 7-day rest period, with docetaxel 75 mg/m² as a 1-hour intravenous infusion every 3 weeks. An oral corticosteroid such as dexamethasone is given before docetaxel, as in the docetaxel SmPC.

Dose Adjustments for Toxicity

• General rules: toxicity may be managed with symptomatic treatment and/or by interrupting or reducing the dose. Once the dose has been reduced, it should not be increased later. Toxicities unlikely to become serious or life-threatening, such as alopecia, altered taste and nail changes, can be treated without reducing or interrupting the dose. Patients should be told to interrupt treatment immediately if moderate or severe toxicity occurs.
• Grade 1 toxicity: maintain the dose level.
• Grade 2 toxicity: at the first appearance, interrupt until it resolves to grade 0–1, then resume at 100% of the starting dose; second appearance, 75%; third appearance, 50%; fourth appearance, stop permanently.
• Grade 3 toxicity: at the first appearance, interrupt until it resolves to grade 0–1, then resume at 75% of the starting dose; second appearance, 50%; third appearance, stop permanently.
• Grade 4 toxicity: at the first appearance, stop permanently or, if the physician judges that continuing is in the patient’s best interest, interrupt until grade 0–1 and resume at 50% of the starting dose; at the second appearance, stop permanently.
• Grading: toxicity is graded with the NCIC CTG Common Toxicity Criteria or the CTCAE. For hand-foot syndrome and hyperbilirubinaemia, see Special Instructions.
• Blood counts: patients with a baseline neutrophil count below 1.5 × 10⁹/L and/or a platelet count below 100 × 10⁹/L should not be treated. If the neutrophil count falls below 1.0 × 10⁹/L or the platelet count below 75 × 10⁹/L during a cycle, treatment is interrupted.
• Omitted doses: doses omitted because of toxicity are not replaced.
• Combination regimens: dose changes for capecitabine follow the steps above and those for the other medicine follow its own SmPC. If a delay is indicated at the start of a cycle for either medicine, all therapy is delayed until the requirements for restarting every medicine are met. If a toxicity is judged unrelated to capecitabine, capecitabine continues and the other medicine is adjusted. If the other medicine is permanently stopped, capecitabine can be resumed once its restart requirements are met. This applies to all indications and special populations.
• Partial DPD deficiency: a reduced starting dose should be considered (see Special Instructions).

Special Populations

• Elderly: no adjustment of the starting dose is needed with capecitabine alone, but grade 3 or 4 treatment-related reactions were more frequent in patients aged 60 or over. In combination with other medicines, patients aged 65 or over had more grade 3 and 4 reactions, including some leading to discontinuation. Careful monitoring of patients aged 60 or over is advisable. With docetaxel, patients aged 60 or over start at 75% of the dose (950 mg/m² twice daily); if no toxicity occurs, the dose may be cautiously raised to 1,250 mg/m² twice daily.
• Renal impairment: contraindicated in severe impairment (creatinine clearance below 30 mL/min by Cockcroft–Gault at baseline). In moderate impairment (30–50 mL/min), grade 3 or 4 reactions are more frequent: a starting dose of 1,250 mg/m² is reduced to 75%, while a starting dose of 1,000 mg/m² needs no reduction. In mild impairment (51–80 mL/min), no adjustment is recommended. Careful monitoring and prompt interruption are advised for any grade 2, 3 or 4 event, and treatment is stopped if creatinine clearance falls below 30 mL/min. This applies to monotherapy and combinations.
• Hepatic impairment: there are not enough data to recommend a dose adjustment, and no information in impairment due to cirrhosis or hepatitis. Mild to moderate liver dysfunction needs careful monitoring; severe impairment is a contraindication.
• Children and adolescents: there is no relevant use of capecitabine in children for colon, colorectal, gastric or breast cancer.

DPD Deficiency and Testing Before Treatment

• Why it matters: DPD activity is rate-limiting in the breakdown of 5-FU. Patients with DPD deficiency are at increased risk of fluoropyrimidine toxicity, for example stomatitis, diarrhoea, mucosal inflammation, neutropenia and neurotoxicity. This toxicity usually appears during the first cycle or after a dose increase.
• Testing: phenotype and/or genotype testing before starting capecitabine is recommended, despite uncertainty about the best testing methods. Applicable clinical guidelines should be considered.
• Complete DPD deficiency (rare, 0.01–0.5% of Caucasians): these patients are at high risk of life-threatening or fatal toxicity and must not be treated with capecitabine.
• Partial DPD deficiency (estimated 3–9% of the Caucasian population): increased risk of severe and potentially life-threatening toxicity. A reduced starting dose should be considered, with DPD status weighed together with other routine measures for dose reduction. An initial reduction may affect efficacy; if there is no serious toxicity, later doses may be increased with careful monitoring.
• Genotype testing: four DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T and c.1236G>A/HapB3) can cause complete absence or reduction of DPD activity, and other rare variants may also raise the risk of severe toxicity. Certain homozygous and compound heterozygous combinations, for example the four variants with at least one c.1905+1G>A or c.1679T>G allele, cause complete or near-complete absence of activity. Heterozygous carriers have an increased risk of severe toxicity. In Caucasian patients the heterozygous frequencies are about 1% for c.1905+1G>A, 1.1% for c.2846A>T, 2.6–6.3% for c.1236G>A/HapB3 and 0.07–0.1% for c.1679T>G. Data in other populations are limited, and the four variants are considered virtually absent in people of African (-American) or Asian origin.
• Phenotype testing: measuring the pre-treatment blood (plasma) level of uracil, the natural DPD substrate, is recommended. A level of 16 ng/mL or more but below 150 ng/mL suggests partial deficiency; 150 ng/mL or more suggests complete deficiency. Impaired kidney function can raise uracil and lead to misdiagnosis of DPD deficiency in moderate renal impairment, so levels should be interpreted with caution there.

Brivudine: Never Combine

• Brivudine must not be given together with capecitabine, and recent treatment with brivudine is a contraindication. Fatal cases of this interaction have been reported.
• There must be at least 4 weeks between the end of brivudine and the start of capecitabine. Brivudine can be started 24 hours after the last dose of capecitabine.
• If brivudine is given by accident to a patient taking capecitabine, effective measures should be taken to reduce capecitabine toxicity, immediate admission to hospital is recommended, and all measures should be started to prevent systemic infections and dehydration.

Diarrhoea and Dehydration

Severe diarrhoea needs careful monitoring and fluid and electrolyte replacement if the patient becomes dehydrated; standard antidiarrhoeal treatment such as loperamide may be used. Grade 2 diarrhoea means 4 to 6 stools a day or nocturnal stools; grade 3 means 7 to 9 stools a day or incontinence and malabsorption; grade 4 means 10 or more stools a day, grossly bloody diarrhoea or the need for parenteral support. Dehydration should be prevented or corrected from the start: patients with anorexia, asthenia, nausea, vomiting or diarrhoea can become dehydrated quickly, and dehydration can cause acute renal failure that may be fatal, especially with pre-existing renal impairment or nephrotoxic medicines. If grade 2 or higher dehydration occurs, interrupt capecitabine at once and correct it; restart only when the patient is rehydrated and the causes are corrected or controlled.

Hand-Foot Syndrome

Grade 1 is numbness, tingling or painless swelling or redness of the hands or feet that does not disrupt normal activities. Grade 2 is painful redness and swelling or discomfort that affects daily living. Grade 3 is moist desquamation, ulceration, blistering and severe pain that prevent work or daily activities. Persistent or severe hand-foot syndrome (grade 2 and above) can eventually lead to loss of fingerprints, which could affect identification. For grade 2 or 3, interrupt capecitabine until the event resolves or falls to grade 1; after grade 3, later doses are reduced. With cisplatin, vitamin B6 is not advised (see Drug Interactions). There is some evidence that dexpanthenol helps prevent hand-foot syndrome in patients taking Xeloda.

Heart, Calcium, Nervous System and Diabetes

• Cardiotoxicity: fluoropyrimidines are associated with myocardial infarction, angina, arrhythmias, cardiogenic shock, sudden death and ECG changes (including very rare QT prolongation), which may be more common with a history of coronary artery disease. Arrhythmias (including ventricular fibrillation, torsade de pointes and bradycardia), angina, myocardial infarction, heart failure and cardiomyopathy have been reported with capecitabine. Caution in significant cardiac disease, arrhythmias and angina.
• Calcium: hypocalcaemia and hypercalcaemia have been reported; caution if either is already present.
• Nervous system disease: caution in central or peripheral nervous system disease, for example brain metastases or neuropathy.
• Diabetes and electrolytes: caution in diabetes mellitus or electrolyte disturbances, which may be aggravated.

Liver and Kidney Function

• Liver: because safety and efficacy data are lacking, capecitabine must be carefully monitored in mild to moderate liver dysfunction, with or without liver metastases. Interrupt if treatment-related bilirubin rises above 3.0 times the upper limit of normal or treatment-related ALT or AST rises above 2.5 times the upper limit. Capecitabine monotherapy may be resumed when bilirubin falls to 3.0 times the upper limit or below, or the aminotransferases fall to 2.5 times the upper limit or below.
• Kidney: grade 3 or 4 reactions are more frequent in moderate renal impairment (creatinine clearance 30–50 mL/min); severe impairment is a contraindication.

Anticoagulant Monitoring

Patients taking capecitabine with an oral coumarin-derivative anticoagulant need close monitoring of INR or prothrombin time and dose adjustment of the anticoagulant (see Drug Interactions).

Eyes and Severe Skin Reactions

• Eyes: monitor for keratitis and corneal disorders, especially with a history of eye disorders, and treat as clinically appropriate.
• Skin: capecitabine can cause severe skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. It must be stopped permanently if a severe skin reaction occurs.

Handling of Tablets

Tablets must not be crushed or cut. Adverse reactions could occur if a patient or caregiver is exposed to crushed or cut tablets.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: contraindicated. There are no studies in pregnant women, but capecitabine should be assumed to cause foetal harm; animal studies showed embryolethality and teratogenicity, which are expected effects of fluoropyrimidines.
• Contraception: women of childbearing potential should avoid becoming pregnant, and if pregnancy occurs the potential hazard to the foetus must be explained. Effective contraception is needed during treatment and for 6 months after the last dose. Men with female partners of reproductive potential should use effective contraception during treatment and for 3 months after the last dose, based on genetic toxicity findings.
• Breastfeeding: contraindicated. It is not known whether capecitabine passes into breast milk; considerable amounts of capecitabine and its metabolites were found in the milk of lactating mice. Breastfeeding should be stopped during treatment and for 2 weeks after the last dose.
• Fertility: the SmPC states that there are no data on the effect of Xeloda on fertility.

Lactose and Sodium

Each 150 mg tablet contains 15.6 mg and each 500 mg tablet 52 mg of anhydrous lactose. Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine. Each tablet contains less than 1 mmol (23 mg) of sodium, that is, it is essentially sodium-free.

Effect on Driving

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

Do not store above 30 °C. Keep the tablets in the original package to protect them from moisture, and out of the sight and reach of children. Xeloda is supplied in PVC/PVDC blisters: 60 tablets of 150 mg (6 blisters of 10) or 120 tablets of 500 mg (12 blisters of 10).

3 years. Do not use after the expiry date on the pack.

Prescription only (Rx), under restricted medical prescription (Annex II B), on the prescription of a qualified physician experienced in anti-neoplastic medicines. Capecitabine tablets are taken at home, so they are supplied to the patient or to the treating clinic on prescription. Two points matter before supply: the SmPC recommends phenotype and/or genotype testing for DPD deficiency before treatment starts, and brivudine must not be taken at the same time as, or within 4 weeks before, capecitabine. Xeloda is the originator brand; Ecansya is a generic marketed by Krka under its own name. The details on this page follow the Xeloda SmPC, and the product information of each generic governs its own strengths, pack sizes and excipients.