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Les traitements par chimiothérapie et autres traitements systémiques pourraient être modifiés en raison de la COVID-19. Vous trouverez de plus amples renseignements à la page Traitements systémiques pendant la pandémie de la COVID-19.

Certaines de ces informations ou toutes, dans certains cas, n’apparaissent qu’en Anglais. Vous pouvez demander la version française

A - Drug Name

capecitabine

COMMON TRADE NAME(S):   Xeloda®

 
B - Mechanism of Action and Pharmacokinetics

Capecitabine is an antimetabolite, belonging to the fluoropyrimidine carbamate class. A prodrug of 5-fluorouracil (5FU), capecitabine is converted to its two active metabolites, 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP) by carboxyesterase, cytidine deaminase and thymidine phosphorylase (present in the liver and in tumours). The cytotoxic effect of capecitabine is produced by inhibition of thymidylate formation, essential for DNA synthesis, and inhibiting RNA and protein synthesis.



Absorption
Bioavailability

Rapid and extensive. Cmax 1.5 hours.

Effects with food Rate and extent of absorption reduced by food.
Time to reach steady state

14 days.


Distribution

Widely distributed.

Cross blood brain barrier? Not known
PPB < 60%; primarily albumin (35%)
Metabolism

Capecitabine is extensively bioactivated and metabolized in the liver

Active metabolites

Yes (FdUMP and FUTP and others)

Inactive metabolites Yes
Elimination
Urine

95.5%; 3% unchanged

Feces

2.6%

Half-life

terminal: 45 minutes

 
C - Indications and Status
Health Canada Approvals:

  • First-line treatment metastatic colorectal cancer (monotherapy)

  • For the adjuvant treatment of patients with stage III (Dukes' stage C) colon cancer (monotherapy)

  • In combination with oxaliplatin for the treatment of metastatic colorectal cancer after failure of irinotecan-containing combination chemotherapy

  • Advanced or metastatic breast cancer after failure of standard therapy (including a taxane), unless therapy with a taxane is clinically contraindicated (monotherapy)

  • In combination with docetaxel for advanced or metastatic breast cancer after failure of anthracycline-containing chemotherapy



Other Uses:

  • GI cancers (anal, rectal, small bowel, appendiceal, gastric, pancreatic, biliary tract)

  • GI neuroendocrine tumours

  • Adrenal, renal cell cancer

  • Cancer of unknown primary

  • Head and neck cancer

 
D - Adverse Effects

Emetogenic Potential:  

Low – No routine prophylaxis; PRN recommended

Extravasation Potential:   Not applicable

The following table contains adverse effects reported in ≥ 5% of patients with colon cancer in the adjuvant setting receiving capecitabine as monotherapy. Severe adverse events from other studies or post-marketing may also be included.

ORGAN SITE SIDE EFFECT* (%) ONSET**
Cardiovascular Arterial thromboembolism (rare) E
Cardiotoxicity (<5%) (maybe severe) E
Venous thromboembolism (rare) E
Dermatological Alopecia (6%) E
Palmar-plantar erythrodysesthesia syndrome (PPES) (60%) (maybe severe) E
Rash (6%) (maybe severe) E
Gastrointestinal Abdominal pain (10%) E
Anorexia, weight loss (9%) E
Constipation (6%) E
Dehydration (4%) E
Diarrhea (46%) (maybe severe) D
Dyspepsia (5%) E
GI obstruction (<5%) E
GI perforation (rare) E
Mucositis (22%) E
Nausea, vomiting (33%) E
General Fatigue (15%) E
Hematological Idiopathic thrombocytopenic purpura (rare) E
Myelosuppression ± infection, bleeding (2%) (maybe severe, including atypical infection) E
Hepatobiliary ↑ Bilirubin (19%) (grade 3/4)
Hepatic failure (<1%) E
Hypersensitivity Hypersensitivity (<1%) I
Nervous System Dizziness (5%) (including vertigo) E
Dysgeusia (6%) E
Leukoencephalopathy (very rare) E
Neuropathy (9%) E
Ophthalmic Conjunctivitis (5%) D
Eye disorders (cataract, lacrimal duct stenosis, keratitis - rare) D
Renal Nephrotoxicity (<1%) D


* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.

** I = immediate (onset in hours to days)     E = early (days to weeks)
D = delayed (weeks to months)      L = late (months to years)

The most common side effects for capecitabine include hand-foot syndrome, diarrhea, nausea, vomiting, mucositis, ↑ bilirubin, fatigue, abdominal pain, anorexia, weight loss, neuropathy and alopecia.

Patients with very low or absent dihydropyrimidine dehydrogenase (DPD) deficiency (rate-limiting enzyme of 5-fluorouracil catabolism) are at increased risk of severe or life-threatening toxicity (i.e. neutropenia, GI and neurotoxicity, including fatalities) and should not receive capecitabine.

Cardiac toxicity is similar to that reported for other fluorinated pyrimidines and includes myocardial infarction, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, ECG changes, and cardiomyopathy. Patients with prior coronary artery disease may be at increased risk.

Dehydration has been observed and may cause acute renal failure which can be fatal. Patients with preexisting renal dysfunction, concomitant use of nephrotoxic drugs, and risk factors such as anorexia, nausea, vomiting, or diarrhea are at an increased risk.

The median time to onset of diarrhea is 34 days. The diarrhea may respond to standard anti-diarrheal therapy (e.g. loperamide). Patients with severe diarrhea should be closely monitored and given fluid and electrolyte replacement for dehydration as indicated.

Palmar-plantar erythrodysesthesia (commonly referred to as hand-foot syndrome) is characterized by numbness, dysesthesia or paresthesia, tingling, painless or painful swelling, erythema, desquamation, blistering, and severe pain of the hands and/or feet and is more common in patients also receiving docetaxel. Persistent or severe (grade 2 or higher) hand-foot syndrome may lead to loss of fingerprints, which could impact identification. The median time to onset was 79 days. Dose interruption, subsequent dose reduction and topical emollients (e.g. hand creams, udder balm) may ameliorate the manifestations of hand-foot syndrome. Oral pyridoxine may not be effective in ameliorating hand-foot syndrome in patients receiving capecitabine.

Severe rashes have been reported (Stevens-Johnson syndrome, Toxic Epidermal Necrolysis). Capecitabine must be permanently discontinued and the patient treated appropriately.

Hyperbilirubinemia has been observed in patients with and without hepatic metastases at baseline, though occurring more frequently in patients with hepatic metastases. The median time to onset for grade 3 or 4 hyperbilirubinemia was 64 days. Transaminase and alkaline phosphatase elevations have also been reported

Very rare cases of leukoencephalopathy have been reported.

 
E - Dosing

Refer to protocol by which patient is being treated.

Use with extreme caution in patients with partial DPD deficiency; reduce the initial dose substantially, monitor frequently and adjust the dose for toxicity as recommended in the dosage with toxicity section.  In patients with unrecognized DPD deficiency, acute, life-threatening toxicity may occur; discontinue if acute grade 2-4 toxicity develops.



Adults:

Doses are given orally approximately 12 hours apart, within 30 minutes after the end of a meal.


Oral: 1250 mg/m² BID for 14 days

(Total daily dose 2500 mg/m2)


Refer to CAPEDOCE and XELOX regimen monographs for capecitabine dosing in combination with docetaxel or oxaliplatin.


Dose Calculation According to Body Surface Area

Dose level 1250mg/m2 PER DOSE (2500mg/m2/day):

 

1250 mg/m2 PER DOSE

Number of tablets to be taken at each dose 

Surface Area (m2)

Dose (mg)*

150mg

500mg

1.26

1500

0

3

1.27 – 1.38

1650

1

3

1.39 – 1.52

1800

2

3

1.53 – 1.66

2000

0

4

1.67 – 1.78

2150

1

4

1.79 – 1.92

2300

2

4

1.93 – 2.06

2500

0

5

2.07 – 2.18

2650

1

5

> 2.19 

2800

2

5

*given twice daily

 

 

Dose level 1000mg/m2 PER DOSE (2000mg/m2/day):

 

1000 mg/m2 PER DOSE

Number of tablets to be taken at each dose 

Surface Area (m2)

Dose (mg)*

150mg

500mg

1.26

1150

1

2

1.27 – 1.38

1300

2

2

1.39 – 1.52

1450

3

2

1.53 – 1.66

1600

4

2

1.67 – 1.78

1750

5

2

1.79 – 1.92

1800

2

3

1.93 – 2.06

2000

0

4

2.07 – 2.18

2150

1

4

> 2.19 

2300

2

4

 *given twice daily




Dosage with Toxicity:

Patients with baseline neutrophil counts of <1.5 x 109/L and/or thrombocyte counts of <100 x 109/L should not receive capecitabine therapy

 

Dose Modification Guidelines for monotherapy:

Patients should be informed of the need to interrupt treatment immediately if moderate or severe toxicity occurs. Supportive care should be provided, including loperamide for diarrhea. 

Doses should not be re-escalated if reduced for toxicity.  Missed or omitted doses of capecitabine should not be replaced.

Dose modifications are mandatory for gastrointestinal, dermatological toxicity, neurotoxicity and hyperbilirubinemia.  Practitioner may elect not to reduce dose for other toxicities unlikely to become serious or life-threatening.


Non-hematologic Toxicity:

 
Toxicity

Action During a Course of Therapy

Dose Adjustment for Next Cycle  

(% of starting dose)

 
Grade 1
 
 
Maintain dose level
 
Maintain dose level
 
Grade 2

1st appearance

2nd appearance

3rd appearance

4th appearance

 
 
 

Hold until resolved to ≤ grade 1

Hold until resolved to ≤ grade 1

Hold until resolved to ≤ grade 1

Discontinue treatment permanently

 
 

100%

75%

50%

Not applicable

 
Grade 3

1st appearance

2nd appearance

3rd appearance, OR any evidence of Stevens-Johnson syndrome or Toxic epidermal necrolysis

 
 

Hold until resolved to ≤ grade 1

Hold until resolved to ≤ grade 1

Discontinue treatment permanently

 
 

75%

50%

Not applicable

 
Grade 4
 
1st appearance, including SJS or TEN, OR cardiotoxicity OR
acute renal failure
 
 
 
 
 
 

 

2nd appearance OR any occurrence of confirmed leukoencephalopathy
 
 
 
Discontinue permanently
                 OR
If physician deems it to be in the patient’s best interest to continue and no evidence of Stevens-Johnson syndrome or toxic epidermal necrolysis, interrupt until resolved to ≤ grade 1.
 
 
 
 

 Discontinue permanently

 
 
 
Discontinue
OR
50%

 

 

 

 

 

Not applicable

 

 

Hematologic Toxicity:

Hold capecitabine during a treatment cycle in the presence of grade 3 or 4 hematologic toxicity.

 

Dose modifications for toxicity for combination regimens:

Refer to the CAPEDOCE and XELOX regimen monographs for capecitabine dose modifications in combination use.

For indicated combinations:

  • If a treatment delay is indicated for either agent, then administration of both capecitabine and the other chemotherapy drug should be delayed until the requirement for starting both drugs are met.

  • During a treatment cycle, if the toxicities are considered by the physician as unrelated to capecitabine, capecitabine may be continued and the dose of the other agent adjusted according to its product monograph.

  • If the other agent needs to be discontinued permanently, capecitabine treatment can be resumed when the requirements for restarting capecitabine are met.



Dosage with Hepatic Impairment:

Hepatic impairment Capecitabine Dose
Mild to moderate impairment No starting dose adjustment necessary
Severe No data, has not been studied


Dosage with Renal Impairment:

Moderate renal impairment results in an increase in severe toxicity.

Creatinine Clearance (mL/min)

% of Starting Dose

51 - 80

100 % with close monitoring

30 - 50

75 % (use with caution)

<30

discontinue 

 

 



Dosage in the elderly:

No dose adjustment for the starting dose is required but patients should be closely monitored. Older patients (≥ 65 years) are more susceptible to the effects of fluoropyrimidine-based therapies with increased grade 3/4 adverse effects, especially when used in combination.



Children:

Safety and efficacy not established.



 
F - Administration Guidelines
  • Oral self-administration; drug available by outpatient prescription.

  • Doses are given orally approximately 12 hours apart, within 30 minutes after the end of a meal.

  • Swallow tablets whole; do not crush or cut tablets.

  • If a capecitabine dose is missed, skip this and give the next dose at the usual time. Missed or omitted doses should not be replaced.

  • Store tablets at 15ºC to 30ºC in the original package.

 
G - Special Precautions
Contraindications:

  • Patients who have a known hypersensitivity to capecitabine, its excipients, 5FU or any ingredient in the formulation or component of the container.

  • Patients with severe renal impairment (CrCl <30 mL/min).

  • Patients with known near or complete absence of DPD (dihydropyrimidine dehydrogenase) activity.

  • Concomitant use with sorivudine or related analogues (i.e. brivudine), given potential fatal drug interaction.

Other Warnings/Precautions:

  • Contains lactose and should not be used in patients with hereditary galactose/glucose/lactase disorders.

  • Use with caution in patients with risk factors for dehydration, pre-existing renal dysfunction or on nephrotoxic agents.

  • Use with caution in patients with a history of cardiovascular disease as well as patients taking anticoagulants such as warfarin.

  • Patients with partial DPD deficiency - use with extreme caution.


Other Drug Properties:

  • Carcinogenicity: Probable

    The long-term carcinogenic potential of capecitabine has not been studied, although 5FU has potential carcinogenic and mutagenic effects.

Pregnancy and Lactation:
  • Teratogenicity: Yes

    Observed in animal studies.

  • Embryotoxicity: Yes

    Observed in animal studies.

    Capecitabine is not recommended for use in pregnancy.  Adequate contraception should be used by both sexes during treatment, and for at least 6 months after the last dose.

  • Excretion into breast milk: Probable
    Observed in animal studies.
  • Breastfeeding:

    Not recommended.

    Due to the potential for serious adverse reactions in the breastfed infant, breast-feeding is not recommended during treatment and for 2 weeks after the last dose.

  • Fertility effects: Probable
 
H - Interactions

Capecitabine is converted to active 5-FU by the enzyme DPD. The drug likely inhibits CYP2C9, resulting in possible drug interactions with CYP2C9 substrates.

AGENT EFFECT MECHANISM MANAGEMENT
sorivudine and chemically related analogues (i.e. brivudine) ↑ capecitabine toxicity; potentially fatal Inhibition of DPD by sorivudine Concomitant use is contraindicated; wait at least 4 weeks after sorivudine (or analogues) treatment before starting capecitabine
Phenytoin/Fosphenytoin and CYP 2C9 substrates ↑ phenytoin levels Capecitabine may inhibit CYP2C9 Monitor phenytoin levels; avoid concomitant administration
Warfarin Abnormal INR/PT bleeding; may occur at anytime Capecitabine may inhibit CYP2C9; ↑ s-warfarin exposure by 57% Caution; monitor PT and INR and adjust anticoagulant dose accordingly
Proton-pump inhibitors ↓ capecitabine efficacy (secondary analysis of RCT data showed reduced survival with concurrent use of PPIs) ↓ capecitabine dissolution and/or absorption Caution and monitor for reduced effectiveness. Consider switching to an antacid
Antacids containing aluminum or magnesium hydroxide small ↑ in plasma concentration of capecitabine ↑ rate and extent of absorption Caution (clinical relevance unknown)
Leucovorin ↑ capecitabine toxicity Potentiates cytotoxicity without increase in efficacy Caution and monitor
 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

Monitor Type Monitor Frequency

CBC

Baseline and at each visit

Renal function tests

Baseline and as clinically indicated

INR and/or PT

Baseline and as clinically indicated if patient is on anticoagulants

Clinical toxicity assessment for diarrhea, dehydration, infection, stomatitis, rash or hand-foot syndrome, cardiac, hepatic and neurotoxicity

At each visit

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

 



Suggested Clinical Monitoring

Monitor Type Monitor Frequency

Liver function tests

Baseline and as clinically indicated (if severe organ failure suspected)
 
J - Supplementary Public Funding

ODB - General Benefit (ODB Formulary )

  • capecitabine

 
K - References

Chu MP, Hecht JR, Slamon D. Association of proton pump inhibitors and capecitabine efficacy in advanced gastroesophageal cancer: secondary analysis of the TRIO-013/LOGiC randomized clinical trial. JAMA Oncol 2017 Jun 1;3(6):767-73.

Dooley M, Goa KL: Capecitabine. Drugs 1999 Jul: 58(1): 69-76.

Kang Y, Lee SS, Yoon DH, et al. Pyridoxine is not effective to prevent hand-foot syndrome associated with capecitabine therapy: results of a randomized, double-blind, placebo-controlled study. J Clin Oncol 2010;28(24):3824-3829.

McEvoy GK, editor. AHFS Drug Information 2009. Bethesda: American Society of Health-System Pharmacists, p. 963-71.

Product monograph: Xeloda® (Capecitabine). Hoffmann-La Roche, August 3, 2016.

Prescribing Information: Xeloda® (Capecitabine). South San Francisco, CA: Genentech USA, Inc; February 2019.

The Medical Letter: 40(1039) November 6, 1998: 106-7.

Reigner B, Clive S, Cassidy J, et al. Influence of the antacid Maalox on the pharmacokinetics of capecitabine in cancer patients. Cancer Chemother Pharmacol 1999;43(4):309-15.


November 2019 Updated Mechanism of Action and Pharmacokinetics, Adverse Effects, Pregnancy and Lactation and Interactions sections and emetic risk category.

 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.

CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.