Capecitabine


Concise Prescribing Info
Indications/Uses
Listed in Dosage.
Dosage/Direction for Use
Adult : PO Adjuvant therapy in stage III colon cancer; Metastatic colorectal cancer As monotherapy: Initial: 1,250 mg/m2 bid for 14 days followed by 7 days rest period. As combination: Initial: 800-1,000 mg/m2 bid for 14 days followed by 7 days rest period. Alternatively, 625 mg/m2 bid given continuously. Treatment duration for adjuvant therapy in stage III colon cancer: 6 months. Metastatic breast cancer; Locally advanced breast cancer As monotherapy or in combination with docetaxel: Initial: 1,250 mg/m2 bid for 14 days followed by 7 days rest period. Gastric cancer In combination with platinum-based regimen: Initial: 800-1,000 mg/m2 bid for 14 days followed by 7 days rest period. Alternatively, 625 mg/m2 bid given continuously.
Dosage Details
Oral
Adjuvant therapy in stage III colon cancer, Metastatic colorectal cancer
Adult: As monotherapy: Initially, 1,250 mg/m2 bid for 14 days followed by 7 days rest period. As combination therapy: Initially, 800-1,000 mg/m2 bid for 14 days followed by 7 days rest period. Alternatively, 625 mg/m2 bid given continuously. Treatment duration for adjuvant therapy in stage III colon cancer: 6 months. Dose reduction, dosing interruption, or discontinuation may be required according to individual safety and tolerability (refer to detailed product guideline).

Oral
Locally advanced breast cancer, Metastatic breast cancer
Adult: As monotherapy or in combination with docetaxel: Initially, 1,250 mg/m2 bid for 14 days followed by 7 days rest period. Dose reduction, dosing interruption, or discontinuation may be required according to individual safety and tolerability (refer to detailed product guideline).

Oral
Gastric cancer
Adult: In combination with platinum-based regimen: Initially, 800-1,000 mg/m2 bid for 14 days followed by 7 days rest period. Alternatively, 625 mg/m2 bid given continuously. Dose reduction, dosing interruption, or discontinuation may be required according to individual safety and tolerability (refer to detailed product guideline).
Special Patient Group
Pharmacogenomics:

Capecitabine is a prodrug that is enzymatically converted to its active form, fluorouracil, an antimetabolite that slows tumour growth. DPYD gene encodes dihydropyrimidine dehydrogenase (DPD), an enzyme that catalyses the rate-limiting step in fluorouracil metabolism. The prevalence of DPD deficiency in Caucasians is approx 3-5%. Individuals who are carriers of non-functional DPYD variants (e.g. DPYD*2A) may not be able to metabolise capecitabine at normal rates and are at risk of potentially life-threatening capecitabine toxicity such as bone marrow suppression and neurotoxicity.

The DPD genotype is assigned using a gene activity score, calculated as the sum of the activity scores of the 2 DPYD variants with the lowest variant activity score. Generally, carriers of 2 no function variant are considered DPYD poor metabolisers (Activity score 0); carriers of 1 no function or decreased function variant are considered DPYD intermediate metabolisers (Activity score 1 or 1.5); those with only normal function variants are classified as DPYD normal metabolisers (Activity score 2).

Recommendation of Capecitabine by DPD phenotype based on 2017 Update Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline:

DPYD normal metabolisers (Activity score 2)
Carriers of 2 normal functional alleles (e.g. c.[5];[5], c.[85T>C];[5], c.[1627A>G];[5]) exhibits normal DPD activity and “normal” risk of fluoropyrimidine toxicity. No dosage adjustment needed.

DPYD intermediate metabolisers (Activity score 1 or 1.5)
Carriers of 1 normal function allele and 1 no function allele or 1 decreased function allele; or carriers of 2 decreased function alleles (e.g. c.[190511G>A];[5], c.[1679T>G];[5], c.[2846A>T];[5]; c.[1129–5923C>G];[5]d; c.[1129–5923C>G];[1129 5923C>G]d; c.[2846A>T];[2846A>T]) have reduced DPD activity and increased risk for severe or fatal toxicities. Reduce initial dose according to activity score followed by titration of dose based on toxicity or therapeutic drug monitoring. Activity score 1: Reduce dose by 50%. Activity score 1.5: Reduce dose by 25-50%.

DPYD poor metabolisers (Activity score 0 or 0.5)
Carriers of 2 no function alleles or carrier of 1 no function and 1 decreased function allele e.g. c.[190511G>A];[190511G>A], c.[1679T>G];[1679T>G], c.[190511G>A];[2846A>T] c.[190511G>A]; [1129-5923C>G] have complete DPD deficiency and increased risk of severe or fatal toxicities. Activity score 0.5: Avoid use of 5-fluorouracil or 5-fluorouracil pro-drug regimens and consider a suitable alternative. If alternative is not possible, administer at strongly reduced dose with early therapeutic drug monitoring. Activity score 0: Avoid use of 5-fluorouracil or 5-fluorouracil pro-drug regimens.

Recommendation for Capecitabine based on November 2018 Update Royal Dutch Pharmacists Association - Pharmacogenetics Working Group (DPWG) Guideline:

DPYD Activity Score 0
Genetic variation increases the risk of severe, life-threatening toxicity. A reduced conversion of capecitabine to inactive metabolites means that the standard dose is a more than 100-fold overdose. Use an alternative drug; if not possible, determine the residual DPD activity in mononuclear cells from peripheral blood and adjust the initial dose accordingly, or adjust the initial dose based on efficacy and toxicity.

DPYD Activity Score 0.5
Genetic variation increases the risk of severe, life-threatening toxicity. A decreased conversion of capecitabine to inactive metabolites means that the normal dose is an overdose. Start with 25% of the standard dose or use an alternative. Initial dose adjustment should be based on toxicity and effectiveness. Tegafur is not an alternative, as it is also metabolised by DPD.

DPYD Activity Score 1
Genetic variation increases the risk of severe, life-threatening toxicity. A reduced conversion of capecitabine to inactive metabolites means that the normal dose is an overdose. Start with 50% of the standard dose or use an alternative. Initial dose adjustment should be based on toxicity and effectiveness. Tegafur is not an alternative, as it is also metabolised by DPD.

DPYD Activity Score 1.5
Genetic variation increases the risk of severe, life-threatening toxicity. A reduced conversion of capecitabine to inactive metabolites means that the normal dose is an overdose. Start with 75% of the standard dose or use an alternative. Initial dose adjustment should be based on toxicity and effectiveness. Tegafur is not an alternative, as it is also metabolised by DPD.
Renal Impairment
 Adjuvant therapy in stage III colon cancer; Metastatic colorectal cancer; Metastatic breast cancer; Advanced or locally advanced breast cancer
 CrCl (mL/min) Dosage
<30 Contraindicated.
30-50 Reduce initial dose of 1,250 mg/m2 to 75% (approx 950 mg/m2).

Gastric cancer
 CrCl (mL/min) Dosage 
 <30  Contraindicated.
Hepatic Impairment
Severe: Contraindicated.
Administration
Should be taken with food. Take w/in 30 min after meals.
Contraindications
Known complete absence of dihydropyrimidine dehydrogenase (DPD) activity; severe leucopenia, neutropenia or thrombocytopenia. Severe renal (CrCl <30 mL/min) and hepatic impairment. Pregnancy and lactation. Concomitant use with brivudine and oral coumarin-derivative anticoagulants (e.g. warfarin, phenprocoumon); if concomitant use with coumarin anticoagulants cannot be avoided, closely monitor INR and prothrombin time with great frequency and adjust anticoagulant dose accordingly.
Special Precautions
Patient with severe diarrhoea, dehydration, electrolyte disturbance, history of coronary artery disease, central or peripheral nervous system disease (e.g. neuropathy, brain metastases), hyperbilirubinaemia, diabetes, pre-existing hypo- or hypercalcaemia. Patient with low DPD activity. Mild to moderate renal and hepatic impairment.
Adverse Reactions
Significant: Hand-and-foot syndrome/palmar-plantar erythrodysaesthesia syndrome, bone marrow suppression (e.g. neutropenia, anaemia), hepatotoxicity (e.g. elevated levels of transaminase, alkaline phosphatase and bilirubin), hypo- or hypercalcaemia.
Cardiac disorders: Chest pain.
Eye disorders: Increased lacrimation, conjunctivitis, eye irritation.
Gastrointestinal disorders: Diarrhoea, vomiting, nausea, stomatitis, abdominal pain, gastrointestinal haemorrhage, constipation, dyspepsia, flatulence, dry mouth, decreased appetite.
General disorders and administration site conditions: Fatigue, asthenia, pyrexia, peripheral oedema, malaise.
Hepatobiliary disorders: Hyperbilirubinemia, LFT abnormalities.
Infections and infestations: Herpes.
Metabolism and nutrition disorders: Dehydration, decreased weight.
Musculoskeletal and connective tissue disorders: Pain in extremity, back pain, arthralgia.
Nervous system disorders: Headache, lethargy, dizziness, paresthesia, dysgeusia.
Psychiatric disorders: Insomnia, depression.
Respiratory, thoracic and mediastinal disorders: Nasopharyngitis, lower respiratory tract infection, dyspnea, epistaxis, cough, rhinorrhea.
Skin and subcutaneous tissue disorders: Alopecia, rash, erythema, dry skin, pruritus, skin hyperpigmentation, macular rash, skin desquamation, dermatitis, pigmentation disorder, nail disorder.
Vascular disorders: Thrombophlebitis.
Potentially Fatal: Stevens-Johnson, toxic epidermal necrolysis, cardiotoxicity (e.g. myocardial infarction, ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, ECG changes, cardiomyopathy), gastrointestinal toxicity (e.g. severe diarrhoea, dehydration).
Patient Counseling Information
This drug may cause dizziness and fatigue, if affected, do not drive or operate machinery.
MonitoringParameters
Monitor hepatic, renal, and cardiac functions. Frequent monitoring of INR or prothrombin time in patients taking concomitant oral coumarin-derivative anticoagulant therapy.
Overdosage
Symptoms: Nausea, vomiting, diarrhoea, mucositis, gastrointestinal irritation and bleeding, and bone marrow depression. Management: Symptomatic and supportive treatment.
Drug Interactions
May increase phenytoin plasma concentration and toxicity. Al- and Mg-containing antacids may slightly increase capecitabine concentration. Allopurinol may decrease the concentration of capecitabine. Decreased Max tolerated dose with folinic acid and interferon-α.
Potentially Fatal: May alter coagulation parameters and cause bleeding when given with oral coumarin-derivative anticoagulants (e.g. warfarin, phenprocoumon). Increased toxicity with brivudine.
Food Interaction
Food reduces the rate and extent of absorption of capecitabine.
Action
Description: Capecitabine is a prodrug of fluorouracil, a pyrimidine antimetabolite, which is metabolised into 5-fluoro-2'-deoxyuridine-5'monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). FdUMP covalently binds to thymidylate synthase, inhibiting the formation of thymidilate, thus interfering with DNA synthesis. Additionally, FUTP interferes with RNA processing and protein synthesis.
Pharmacokinetics:
Absorption: Rapidly and extensively absorbed. Food reduces rate and extent of absorption. Time to peak plasma concentration: Approx 1.5 hours.
Distribution: Plasma protein binding: <60% (approx 35% to albumin).
Metabolism: Enzymatically metabolised to fluorouracil which is further metabolised to active metabolites 5-fluoroxyuridine monophosphate (F-UMP) and F-dUMP.
Excretion: Mainly via urine (96%, 57% as α-fluoro-ß-alanine; <3% as unchanged drug), as faeces (<3%). Elimination half-life: Approx 0.75 hour.
Chemical Structure

Click on icon to see table/diagram/image
Storage
Store below 30°C. This is a cytotoxic drug. Follow applicable procedures for receiving, handling, administration, and disposal.
ATC Classification
L01BC06 - capecitabine ; Belongs to the class of antimetabolites, pyrimidine analogues. Used in the treatment of cancer.
Disclaimer: This information is independently developed by MIMS based on Capecitabine from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2020 MIMS. All rights reserved. Powered by MIMS.com
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