Drug Monograph

Drug Name | Mechanism of Action and Pharmacokinetics | Indications and Status | Adverse Effects | Dosing | AdministrationGuidelines | Special Precautions | Interactions | Recommended Clinical Monitoring | Supplementary Public Funding |References | Disclaimer

A - Drug Name

capecitabineSYNONYM(S): 5'-Deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytidine

COMMON TRADE NAME(S): Xeloda® (Hoffmann-LaRoche)

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B - Mechanism of Action and Pharmacokinetics

Capecitabine is an antimetabolite, belonging to the fluoropyrimidine carbamate class and causescell injury via RNA- and DNA-related mechanisms. It is an orally administered precursor of 5-fluorouracil (5FU). Capecitabine is converted to 5FU by carboxyesterase, cytidine deaminase andthymidine phosphorylase (present in the liver and in tumours). Docetaxel appears to upregulatethymidine phosphorylase. The daily oral administration of capecitabine mimics the continuousintravenous infusion of 5-FU.

Absorption

70%; rapid with Cmax 1.5 hours.Pharmacokinetics are largely dose proportional; insignificant food effect.Pharmacokinetics altered with advanced age and renal function, but notwith gender, race, performance status, liver function and albumin

Distribution Widely distributed

Cross blood brain barrier? Not known

PPB < 60%; primarily albumin (35%)

Metabolism Capecitabine is extensively bioactivated and metabolized in the liver

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Active metabolites Yes (FdUMP and FuTP)

Inactive metabolites Yes

Elimination

Urine 70%; 3% unchanged

Feces 2.6%

Half-life terminal: 45-60 minutes

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C - Indications and Status

Health Canada Approvals:

First-line treatment metastatic colorectal cancerFor the adjuvant treatment of patients with stage III (Dukes' stage C) colon cancerIn combination with oxaliplatin for the treatment of metastatic colorectal cancer after failure ofirinotecan-containing combination chemotherapyAdvanced or metastatic breast cancer after failure of standard therapy (including a taxane),unless therapy with a taxane is clinically contraindicatedIn combination with docetaxel for advanced or metastatic breast cancer after failure ofanthracycline-containing chemotherapy

Other Uses:

• Neo-adjuvant treatment of rectal cancer• Metastatic adenocarcinoma of the stomach or gastro-esophageal junction (as combinationchemotherapy)• Cholangiocarcinoma (as combination chemotherapy)• Metastatic carcinoma of the pancreas, head and neck, unknown primary tumour, renal cell,neuroendocrine tumour

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D - Adverse Effects

Emetogenic Potential: Low

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Extravasation Potential: Not applicable

The following table contains adverse effects reported mainly in adjuvant colorectal cancer oradvanced breast cancer studies as monotherapy.

ORGAN SITE SIDE EFFECT* (%) ONSET**

Cardiovascular Arterial thromboembolism (rare) E

Cardiotoxicity (<5%) E

Hypertension (<5%) E

Hypotension (<5%) E

Venous thromboembolism (1%) E

Dermatological Alopecia (6%) E

Hand-foot syndrome (60%) E

Nail disorder (7%) E

Rash (6%) (may be severe) E

Gastrointestinal Abdominal pain (10%) E

Anorexia, weight loss (9%) E

Constipation (6%) E

Diarrhea (46%) D

Dyspepsia (5%) E

GI hemorrhage (<5%) E

GI obstruction (<5%) E

GI perforation (rare) E

Mucositis (22%) E

Nausea, vomiting (33%) E

General Edema (9%) E

Fatigue (15%) E

Pain (6%) E

Hematological Idiopathic thrombocytopenic purpura (rare) E

Myelosuppression ± infection, bleeding (2%) (grade 3/4, may besevere, including atypical infection)

E

Hepatobiliary ↑ LFTs (20%) (grade 3/4, may be severe) E

Hypersensitivity Hypersensitivity (<5%) I

Musculoskeletal Musculoskeletal pain (9%) E

NervousSystem

Confusion (<5%) E

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Dizziness (5%) (including vertigo) E

Dysgeusia (6%) E

Headache (9%) E

Leukoencephalopathy (%) (very rare) E

Neuropathy (9%) E

Ophthalmic Conjunctivitis (5%) D

Eye disorders (cataract, lacrimal duct stenosis, keratitis - rare) D

Renal Nephrotoxicity (<5%) D

Respiratory Cough, dyspnea (7%) E

* "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.Dose-limiting side effects are underlined.

** 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, ↑ lfts, fatigue, abdominal pain, anorexia, weight loss, edema and headache.

The median time to onset of diarrhea, a dose-limiting adverse effect of capecitabine, is 34 days.The diarrhea may respond to standard anti-diarrheal therapy (e.g. loperamide). Patients with severediarrhea should be closely monitored and given fluid and electrolyte replacement for dehydration asindicated. Dehydration may result in acute renal failure, particularly with other risk factors (pre-existing renal dysfunction, concomitant nephrotoxic agents). Capecitabine should be held and thedose reduced after recovery (See Dosing section). Older patients (≥ 65years) may be at higher risk.

Palmar-plantar erythrodysesthesia (commonly referred to as hand-foot syndrome) ischaracterized 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 commonin patients also receiving docetaxel. The median time to onset was 79 days. Dosageinterruption/adjustment is required according to severity. In addition to dose interruption andsubsequent dose reduction, topical emollients (e.g. hand creams, udder balm) may ameliorate themanifestations of hand-foot syndrome in patients receiving capecitabine. Current evidenceindicates that oral pyridoxine may not be effective in ameliorating hand-foot syndrome in patientsreceiving capecitabine. (Kang 2010).

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

Hyperbilirubinemia associated with capecitabine therapy occurs more frequently in patients withhepatic metastases.

Patients with dihydropyrimidine dehydrogenase (DPD) deficiency (rate-limiting enzyme of 5-fluorouracil catabolism) are at risk of severe toxicity (i.e. neutropenia, GI and neurotoxicity, including

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fatalities) secondary to reduced drug metabolism.

Cardiac toxicity is similar to that reported for other fluorinated pyrimidines and includes ECGchanges, angina, infarction, EKG changes, dysrhythmias and cardiac failure. The risk may beincreased in patients with prior coronary artery disease.

Very rare cases of leukoencephalopathy have been reported.

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E - Dosing

Refer to protocol by which patient is being treated.

Adults:

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

Monotherapy: Oral: 1250 mg/m² BID for 14 days

(Total daily dose 2500 mg/m2)In combination with oxaliplatin (q3w): Oral: 1000 mg/m² BID for 14 days

In combination with docetaxel (q3w): Oral: 1250 mg/m² BID for 14 days

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 31.27 – 1.38 1650 1 31.39 – 1.52 1800 2 31.53 – 1.66 2000 0 41.67 – 1.78 2150 1 41.79 – 1.92 2300 2 41.93 – 2.06 2500 0 5

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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 21.27 – 1.38 1300 2 21.39 – 1.52 1450 3 21.53 – 1.66 1600 4 21.67 – 1.78 1750 5 21.79 – 1.92 1800 2 31.93 – 2.06 2000 0 42.07 – 2.18 2150 1 4> 2.19 2300 2 4

*given twice daily

Dosage with Toxicity:

Dose Modification Guidelines for monotherapy:

Do not start treatment with capecitabine unless baseline neutrophil counts are ≥ 1.5 x 109/L

and/or platelet counts of ≥ 100 x 109/L. Patients should be informed of the need to interrupttreatment immediately if moderate or severe toxicity occurs. Supportive care should beprovided, including loperamide for diarrhea. Doses should not be re-escalated if reduced fortoxicity. 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 othertoxicities unlikely to become serious or life-threatening.

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Toxicity

Action During a Course of Therapy Dose Adjustment for NextCycle (% of starting dose)

Grade 1

Maintain dose level

Maintain dose level

Grade 21st appearance2nd appearance3rd appearance4th appearance

Interrupt until resolved to grade 0-1Interrupt until resolved to grade 0-1Interrupt until resolved to grade 0-1Discontinue treatment permanently

100%75%50%--

Grade 31st appearance2nd appearance3rd appearance, ORany evidence ofStevens-Johnsonsyndrome or Toxicepidermal necrolysis

Interrupt until resolved to grade 0-1Interrupt until resolved to grade 0-1Discontinue treatment permanently

75%50%--

Grade 4 1st appearance,including SJS or TEN,OR cardiotoxicity ORacute renal failure 2nd appearance ORany occurrence ofconfirmedleukoencephalopathy

Discontinue permanently ORIf physician deems it to be in the patient’sbest interest to continue and no evidenceof Stevens-Johnson syndrome or toxicepidermal necrolysis, interrupt untilresolved to grade 0-1.

Discontinue permanently

DiscontinueOR

50% --

Dosage in myelosuppression:

Modify according to protocol by which patient is being treated; if no guidelines available, referto Appendix 6 "Dosage Modification for Hematologic and Non-Hematologic Toxicities." Hold

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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 docetaxel, oxaliplatin monographs and CAPEDOCE, XELOX regimenmonographs for recommended dose modifications in combination use.

For the indicated combinations,

If a treatment delay is indicated for either agent, then administration of bothcapecitabine and the other chemotherapy drug should be delayed until the requirementfor starting both are met.During a treatment cycle, if the toxicities are considered by the physician as unrelated tocapecitabine, may continue capecitabine and adjust the dose of the other agentaccording to its product monograph.If the other agent needs to be discontinued permanently, capecitabine treatment can beresumed when the requirements for restarting capecitabine are met.

Dosage with Hepatic Impairment:

In patients with mild to moderate hepatic impairment, exposure is increased but no doseadjustment is necessary, although caution should be exercised. Use dose modification tableabove for increases in bilirubin. The use of capecitabine in patients with severe hepaticimpairment 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 closemonitoring

30 - 50 75 % (use with caution)

<30 CONTRAINDICATED

Dosage in the elderly:

No dose adjustment for the starting dose is required, but patients should be closely monitoredand dose modification should be performed as described above. Older patients are more

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susceptible to the effects of fluoropyrimidine-based therapies with increased grade 3 / 4adverse effects, especially when used in combination.

Children:

Safety and efficacy not established.

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F - Administration Guidelines

Oral self-administration; drug available by outpatient prescription.Clinical studies performed with capecitabine administered 30 minutes after food.Administering capecitabine on an empty stomach may result in slightly higher exposure andthus toxicity.If a capecitabine dose is missed, skip this and give the next dose at the usual time. Missed oromitted doses should not be replaced.Store tablets at 15ºC to 30ºC in the original package.

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G - Special Precautions

Contraindications:

Patients who have a known hypersensitivity to capecitabine, its excipients, or 5-fluorouracilPatients with severe renal impairment (CrCl <30 mL/min)Patients with known DPD (dihydropyrimidine dehydrogenase) deficiencyConcomitant use with sorivudine or related analogues (i.e. brivudine), given potential fatal druginteractionContains lactose and should not be used in patients with hereditary galactose/glucose/lactasedisorders.

Other Warnings/Precautions:

Patients with risk factors for dehydration, pre-existing renal dysfunction or on nephrotoxicagentsPatients with a history of cardiovascular diseasePatients taking anticoagulants such as warfarin (see Drug Interactions section)

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Other Drug Properties:

Carcinogenicity: ProbableThe long-term carcinogenic potential of capecitabine has not been studied, although 5-fluorouracil has potential carcinogenic and mutagenic effects.

Pregnancy and Lactation:

Teratogenicity: YesEmbryotoxicity: YesCapecitabine is not recommended for use in pregnancy. Adequate contraception should beused by both sexes during treatment, and for at least 6 months after the last dose.Excretion into breast milk: ProbableBreastfeeding is not recommended.Fertility effects: Probable

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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

Phenytoin/Fosphenytoinand CYP 2C9substrates

↑ phenytoin levels Capecitabine mayinhibit CYP2C9

Monitor phenytoinlevels; avoidconcomitantadministration

Leucovorin ↑ capecitabine toxicity Potentiatescytotoxicity withoutincrease in efficacy

Avoid

Coumadin Abnormal INR/PTbleeding; may occur atanytime

Capecitabine mayinhibit CYP2C9; ↑ s-warfarin exposure by57%

Caution; monitor PTand INR and adjustanticoagulant doseaccordingly

Antacids containingaluminum ormagnesium hydroxide

small ↑ in plasmaconcentration ofcapecitabine

↑ rate and extent ofabsorption

Avoid concomitantadministration

Docetaxel ↑ incidence of grade 3/4treatment-related adverseevents in patients ≥ 60years old

Synergistic; Possiblydue to upregulation ofthymidinephosphorylase

Caution

sorivudine and ↑ capecitabine toxicity; Inhibition of DPD by Avoid concomitant

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analogues potentially fatal sorivudine administration; wait 4weeks aftersorivudine treatmentbefore startingcapecitabine

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I - Recommended Clinical Monitoring

Recommended Clinical Monitoring

Monitor Type Monitor Frequency

CBC Baseline and regular

Renal function tests Baseline and regular

INR and/or PT Baseline and regular if onanticoagulants

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

regular

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 regular (if severeorgan failure suspected)

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J - Supplementary Public Funding

ODB Limited Use (ODB Formulary)

Part of the CAPOX regimen for the first-line and second-line treatment of metastatic colorectalcancerAdjuvant treatment of stage 3 or high risk stage 2 colon cancer in patients who havecompleted surgery (within three months), who would normally be candidates for adjuvant

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chemotherapy with 5FU/LVFirst-line treatment of patients with metastatic colorectal cancer in whom combinationchemotherapy is not recommendedTreatment of metastatic breast cancer where patients have progressed after priorchemotherapyIn combination with trastuzumab and cisplatin for the treatment of patients with HER2-positivemetastatic adenocarcinoma of the stomach or gastro-esophageal junction who have notreceived prior anti-cancer treatment for their metastatic diseaseNeo-adjuvant treatment of rectal cancerIn combination with a platinum-containing product and epirubicin for the treatment of advanced(non-resectable; either locally advanced or metastatic) gastric or gastro esophageal junctioncancer

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K - References

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

Hoffman La Roche. Dear Doctor Letter: Important drug warning (Xeloda). December 18th, 2000.

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

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

Personal communications. Hoffmann La Roche: Revised HFS treatment guidelines. October 2000.

Product monograph: Xeloda® (Capecitabine). Hoffmann-La Roche, December 11, 2014.

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

May 2015 updated supplementary public funding section

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L - Disclaimer

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

The information set out in the drug monographs, regimen monographs, appendices and symptom management

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information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcareproviders 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 indicatethat use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary isnot intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. Alluses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the informationprovided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom managementinformation contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date oflast revision will be visible on each page of the monograph and regimen. Since standards of usage are constantlyevolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommendedthat 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 symptommanagement information (for patients), are intended for patients. Patients should always consult with their healthcareprovider 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 isprovided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutoryor 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 onbreach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using theinformation in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCOand its content providers from any and all liability, loss, damages, costs and expenses (including legal fees andexpenses) arising from such person’s use of the information in the Formulary.

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