Capecitabine

Capecitabine may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• stomach pain or upset stomach
• constipation
• loss of appetite
• change in ability to taste food
• increased thirst
• unusual tiredness or weakness
• dizziness
• headache
• hair loss
• skin rash
• back, join, or muscle pain
• red, swollen, itchy, or teary eyes
• trouble falling asleep or staying asleep

Some side effects can be serious. If you experience any of these symptoms or those listed in the IMPORTANT WARNING section, call your doctor immediately:

• diarrhea
• nausea
• vomiting
• sores in the mouth
• swelling, pain, redness, or peeling of skin on the palms and soles of the feet
• fever, chills, sore throat, or other signs of an infection
• swelling of the hands, feet, ankles, or lower legs
• chest pain or pressure
• fast heartbeat
• dark urine
• yellowing of skin or eyes

Capecitabine may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adjuvant Colon Cancer

Table 4 shows the adverse reactions occurring in =5% of patients from one phase 3 trial in patients with Dukes' C colon cancer who received at least one dose of study medication and had at least one safety assessment. A total of 995 patients were treated with 1250 mg/m2 twice a day of XELODA administered for 2 weeks followed by a 1-week rest period, and 974 patients were administered 5-FU and leucovorin (20 mg/m2 leucovorin IV followed by 425 mg/m2 IV bolus 5-FU on days 1-5 every 28 days). The median duration of treatment was 164 days for capecitabine-treated patients and 145 days for 5-FU/LV-treated patients. A total of 112 (11%) and 73 (7%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse reactions. A total of 18 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 8 (0.8%) patients randomized to XELODA and 10 (1.0%) randomized to 5-FU/LV.

Table 5 shows grade 3/4 laboratory abnormalities occurring in =1% of patients from one phase 3 trial in patients with Dukes' C colon cancer who received at least one dose of study medication and had at least one safety assessment.

Table 4 Percent Incidence of Adverse Reactions Reported in =5% of Patients Treated With XELODA or 5-FU/LV for Colon Cancer in the Adjuvant Setting (Safety Population)

Table 5 Percent Incidence of Grade 3/4 Laboratory Abnormalities Reported in =1% of Patients Receiving XELODA Monotherapy for Adjuvant Treatment of Colon Cancer (Safety Population)

Metastatic Colorectal Cancer

Table 6 shows the adverse reactions occurring in =5% of patients from pooling the two phase 3 trials in first line metastatic colorectal cancer. A total of 596 patients with metastatic colorectal cancer were treated with 1250 mg/m2 twice a day of XELODA administered for 2 weeks followed by a 1-week rest period, and 593 patients were administered 5-FU and leucovorin in the Mayo regimen (20 mg/m2 leucovorin IV followed by 425 mg/m2 IV bolus 5-FU, on days 1-5, every 28 days). In the pooled colorectal database the median duration of treatment was 139 days for capecitabine-treated patients and 140 days for 5-FU/LV-treated patients. A total of 78 (13%) and 63 (11%) capecitabine and 5-FU/LVtreated patients, respectively, discontinued treatment because of adverse reactions/intercurrent illness. A total of 82 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 50 (8.4%) patients randomized to XELODA and 32 (5.4%) randomized to 5-FU/LV.

Table 6 Pooled Phase 3 Colorectal Trials : Percent Incidence of Adverse Reactions in =5% of Patients

Breast Cancer

The following data are shown for the combination study with XELODA and docetaxel in patients with metastatic breast cancer in Table 7 and Table 8. In the XELODA and docetaxel combination arm the treatment was XELODA administered orally 1250 mg/m2 twice daily as intermittent therapy (2 weeks of treatment followed by 1 week without treatment) for at least 6 weeks and docetaxel administered as a 1- hour intravenous infusion at a dose of 75 mg/m2 on the first day of each 3-week cycle for at least 6 weeks. In the monotherapy arm docetaxel was administered as a 1-hour intravenous infusion at a dose of 100 mg/m2 on the first day of each 3-week cycle for at least 6 weeks. The mean duration of treatment was 129 days in the combination arm and 98 days in the monotherapy arm. A total of 66 patients (26%) in the combination arm and 49 (19%) in the monotherapy arm withdrew from the study because of adverse reactions. The percentage of patients requiring dose reductions due to adverse reactions was 65% in the combination arm and 36% in the monotherapy arm. The percentage of patients requiring treatment interruptions due to adverse reactions in the combination arm was 79%. Treatment interruptions were part of the dose modification scheme for the combination therapy arm but not for the docetaxel monotherapy-treated patients.

Table 7 Percent Incidence of Adverse Events Considered Related or Unrelated to Treatment in =5% of Patients Participating in the XELODA and Docetaxel Combination vs Docetaxel Monotherapy Study

Table 8 Percent of Patients With Laboratory Abnormalities Participating in the XELODA and Docetaxel Combination vs Docetaxel Monotherapy Study

The following data are shown for the study in stage IV breast cancer patients who received a dose of 1250 mg/m2 administered twice daily for 2 weeks followed by a 1-week rest period. The mean duration of treatment was 114 days. A total of 13 out of 162 patients (8%) discontinued treatment because of adverse reactions/intercurrent illness.

Table 9 Percent Incidence of Adverse Reactions Considered Remotely, Possibly or Probably Related to Treatment in =5% of Patients Participating in the Single Arm Trial in Stage IV Breast Cancer

Clinically Relevant Adverse Events In <5% Of Patients

Clinically relevant adverse events reported in <5% of patients treated with XELODA either as monotherapy or in combination with docetaxel that were considered at least remotely related to treatment are shown below; occurrences of each grade 3 and 4 adverse event are provided in parentheses.

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:

Capecitabine is a white to off-white crystalline powder with an aqueous solubility of 26 mg/mL at 20°C.

Capecitabine tablets are supplied as biconvex, oblong film-coated tablets for oral administration. Each light peach-colored tablet contains 150 mg capecitabine and each peach-colored tablet contains 500 mg capecitabine. The inactive ingredients in capecitabine tablets include: anhydrous lactose, croscarmellose sodium, hypromellose, microcrystalline cellulose and magnesium stearate. The peach or light peach film coating contains hypromellose, purified talc, titanium dioxide, and ferric oxide red and ferric oxide yellow.

Capecitabine is a prescription medication used to treat breast cancer and cancer of the colon or rectum. Capecitabine belongs to a group of drugs called antimetabolites which work by interfering with DNA production, stopping cells from multiplying.

This medication comes in tablet form and is usually taken twice daily, within 30 minutes after the end of a meal.

Swallow tablets whole. Do not cut or crush tablets.

Common side effects include diarrhea, nausea, vomiting, and mouth sores.

Capecitabine is a prescription medication used to treat:

• cancer of the colon after surgery
• cancer of the colon or rectum (colorectal cancer) that has spread to other parts of the body (metastatic colorectal cancer). 
• breast cancer that has spread to other parts of the body (metastatic breast cancer) together with another medicine called docetaxel (Taxotere)
• breast cancer that has spread to other parts of the body and has not improved after treatment with other medicines such as paclitaxel (Taxol) and anthracycline-containing medicine such as Adriamycin and doxorubicin.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Take capecitabine exactly as prescribed by your doctor. Follow the directions on your prescription label carefully. Your doctor will determine the best dose for you.

Standard Starting Dose

• The recommended dose of capecitabine is 1250 mg/m² given by mouth twice daily for 2 weeks. This is followed by by a 1-week rest period.
• In those with Dukes' C colon cancer is recommended for a total of 6 months.

In Combination With Docetaxel (Metastatic Breast Cancer)

• The recommended dose of capecitabine is 1250 mg/m² twice daily for 2 weeks. This is followed by a 1-week rest period.
• You will be carefully monitored for toxicity.
• Doses of capecitabine should be adjusted as necessary to accommodate tolerance to treatment.

If you take too much capecitabine call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

If capecitabine is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

• Never share capecitabine with anyone.
• Store capecitabine at normal room temperature (about 65° to 85°F).
• Keep capecitabine and all other medicines out of the reach of children.

Capecitabine is usually taken twice per day. Follow the directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Capecitabine is given in a 3-week treatment cycle, and you may only need to take the medicine during the first 2 weeks of each cycle. Your doctor will determine how long to treat you with capecitabine.

Capecitabine is only part of a treatment program that may also include other medications taken on different schedules. Follow your doctor's dosing instructions very carefully.

Capecitabine should be taken with food or within 30 minutes after eating a meal.

Take capecitabine with a full glass (8 ounces) of water.

Call your doctor if you are sick with vomiting or diarrhea, if you are unable to eat because of stomach illness, or if you are sweating more than usual. Prolonged illness can lead to dehydration or kidney failure.

You may need frequent medical tests to be sure this medicine is not causing harmful effects. Your cancer treatments may be delayed based on the results of these tests. Capecitabine can have long lasting effects on your body. You may need frequent medical tests for a short time after you stop using this medicine.

You must remain under the care of a doctor while you are taking capecitabine.

Store at room temperature away from moisture and heat. Keep the bottle tightly closed when not in use.

Read all patient information, medication guides, and instruction sheets provided to you. Ask your doctor or pharmacist if you have any questions.

Antineoplastic agent; prodrug of fluorouracil (an antimetabolite).1 2 3 5 6 7 14

• Importance of informing clinician of any known deficiency in DPD activity.48

• Importance of discontinuing the drug and contacting clinician if stool output increases by 4–6 stools or more daily or if nocturnal stools or severe bloody diarrhea with severe abdominal pain and fever occurs.48

• Importance of discontinuing the drug and contacting clinician if grade 2 or greater dehydration occurs.48

• Importance of discontinuing the drug and contacting clinician if 2–5 or more episodes of vomiting occur in a 24-hour period.48

• Importance of discontinuing the drug and contacting clinician if nausea resulting in a substantial decrease in food intake occurs.48

• Importance of discontinuing the drug and contacting clinician if pain, redness, swelling, or sores in mouth occur.1

• Importance of discontinuing the drug and contacting clinician if pain and swelling or redness of hands or feet that prevents normal activity occur.1

• Importance of notifying clinician if fever (≥100.5°F) or other signs of infection occur.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy and to advise pregnant women of risk to the fetus.1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

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.

Pharmacokinetics

Absorption

Following oral administration of 1255 mg/m 2 BID 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 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 T max of both parent and 5-FU by 1.5 hours [see Warnings and Precautions (5), Dosage and Administration (2), and Drug-Food Interaction (7.2)] .

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 2/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 max 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 (approximately 35%). 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 hydrolyzes much of the compound to 5'-deoxy-5-fluorocytidine (5'-DFCR). Cytidine deaminase, an enzyme found in most tissues, including tumors, subsequently converts 5'-DFCR to 5'-DFUR. The enzyme, thymidine phosphorylase (dThdPase), then hydrolyzes 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 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 tumors 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.

The enzyme dihydropyrimidine dehydrogenase hydrogenates 5-FU, the product of Capecitabine metabolism, to the much less toxic 5-fluoro-5, 6-dihydro-fluorouracil (FUH 2). Dihydropyrimidinase cleaves the pyrimidine ring to yield 5-fluoro-ureido-propionic acid (FUPA). Finally, β-ureido-propionase cleaves FUPA to α-fluoro-β-alanine (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 P450 isoenzymes 1A2, 2A6, 3A4, 2C19, 2D6, and 2E1.

Excretion

Capecitabine and its metabolites are predominantly excreted in urine; 95.5% of administered Capecitabine dose is recovered in urine. Fecal 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 urine as unchanged drug. The elimination half-life of both parent Capecitabine and 5-FU was about 0.75 hour.

Effect of Age, Gender, and Race on the Pharmacokinetics of Capecitabine

A population analysis of pooled data from the two large controlled studies in patients with metastatic colorectal cancer (n=505) who were administered Capecitabine at 1250 mg/m 2 twice a day indicated that gender (202 females and 303 males) and race (455 white/Caucasian patients, 22 black patients, and 28 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 AUC of FBAL [see Warnings and Precautions (5.11) and Dosage and Administration (2.4)] .

Following oral administration of 825 mg/m 2 Capecitabine twice daily for 14 days, Japanese patients (n=18) had about 36% lower C max and 24% lower AUC for Capecitabine than the Caucasian patients (n=22). Japanese patients had also 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 Insufficiency

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 1255 mg/m 2 dose of Capecitabine. Both AUC 0-∞ and C max of Capecitabine increased by 60% in patients with hepatic dysfunction compared to patients with normal hepatic function (n=14). 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 [see Warnings and Precautions (5.11) and Use in Special Populations (8.6)].

Effect of Renal Insufficiency

Following oral administration of 1250 mg/m 2 Capecitabine twice a day to cancer patients with varying degrees of renal impairment, patients with moderate (creatinine clearance = 30 to 50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment showed 85% and 258% higher systemic exposure to FBAL on day 1 compared to normal renal function patients (creatinine clearance >80 mL/min). 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 [see Dosage and Administration (2.4), Contraindications (4.2), Warnings and Precautions (5.5), and Use in Special Populations (8.7)] .

Effect of Capecitabine on the Pharmacokinetics of Warfarin

In four patients with cancer, chronic administration of Capecitabine (1250 mg/m 2 bid) 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 4 patients increased by 2.8-fold, and the maximum observed mean INR value was increased by 91% [see Boxed Warning and Drug Interactions (7.1)].

Effect of Antacids on the Pharmacokinetics of Capecitabine

When Maalox® (20 mL), an aluminum hydroxide- and magnesium hydroxide-containing antacid, was administered immediately after Capecitabine (1250 mg/m 2, n=12 cancer patients), 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

A Phase 1 study evaluated the effect of Capecitabine on the pharmacokinetics of docetaxel (Taxotere ®) and the effect of docetaxel on the pharmacokinetics of Capecitabine was conducted in 26 patients with solid tumors. 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.

1. “OSHA Hazardous Drugs.” OSHA.

http://www.osha.gov/SLTC/hazardousdrugs/index.html.

Capecitabine is a prodrug of fluorouracil. It undergoes hydrolysis in the liver and tissues to form fluorouracil which is the active moiety. Fluorouracil is a fluorinated pyrimidine antimetabolite that inhibits thymidylate synthetase, blocking the methylation of deoxyuridylic acid to thymidylic acid, interfering with DNA, and to a lesser degree, RNA synthesis. Fluorouracil appears to be phase specific for the G1 and S phases of the cell cycle.

Absorption

Rapid and extensive (rate and extent reduced by food)

Metabolism

Hepatic: Inactive metabolites: 5′-deoxy-5-fluorocytidine, 5′-deoxy-5-fluorouridine; Tissue: Enzymatically metabolized to fluorouracil, which is then metabolized to active metabolites, 5-fluoroxyuridine monophosphate (F-UMP) and 5-5-fluoro-2’-deoxyuridine-5’-O-monophosphate (F-dUMP)

Excretion

Urine (96%, 57% as α-fluoro-β-alanine; <3% as unchanged drug); feces (<3%)

Time to Peak

1.5 hours; Fluorouracil: 2 hours

Half-Life Elimination

~0.75 hour

Protein Binding

<60%; ~35% to albumin

In moderate-to-severe renal function impairment, there is increased exposure to inactive metabolites (FBAL and 5’-DFUR) and a 25% increase in exposure to capecitabine.

Breast cancer (metastatic):

Monotherapy: Treatment of metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing regimen or resistant to paclitaxel in patients for whom further anthracycline therapy is not indicated

Combination therapy: Treatment of metastatic breast cancer (in combination with docetaxel) after failure of a prior anthracycline-containing regimen

Colorectal cancer: First-line treatment of metastatic colorectal cancer when treatment with a fluoropyrimidine alone is preferred; adjuvant therapy of Dukes' C colon cancer after complete resection of the primary tumor when fluoropyrimidine therapy alone is preferred

Anal carcinoma

Data from a phase II study supports the use of capecitabine as an alternative to continuous fluorouracil infusion (in combination with mitomycin and radiation therapy) in the treatment of squamous cell carcinoma of the anal canal [Oliveria 2016]. Additional data from two retrospective studies also support the use of capecitabine in combination with mitomycin and radiation therapy in the treatment of anal carcinoma [Meulendijks 2014], [Thind 2014].

Breast cancer (adjuvant therapy)

Data from a multicenter, open-label, randomized phase 3 trial supports the use of capecitabine as adjuvant treatment in patients with HER2-negative primary breast cancer who had residual invasive disease after neoadjuvant therapy (containing an anthracycline, taxane, or both) and surgery [Masuda 2017].

Esophageal and gastric cancers

Data from multiple well-done prospective clinical trials [Bang 2010], [Cunningham 2008], [Hong 2004], [Javle 2009], [Kang 2009], [Lee 2006], [Sumpter 2005] and one retrospective study [Lee 2007] supports the use of capecitabine in the treatment of patients with esophageal and gastric cancers.

Hepatobiliary cancer (adjuvant therapy)

Data from a randomized controlled phase III study supports the use of capecitabine in the adjuvant treatment following complete radical resection of gall bladder cancer (including liver and pancreatic resection as appropriate) or choleangiocarcinoma [Primrose 2017].

Hepatobiliary cancers (advanced)

Data from multiple phase II clinical trials in patients with advanced hepatobiliary cancers supports the use of capecitabine (in combination with either cisplatin, gemcitabine, or oxaliplatin) for the treatment of this condition [Kim 2003], [Knox 2005], [Nehls 2008]. Additional trials may be necessary to further define the role of capecitabine in the treatment of advanced hepatobiliary cancers.

Neuroendocrine (islet cell) tumors (metastatic or unresectable)

Data from a retrospective cohort study in patients with metastatic pancreatic endocrine carcinomas who had received capecitabine and temozolomide at a single center suggests that capecitabine (in combination with temozolomide) may be beneficial for the treatment of this condition [Strosberg 2011]. Additional trials may be necessary to further define the role of capecitabine in the treatment of metastatic or unresectable neuroendocrine (islet cell) tumors.

Ovarian, fallopian tube, or peritoneal cancers (refractory)

Data from a phase II, single-arm study in patients with platinum and taxane resistant ovarian, fallopian tube, or peritoneal cancer supports the use of capecitabine in the treatment of this condition [Wolf 2006]. Additional trials may be necessary to further define the role of capecitabine in the treatment of refractory ovarian, fallopian tube, or peritoneal cancers.

Pancreatic cancer (adjuvant therapy)

Data from a randomized, multicenter phase III study supports the use of capecitabine (in combination with gemcitabine) in the adjuvant treatment of completely resected pancreatic adenocarcinoma [Neoptolemos 2017].

According to the American Society of Clinical Oncology Guidelines for Potentially Curable Pancreatic Cancer, patients with resected pancreatic cancer who did not receive pre-operative therapy should be offered 6 months of adjuvant therapy beginning within 8 weeks of resection (if recovery is complete); capecitabine (in combination with gemcitabine) is the preferred therapy in the absence of contraindications.

Pancreatic cancer (locally advanced or metastatic)

Data from a phase II study evaluating the use of capecitabine in patients with advanced or metastatic pancreatic cancer supports the use of capecitabine (monotherapy) for the treatment of this condition [Cartwright 2002]. Additionally, data from a phase III, randomized study demonstrated that the combination of capecitabine and gemcitabine (GEM-CAP regimen) significantly improved objective response and progression-free survival as compared to gemcitabine alone [Cunningham 2009].

Unknown primary cancer

Data from a phase II study in patients with cancer of an unknown primary site treated with capecitabine (in combination with carboplatin and gemcitabine) supports the use of capecitabine for the treatment of this condition especially in patients with liver metastases [Schneider 2007]. Additional data from a phase II study using capecitabine (in combination with oxaliplatin) also supports the use of capecitabine for the treatment of patients with unknown primary cancer [Hainsworth 2010]. Additional trials may be necessary to further define the role of capecitabine in the treatment of this condition.

Known hypersensitivity to capecitabine, fluorouracil, or any component of the formulation; severe renal impairment (CrCl <30 mL/minute)

Canadian labeling: Additional contraindications (not in the US labeling): Known complete absence of dihydropyrimidine dehydrogenase (DPD) activity; concomitant administration with sorivudine or chemically related analogues (eg, brivudine)

A 10 mg/mL oral solution may be made with tablets. Crush four 500 mg tablets in a mortar and reduce to a fine powder; add to 200 mL water. Capecitabine tablets are water soluble (data on file from Roche). Administer immediately after preparation, 30 minutes after a meal.

Frequency listed derived from monotherapy trials. Incidence reported for all indications and usage, unless otherwise noted. Frequency not always defined.

>10%:

Cardiovascular: Edema (≤15%)

Central nervous system: Fatigue (≤42%), paresthesia (stage IV breast cancer: 21%; grades 3/4: 1%), pain (≤12%)

Dermatologic: Palmar-plantar erythrodysesthesia (54% to 60%; grades ≥3: 11% to 17%), dermatitis (27% to 37%, grades ≥3: 1%)

Gastrointestinal: Diarrhea (47% to 57%, grades 3/4: 2% to 13%), nausea (34% to 43%; stage IV breast cancer: 53%), vomiting (metastatic colorectal cancer, stage IV breast cancer: 27% to 37%; Dukes' C colon cancer: 15%), abdominal pain (metastatic colorectal cancer: 35%; stage IV breast cancer: 20%; Dukes' C colon cancer: 14%), decreased appetite (26%), stomatitis (22% to 25%), anorexia (stage IV breast cancer: 23%; Dukes' C colon cancer: 9%), constipation (9% to 15%)

Hematologic & oncologic: Lymphocytopenia (stage IV breast cancer: 94%; stage IV breast cancer, grades 3/4: 15% to 44%), anemia (72% to 80%, grades 3/4: ≤3%), neutropenia (≤26%, grades 3/4: ≤3%), thrombocytopenia (stage IV breast cancer: 24%; all: grades 3/4: 1% to 3%)

Hepatic: Hyperbilirubinemia (Metastatic colorectal cancer: 48%; stage IV breast cancer: 22%; all: grades 3/4: 2% to 23%)

Neuromuscular & skeletal: Weakness (≤42%)

Ophthalmic: Eye irritation (13% to 15%)

Miscellaneous: Fever (7% to 18%)

1% to 10%:

Cardiovascular: Venous thrombosis (8%), chest pain (≤6%), atrial fibrillation (<5%), bradycardia (<5%), collapse (<5%), extrasystoles (<5%), pericardial effusion (<5%), ventricular premature contractions (<5%), angina pectoris, cardiac arrest, cardiac arrhythmia, cardiac failure, cardiomyopathy, ECG changes, ischemic heart disease, myocardial infarction

Central nervous system: Lethargy (10%), peripheral sensory neuropathy (10%), headache (5% to 10%), insomnia (≤8%), dizziness (6% to 8%), ataxia (<5%), depression (≤5%), mood changes (5%), abnormal gait (<5%), brain disease (<5%), dysarthria (<5%), dysphasia (<5%), equilibrium disturbance (<5%), irritability (<5%), myasthenia (<5%), sedation (<5%), vertigo (<5%)

Dermatologic: Nail disease (≤7%), skin discoloration (7%), skin rash (7%), alopecia (6%), erythema (6%), dermal ulcer (<5%), pruritus (<5%)

Endocrine & metabolic: Dehydration (7%), hot flash (<5%), hypokalemia (<5%), hypomagnesemia (<5%), increased thirst (<5%), weight gain (<5%), decreased serum calcium (Dukes' C colon cancer: grades 3/4: 2%), increased serum calcium (Dukes' C colon cancer: grades 3/4: 1%)

Gastrointestinal: Gastrointestinal motility disorder (10%), GI inflammation (upper: 8%), oral discomfort (grades 3/4: 10%), dyspepsia (6% to 8%), upper abdominal pain (7%), intestinal obstruction (≤6%), dysgeusia (6%), gastrointestinal hemorrhage (6%), abdominal distention (<5%), dysphagia (<5%), rectal pain (<5%), toxic dilation of intestine (<5%), increased serum alanine aminotransferase (Dukes' C colon cancer: grades 3/4: 2%), sore throat (2%), necrotizing enterocolitis

Hematologic & oncologic: Hemorrhage (<5%), lymphedema (<5%), granulocytopenia (Dukes' C colon cancer: grades 3/4: 3%), immune thrombocytopenia (1%)

Hepatic: Abnormal hepatic function tests (<5%), increased serum ALT (Dukes' C colon cancer: grades 3/4: 2%)

Hypersensitivity: Drug-induced hypersensitivity (<5%)

Infection: Viral infection (metastatic colorectal cancer: 5%)

Neuromuscular & skeletal: Back pain (10%), myalgia (≤9%), arthralgia (8%), limb pain (stage IV breast cancer: 6%), tremor (<5%)

Ophthalmic: Visual disturbance (metastatic colorectal cancer: 5%), conjunctivitis (≤5%), keratoconjunctivitis (<5%)

Respiratory: Cough (≤7%), chest mass (<5%), dyspnea (<5%), flu-like symptoms (<5%), hemoptysis (<5%), hoarseness (<5%), pharyngeal disease (metastatic colorectal cancer: 5%), epistaxis (≤3%), laryngitis (1%)

<1% (limited to important or life-threatening): Acute renal failure, ascites, blood coagulation disorder, bronchitis, bronchospasm, cachexia, cerebrovascular accident, cholestatic hepatitis, confusion, cutaneous lupus erythematosus, ecchymoses, esophagitis, fibrosis, fungal infection, gastric ulcer, gastroenteritis, gastrointestinal perforation, hemorrhage, hepatic failure, hepatic fibrosis, hepatitis, hypersensitivity, hypertension, hypertriglyceridemia, hypotension, keratitis, lacrimal stenosis, leukoencephalopathy, loss of consciousness, myocarditis, nocturia, ostealgia, pancytopenia, phlebitis (venous), photophobia, pneumonia, pulmonary embolism, radiation recall phenomenon, respiratory distress, sepsis, Stevens-Johnson syndrome, syncope, tachycardia, toxic epidermal necrolysis

Applies to capecitabine: oral tablet

Along with its needed effects, capecitabine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking capecitabine:

• Abdominal or stomach pain
• diarrhea
• loss of fingerprints
• nausea
• numbness, pain, tingling, or other unusual sensations in the palms of the hands or bottoms of the feet
• pain, blistering, peeling, redness, or swelling of the palms of the hands or bottoms of the feet
• pain, redness, swelling, sores, or ulcers in your mouth or on your lips
• unusual tiredness or weakness
• vomiting

• Abdominal or stomach cramping or pain (severe)
• agitation
• back pain
• bleeding and bruising
• bleeding gums
• blood in the urine or stools
• bloody nose
• bloody or black, tarry stools
• blurred vision
• burning, dry, or itching eyes
• chest pain
• chills
• clumsiness or unsteadiness
• cold
• collapse
• coma
• confusion
• constipation
• convulsions
• cough or hoarseness (accompanied by fever or chills)
• cough producing mucus
• coughing or spitting up blood
• dark urine
• decreased frequency or amount of urine
• difficulty with breathing
• difficulty with swallowing or pain in the back of throat or chest when swallowing
• discharge from the eyes
• drowsiness
• dry mouth
• excessive tearing
• extra heartbeats
• eye redness, irritation, or pain
• fainting
• fast or irregular heartbeat
• fever or chills
• flu-like symptoms
• hallucinations
• headache, sudden and severe
• heavier menstrual periods
• high fever
• hot, red skin on the feet or legs
• inability to speak
• increased menstrual flow or vaginal bleeding
• increased thirst
• irritability
• itching in the genital or other skin areas
• lightheadedness
• light-colored stools
• loss of consciousness
• lower back or side pain (accompanied by fever or chills)
• muscle aches or cramps
• muscle spasms
• nosebleeds
• numbness or tingling in the hands, feet, or lips
• painful or difficult urination (accompanied by fever or chills)
• painful, swollen feet or legs
• pain, tenderness, or swelling in the upper abdominal or stomach area
• pale skin
• paralysis
• pinpoint red spots on the skin
• problems with coordination
• prolonged bleeding from cuts
• rapid, shallow breathing
• red or dark brown urine
• redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid
• scaling
• seizures
• severe constipation
• skin rash or itching
• slow or irregular heartbeat
• slurred speech
• sneezing, sore throat, or stuffy nose
• sores, ulcers, or white spots on the lips or in the mouth
• stiff neck
• stomach bloating, burning, or cramping
• swelling of the face, fingers, feet, or lower legs
• swelling of the lymph nodes
• swollen glands
• temporary blindness
• tiredness or weakness
• trouble with speaking
• troubled breathing or tightness in the chest
• unexplained nosebleeds
• unusual bleeding or bruising
• unusual lump or swelling in the chest
• vomiting blood or material that looks like coffee grounds
• weakness in the arm or leg on one side of the body, sudden and severe
• weight gain or loss
• white patches in the mouth or throat or on the tongue
• white patches with diaper rash
• yellow eyes or skin

• Chest discomfort, tightness, or heaviness
• dilated neck veins
• dizziness
• extreme fatigue
• irregular breathing
• no blood pressure or pulse
• pain or discomfort in the arms, jaw, back, or neck
• stopping of heart
• sweating
• unconsciousness
• weight gain

Some side effects of capecitabine may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feelings
• changes or discoloration in the fingernails or toenails
• difficulty with moving
• discouragement
• headache
• heartburn
• increased sensitivity of the skin to sunlight
• muscle pain
• pain
• pain and redness of the skin at the place of x-ray treatment
• pain in the joints or limbs
• red, sore eyes
• sunken eyes
• thirst
• trouble sleeping
• weakness
• wrinkled skin

• Bone pain
• change in color of treated skin
• difficulty with walking
• discouragement
• feeling of constant movement of self or surroundings
• feeling sad or empty
• full or bloated feeling or pressure in the stomach
• general feeling of discomfort or illness
• hot flushes
• impaired balance
• increased sweating
• joint pain
• lack of appetite
• loss of interest or pleasure
• muscle weakness
• noisy breathing
• pain in the rectum
• pain, swelling, or redness in the joints
• passing less gas
• rough, scratchy sound to voice
• runny nose
• sensation of spinning
• shakiness in the legs, arms, hands, or feet
• shivering
• sores on the skin
• swelling of abdominal or stomach area
• tremor or shaking of the hands or feet
• trouble concentrating
• voice changes

-Mild renal impairment (CrCl 51 to 80 mL/min): No adjustment recommended
-Moderate renal impairment (CrCl 30 to 50 mL/min): Reduce the capecitabine starting dose to 75% (from 1250 mg/m2 to 950 mg/m2 orally 2 times a day)
-Severe renal impairment (CrCl less than 30 mL/min): Contraindicated

Data not available

UK: Contraindicated AU, US: A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. Excreted into human milk: Unknown Excreted into animal milk: Yes Comment: The effects in the nursing infant are unknown.