1.1 Colorectal Cancer

Capecitabine tablets are indicated for the:

• adjuvant treatment of patients with Stage III colon cancer as a single agent or as a component of a combination chemotherapy regimen.
• perioperative treatment of adults with locally advanced rectal cancer as a component of chemoradiotherapy.
• treatment of patients with unresectable or metastatic colorectal cancer as a single agent or as a component of a combination chemotherapy regimen.

1.2 Breast Cancer

Capecitabine tablets are indicated for the:

• treatment of patients with advanced or metastatic breast cancer as a single agent if an anthracycline- or taxane-containing chemotherapy is not indicated.
• treatment of patients with advanced or metastatic breast cancer in combination with docetaxel after disease progression on prior anthracycline-containing chemotherapy.

1.3 Gastric, Esophageal, or Gastroesophageal Junction Cancer

Capecitabine tablets are indicated for the:

• treatment of adults with unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer as a component of a combination chemotherapy regimen.
• treatment of adults with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease as a component of a combination regimen.

1.4 Pancreatic Cancer

Capecitabine tablets are indicated for the adjuvant treatment of adults with pancreatic adenocarcinoma as a component of a combination chemotherapy regimen.

2. 1 Recommended Dosage for Colorectal Cancer

Adjuvant Treatment of Colon Cancer

Single Agent

The recommended dosage of capecitabine tablet is 1,250 mg/m2 orally twice daily for the first 14 days of each 21-day cycle for a maximum of 8 cycles.

In Combination with Oxaliplatin-Containing Regimens

The recommended dosage of capecitabine tablet is 1,000 mg/m2 orally twice daily for the first 14 days of each 21-day cycle for a maximum of 8 cycles in combination with oxaliplatin 130 mg/m2 administered intravenously on day 1 of each cycle.

Refer to the oxaliplatin prescribing information for additional dosing information as appropriate.

 Perioperative Treatment of Rectal Cancer

The recommended dosage of capecitabine is 825 mg/m2 orally twice daily when administered with concomitant radiation therapy and 1,250 mg/m2 orally twice daily when administered without radiation therapy as part of a peri-operative combination regimen.

Unresectable or Metastatic Colorectal Cancer

Single Agent

The recommended dosage of capecitabine tablet is 1,250 mg/m2 orally twice daily for the first 14 days of a 21-day cycle until disease progression or unacceptable toxicity.

In Combination with Oxaliplatin

The recommended dosage of capecitabine tablet is 1,000 mg/m2 orally twice daily for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity in combination with oxaliplatin 130 mg/m2 administered intravenously on day 1 of each cycle.

Refer to the Prescribing Information for oxaliplatin for additional dosing information as appropriate.

2.2 Recommended Dosage for Breast Cancer

Advanced or Metastatic Breast Cancer

Single Agent

The recommended dosage of capecitabine tablet is 1,000 mg/m2 or 1,250 mg/m2 orally twice daily for the first 14 days of a 21-day cycle until disease progression or unacceptable toxicity. Individualize the dose and dosing schedule of capecitabine tablets based on patient risk factors and adverse reactions.

In Combination with Docetaxel

The recommended dosage of capecitabine tablet is 1,000 mg/m2 or 1,250 mg/m2 orally twice daily for the first 14 days of a 21-day cycle until disease progression or unacceptable toxicity in combination with docetaxel 75 mg/m2 administered intravenously on day 1 of each cycle.

Refer to the Prescribing Information for docetaxel for additional dosing information as appropriate.

2.3 Recommended Dosage for Gastric, Esophageal, or Gastroesophageal Junction Cancer

The recommended dosage of capecitabine tablets for unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer is:

• 625 mg/m2 orally twice daily on days 1 to 21 of each 21-day cycle for a maximum of 8 cycles in combination with platinum-containing chemotherapy.

OR

• 850 mg/m2 or 1,000 mg/m2 orally twice daily for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity in combination with oxaliplatin 130 mg/m2 administered intravenously on day 1 of each cycle. Individualize the dose and dosing schedule of capecitabine tablets based on patient risk factors and adverse reactions.

The recommended dosage of capecitabine tablets for HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma is 1,000 mg/m2 orally twice daily for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity in combination with cisplatin and trastuzumab.

Refer to the Prescribing Information for agents used in combination for additional dosing  information as appropriate.

2.4 Recommended Dosage for Pancreatic Cancer

The recommended dosage of capecitabine tablet is 830 mg/m2 orally twice daily for the first 21 days of each 28-day cycle until disease progression, unacceptable toxicity, or for a maximum 6 cycles in combination with gemcitabine 1,000 mg/m2 administered intravenously on days 1, 8, and 15 of each cycle.

Refer to Prescribing Information for gemcitabine for additional dosing information as appropriate.

2.5 Dosage Modifications for Adverse Reactions

Monitor patients for adverse reactions and modify dosages of capecitabine tablets as described in Table 1.    Do not replace missed doses of capecitabine tablets; instead resume capecitabine tablets with the next planned dosage.

When capecitabine tablets are administered with docetaxel, withhold capecitabine tablets and docetaxel until the  requirements for resuming both capecitabine tablets and docetaxel are met. Refer to the Prescribing Information for docetaxel for additional dosing information as appropriate.

Table 1 Recommended Dosage Modifications for Adverse Reactions

Hyperbilirubinemia

Patients with Grade 3 to 4 hyperbilirubinemia may resume treatment once the event is Grade 2 or less (less than three times the upper limit of normal), using the percent of current dose as shown in column 3 of Table 1 [see Warnings and Precautions (5.10)].

2.6 Dosage Modification For Renal Impairment

Reduce the dose of capecitabine tablets by 25% for patients with creatinine clearance (CLcr) of 30 to 50 mL/min as determined by Cockcroft-Gault equation. A dosage has not been established in patients with severe renal impairment (CLcr <30 mL/min) [see Use in Specific Populations (8.6)].

2.7 Administration

Round the recommended dosage for patients to the nearest 150 mg dose to provide whole capecitabine tablets.

Swallow capecitabine tablets whole with water within 30 minutes after a meal. Do not chew, cut, or crush capecitabine tablets [see Warnings and Precautions (5.12)].

Take capecitabine tablets at the same time each day approximately 12 hours apart.

Do not take an additional dose after vomiting and continue with the next scheduled dose. Do not take a missed dose and continue with the next scheduled dose.

Capecitabine tablets are a hazardous drug. Follow applicable special handling and disposal procedures.1

5.1 Increased Risk of Bleeding With Concomitant Use of Vitamin K Antagonists

Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking capecitabine tablets concomitantly with vitamin K antagonists, such as warfarin.

Clinically significant increases in PT and INR have been reported in patients who were on stable doses of oral vitamin K antagonists at the time capecitabine tablets was introduced. These events occurred within several days and up to several months after initiating capecitabine tablets and, in a few cases, within 1 month after stopping capecitabine tablets. These events occurred in patients with and without liver metastases.

Monitor INR more frequently and adjust the dose of the vitamin K antagonist as appropriate [see Drug Interactions (7.1)].

5.2 Serious Adverse Reactions from Dihydropyrimidine Dehydrogenase (DPD) Deficiency

Patients with certain homozygous or compound heterozygous variants in the DPYD gene known to result in complete or near complete absence of DPD activity (complete DPD deficiency) are at increased risk for acute early-onset toxicity and serious, including fatal, adverse reactions due to capecitabine tablets (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity).    Patients with partial DPD activity (partial DPD deficiency) may also have increased risk of serious, including fatal, adverse reactions.

Capecitabine tablets are not recommended for use in patients known to have certain homozygous or compound heterozygous DPYD variants that result in complete DPD deficiency.

Withhold or permanently discontinue capecitabine tablets based on clinical assessment of the onset, duration, and severity of the observed adverse reactions in patients with evidence of acute early- onset or unusually severe reactions, which may indicate complete DPD deficiency. No capecitabine tablets  dose has been proven safe for patients with complete DPD deficiency. There are insufficient data to recommend a specific dose in patients with partial DPD deficiency.

Consider testing for genetic variants of DPYD prior to initiating capecitabine tablets to reduce the risk of serious adverse reactions if the patient’s clinical status permits and based on clinical judgement [see Clinical Pharmacology (12.5)]. Serious adverse reactions may still occur even if no DPYD variants are identified.

An FDA-authorized test for the detection of genetic variants of DPYD to identify patients at risk of serious adverse reactions due to increased systemic exposure to capecitabine tablets are not currently available. Currently available tests used to identify DPYD variants may vary in accuracy and design (e.g., which DPYD variant(s) they identify).

5.3 Cardiotoxicity

Cardiotoxicity can occur with capecitabine tablets. Myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy have been reported with capecitabine tablets. These adverse reactions may be more common in patients with a prior history of coronary artery disease.

Withhold capecitabine tablets for cardiotoxicity as appropriate [see Dosage and Administration (2.5)]. The safety of resumption of capecitabine tablets in patients with cardiotoxicity that has resolved have not been established. 

5.4 Diarrhea

Diarrhea, sometimes severe, can occur with capecitabine tablets. In 875 patients with metastatic breast or          colorectal cancer who received capecitabine tablets as a single agent, the median time to first occurrence of grade 2 to 4 diarrhea was 34 days (range: 1 day to 1 year). The median duration of grade 3 to  4 diarrhea was 5 days.

Withhold capecitabine tablets and then resume at same or reduced dose or permanently discontinue based on severity and occurrence [see Dosage and Administration (2.5)].

5.5 Dehydration

Dehydration can occur with capecitabine tablets. Patients with anorexia, asthenia, nausea, vomiting, or diarrhea may be at an increased risk of developing dehydration with capecitabine tablets. Optimize hydration before starting capecitabine tablets. Monitor hydration status and kidney function at baseline and as clinically indicated. Withhold capecitabine tablets and then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence [see Dosage and Administration (2.5)].

5.6 Renal Toxicity

Serious renal failure, sometimes fatal, can occur with capecitabine tablets. Renal impairment or coadministration of capecitabine tablets with other products known to cause renal toxicity may increase the risk of renal toxicity [see Drug Interactions (7.3)].

Monitor renal function at baseline and as clinically indicated. Optimize hydration before starting capecitabine tablets. Withhold capecitabine tablets and then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence [see Dosage and Administration (2.5)].

5.7 Serious Skin Toxicities

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson Syndrome and toxic epidermal necrolysis (TEN), which can be fatal, can occur with capecitabine tablets [see Adverse Reactions (6.2)].

Monitor for new or worsening serious skin reactions. Permanently discontinue capecitabine tablets for severe cutaneous adverse reactions.

5.8 Palmar-Plantar Erythrodysesthesia Syndrome

Palmar-plantar erythrodysesthesia syndrome (PPES) can occur with capecitabine tablets.

In patients with metastatic breast or colorectal cancer who received capecitabine tablets as a single agent, the median time to onset of grades 1 to 3 PPES was 2.6 months (range: 11 days to 1 year).

Withhold capecitabine tablets and then resume at same or reduced dose or permanently discontinue based on severity and occurrence [see Dosage and Administration (2.5)].

5.9 Myelosuppression

Myelosuppression can occur with capecitabine tablets.

In the 875 patients with metastatic breast or colorectal cancer who received capecitabine tablets as a single  agent, 3.2% had grade 3 or 4 neutropenia, 1.7% had grade 3 or 4 thrombocytopenia, and 2.4% had grade 3 or 4 anemia.

In the 251 patients with metastatic breast cancer who received capecitabine tablets with docetaxel, 68% had grade 3 or 4 neutropenia, 2.8% had grade 3 or 4 thrombocytopenia, and 10% had grade 3 or 4 anemia.

Necrotizing enterocolitis (typhlitis) has been reported. Consider typhlitis in patients with fever, neutropenia and abdominal pain.

Monitor complete blood count at baseline and before each cycle. Capecitabine tablets are not recommended if baseline neutrophil count <1.5 x 109/L or platelet count <100 x 109/L. For grade 3 to 4 myelosuppression, withhold capecitabine tablets and then resume at same or reduced dose, or permanently discontinue, based on occurrence [see Dosage and Administration (2.5)].

5.10 Hyperbilirubinemia

Hyperbilirubinemia can occur with capecitabine tablets. In the 875 patients with metastatic breast or colorectal cancer who received capecitabine tablets as a single agent, grade 3 hyperbilirubinemia occurred in 15% of patients and grade 4 hyperbilirubinemia occurred in 3.9%. Of the 566 patients who had hepatic metastases at baseline and the 309 patients without hepatic metastases at baseline, grade 3 or 4 hyperbilirubinemia occurred in 23% and 12%, respectively. Of these 167 patients with grade 3 or 4 hyperbilirubinemia, 19% had postbaseline increased alkaline phosphatase and 28% had postbaseline increased transaminases at any time (not necessarily concurrent). The majority of these patients with increased transaminases or alkaline phosphatase had liver metastases at baseline. In addition, 58% and 35% of the 167 patients with grade 3 or 4 hyperbilirubinemia had pre- and postbaseline increased alkaline phosphatase or transaminases (grades 1 to 4), respectively. Only 8% (n=13) and 3% (n=5) had grade 3 or 4 increased alkaline phosphatase or transaminases. 

In the 596 patients who received capecitabine tablets for metastatic colorectal cancer, the incidence of grade 3 or 4 hyperbilirubinemia was similar to that observed for the pooled population of patients with metastatic breast and colorectal cancer. The median time to onset for grade 3 or 4 hyperbilirubinemia was 64 days and median total bilirubin increased from 8 µm/L at baseline to 13 µm/L during treatment with capecitabine tablets. Of the 136 patients with grade 3 or 4 hyperbilirubinemia, 49 patients had grade 3 or 4 hyperbilirubinemia as their last measured value, of which 46 had liver metastases at baseline.

In the 251 patients with metastatic breast cancer who received capecitabine tablets with docetaxel, grade 3 hyperbilirubinemia occurred in 7% and grade 4 hyperbilirubinemia occurred in 2%.

Withhold capecitabine tablets and then resume at a same or reduced dose, or permanently discontinue, based on occurrence [see Dosage and Administration (2.5)]. Patients with Grade 3 to 4 hyperbilirubinemia may resume treatment once the event is Grade 2 or less than three times the upper limit of normal, using the percent of current dose as shown in Table 1 [see Dosage and Administration (2.5)].

5.11 Embryo-Fetal Toxicity

Based on findings from animal reproduction studies and its mechanism of action, capecitabine tablets can cause fetal harm when administered to a pregnant woman. Insufficient data is available on capecitabine tablets use in pregnant women to evaluate a drug-associated risk. In animal reproduction studies, administration of capecitabine to pregnant animals during the period of organogenesis caused embryolethality and teratogenicity in mice and embryolethality in monkeys at 0.2 and 0.6 times the human exposure (AUC) in patients who received a dosage of 1,250 mg/m2 twice daily, respectively.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with capecitabine tablets and for 6 months following the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with capecitabine tablets and for 3 months following the last dose [see Use in Specific Populations (8.1, 8.3)].

5.12 Eye Irritation, Skin Rash and Other Adverse Reactions from Exposure to Crushed Tablets

In instances of exposure to crushed capecitabine tablets, the following adverse reactions have been reported: eye irritation and swelling, skin rash, diarrhea, paresthesia, headache, gastric irritation, vomiting and nausea. Advise patients not to cut or crush tablets.

If capecitabine tablets must be cut or crushed, this should be done by a professional trained in safe handling of cytotoxic drugs using appropriate equipment and safety procedures [see Dosage and Administration (2.7)]. The safety and effectiveness have not been established for the administration of crushed capecitabine tablets.

6.1 Clinical Trials Experience

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 Treatment of Colon Cancer

Single Agent

The safety of capecitabine tablets as a single agent was evaluated in patients with Stage III colon cancer in X-ACT [see Clinical Studies (14.1)]. Patients received capecitabine tablets 1,250 mg/m2 orally twice daily for the first 14 days of a 21-day cycle (N=995) or leucovorin 20 mg/m2 intravenously followed by fluorouracil 425 mg/m2 as an intravenous bolus on days 1 to 5 of each 28-day cycle (N=974). Among patients who received capecitabine tablets, the median duration of treatment was 5.4 months.

Deaths due to all causes occurred in 0.8% of patients who received capecitabine tablets on study or within 28 days of receiving study drug. Permanent discontinuation due to an adverse reaction occurred in 11% of patients who received capecitabine tablets.

Most common adverse reactions (>30%) were palmar-plantar erythrodysesthesia syndrome, diarrhea, and nausea.

Tables 2 and 3 summarize the adverse reactions and laboratory abnormalities in X-ACT.

Table 2 Adverse Reactions (>10%) in Patients Who Received Capecitabine Tablets for Adjuvant Treatment of Colon Cancer in X-ACT

Clinically relevant adverse reactions in <10% of patients are presented below:

Eye: conjunctivitis

Gastrointestinal: constipation, upper abdominal pain, dyspepsia

General: pyrexia

Metabolism and Nutrition: anorexia

Nervous System: dizziness, dysgeusia, headache

Skin & Subcutaneous Tissue: rash, alopecia, erythema

Table 3 Grade 3 or 4 Laboratory Abnormalities (>1%) in Patients Who Received Capecitabine Tablets as a Single Agent for Adjuvant Treatment of Colon Cancer in X- ACT

In Combination with Oxaliplatin-Containing Regimens

The safety of capecitabine tablets for the perioperative treatment of adults with Stage III colon cancer as a component of a combination chemotherapy regimen was derived from published literature [see Clinical Studies (14.1)]. The safety of capecitabine tablets for the adjuvant treatment of patients with Stage III colon cancer as a component of a combination chemotherapy regimen was similar to those in patients treated with capecitabine tablets as a single agent, with the exception of an increased incidence of neurosensory toxicity.

Perioperative Treatment of Rectal Cancer

The safety of capecitabine tablets for the perioperative treatment of adults with locally advanced rectal cancer as a component of chemoradiotherapy was derived from published literature [see Clinical               Studies (14.1)]. The safety of capecitabine tablets for the perioperative treatment of adults with locally advanced rectal cancer as a component of chemoradiotherapy was similar to those in patients treated with capecitabine tablets as a single agent, with the exception of an increased incidence of diarrhea.

Metastatic Colorectal Cancer

Single Agent

The safety of capecitabine tablets as a single agent was evaluated in a pooled metastatic colorectal cancer population (Study SO14695 and Study SO14796) [see Clinical Studies (14.1)]. Patients received       capecitabine tablets 1,250 mg/m2 orally twice a day for the first 14 days of a 21-day cycle (N=596) or leucovorin 20 mg/m2 intravenously followed by fluorouracil 425 mg/m2 as an intravenous bolus on days 1 to 5 of each 28-day cycle (N=593). Among the patients who received capecitabine tablets, the median duration of treatment was 4.6 months.

Deaths due to all causes occurred in 8% of patients who received capecitabine tablets on study or within 28 days of receiving study drug. Permanent discontinuation due to an adverse reaction or intercurrent illness occurred in 13% of patients who received capecitabine tablets.

Most common adverse reactions (>30%) were anemia, diarrhea, palmar-plantar erythrodysesthesia syndrome, hyperbilirubinemia, nausea, fatigue, and abdominal pain.

Table 4 shows the adverse reactions occurring in this pooled colorectal cancer population.

 Table 4 Adverse Reactions (>10%) in Patients Who Received Capecitabine Tablets in Pooled Metastatic Colorectal Cancer Population (Study SO14695 and Study SO14796)

– Not observed

*Includes weakness 

 NA = Not Applicable

Clinically relevant adverse reactions in <10% of patients are presented below:

 Eye: abnormal vision

Gastrointestinal: upper gastrointestinal tract inflammatory disorders, gastrointestinal hemorrhage, ileus

General: chest pain

Infections: viral

Metabolism and Nutrition: dehydration

Musculoskeletal: arthralgia

Nervous System: dizziness (excluding vertigo), insomnia, taste disturbance

Psychiatric: mood alteration, depression

Respiratory, Thoracic, and Mediastinal: cough, pharyngeal disorder 

Skin and Subcutaneous Tissue: skin discoloration, alopecia 

Vascular: venous thrombosis

In Combination with Oxaliplatin

The safety of capecitabine tablets for the treatment of patients with unresectable or metastatic colorectal cancer as a component of a combination chemotherapy regimen was derived from published literature [see Clinical Studies (14.1)]. The safety of capecitabine tablets for the treatment of patients with unresectable or metastatic colorectal cancer as a component of a combination chemotherapy regimen was similar to those in patients treated with capecitabine tablets as a single agent, with the exception of an increased incidence of peripheral neuropathy.

Metastatic Breast Cancer

In Combination with Docetaxel

The safety of capecitabine tablets in combination with docetaxel was evaluated in patients with metastatic breast cancer in Study SO14999 [see Clinical Studies (14.2)]. Patients received capecitabine tablets 1,250 mg/m2 orally twice daily for the first 14 days of a 21-day cycle with docetaxel 75 mg/m2 as 1- hour intravenous infusion on day 1 of each 21-day cycle for at least 6 weeks or docetaxel 100 mg/m2 as a 1-hour intravenous infusion on day 1 of each 21-day cycle for at least 6 weeks. Among patients who received capecitabine tablets, the mean duration of treatment was 4.2 months.

Permanent discontinuation due to an adverse reaction occurred in 26% of patients who received capecitabine tablets. Dosage interruptions due to an adverse reaction occurred in 79% of patients who received capecitabine tablets and dosage reductions due to an adverse reaction occurred in 65%.

Most common adverse reactions (>30%) were diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, nausea, alopecia, vomiting, edema, and abdominal pain.

Table 5 summarizes the adverse reactions in Study SO14999.

Table 5 Adverse Reactions (≥10%) in Patients Who Received Capecitabine Tablets with Docetaxel for Metastatic Breast Cancer in Study SO14999

– Not observed

NA = Not Applicable

Clinically relevant adverse reactions in <10% of patients are presented below: 

Blood and Lymphatic System: agranulocytosis, prothrombin decreased 

Cardiac: supraventricular tachycardia

Eye: conjunctivitis, eye irritation

Gastrointestinal: ileus, necrotizing enterocolitis, esophageal ulcer, hemorrhagic diarrhea, dry  mouth

General: chest pain (non-cardiac), lethargy, pain, influenza-like illness

Hepatobiliary: jaundice, abnormal liver function tests, hepatic failure, hepatic coma, hepatotoxicity

Immune System: hypersensitivity

Infection: hypoesthesia, neutropenic sepsis, sepsis, bronchopneumonia, oral candidiasis, urinary tract infection

Metabolism and Nutrition: weight decreased

Musculoskeletal and Connective Tissue: bone pain

Nervous System: insomnia, peripheral neuropathy, ataxia, syncope, taste loss, polyneuropathy, migraine

Psychiatric: depression

Renal and Urinary: renal failure

Respiratory, Thoracic and Mediastinal: upper respiratory tract infection, pleural effusion, epistaxis, rhinorrhea

Skin and Subcutaneous Tissue: pruritis, rash erythematous, dermatitis, nail discoloration, onycholysis

Vascular: lymphedema, hypotension, venous phlebitis and thrombophlebitis, postural  hypotension, flushing

Table 6 summarizes the laboratory abnormalities in this trial.

Table 6 Laboratory Abnormalities (≥20%) in Patients Who Received Capecitabine Tablets with Docetaxel for Metastatic Breast Cancer in Study SO14999

Single Agent

The safety of capecitabine tablets as a single agent was evaluated in patients with metastatic breast cancer in Study SO14697 [see Clinical Studies (14.2)]. Patients received capecitabine tablets 1,250 mg/m2 orally twice daily for the first 14 days of a 21-day cycle. The mean duration of treatment was 3.7 months.

Permanent discontinuation due to an adverse reaction or intercurrent illness occurred in 8% of patients.

Most common adverse reactions (>30%) were lymphopenia, anemia, diarrhea, hand-and-foot syndrome, nausea, fatigue, vomiting, and dermatitis.

Table 7 summarizes the adverse reactions in Study SO14697.

Table 7 Adverse Reactions (>10%) in Patients Who Received Capecitabine Tablets for Metastatic Breast Cancer in Study SO14697

– = Not observed 

 NA = Not Applicable

Pooled Safety Population

Clinically relevant adverse reactions in <10% of patients who received capecitabine tablets as a single agent are presented below.

Blood & Lymphatic System: leukopenia, coagulation disorder, bone marrow depression, pancytopenia

Cardiac: tachycardia, bradycardia, atrial fibrillation, myocarditis, edema

Ear: vertigo

Eye: conjunctivitis

Gastrointestinal: abdominal distension, dysphagia, proctalgia, gastric ulcer, ileus, gastroenteritis, dyspepsia

General: chest pain, influenza-like illness, hot flushes, pain, thirst, fibrosis, hemorrhage, edema, pain in limb

Hepatobiliary: hepatic fibrosis, hepatitis, cholestatic hepatitis, abnormal liver function tests

Immune System: drug hypersensitivity               

Infections: bronchitis, pneumonia, keratoconjunctivitis, sepsis, fungal infections

Metabolism and Nutrition: cachexia, hypertriglyceridemia, hypokalemia, hypomagnesemia, dehydration

Musculoskeletal and Connective Tissue: myalgia, arthritis, muscle weakness

Nervous System: insomnia, ataxia, tremor, dysphasia, encephalopathy, dysarthria, impaired balance, headache, dizziness

Psychiatric: depression, confusion

Renal and Urinary: renal impairment

Respiratory, Mediastinal and Thoracic: cough, epistaxis, respiratory distress, dyspnea

Skin and Subcutaneous Tissue: nail disorder, sweating increased, photosensitivity reaction, skin ulceration, pruritus, radiation recall syndrome

Vascular: hypotension, hypertension, lymphedema, pulmonary embolism

Unresectable or Metastatic Gastric, Esophageal, or Gastroesophageal Junction Cancer

 The safety of capecitabine tablets for the treatment of adults with unresectable or metastatic gastric,

esophageal, or gastroesophageal junction cancer as a component of a combination chemotherapy regimen was derived from published literature [see Clinical Studies (14.3)]. The safety of capecitabine tablets for the treatment of adults with unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer as a component of a combination chemotherapy regimen was consistent with the known safety profile of capecitabine tablets.

The safety of capecitabine tablets for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease as a component of a combination regimen was derived from the published literature [see Clinical Studies (14.3)]. The safety of capecitabine tablets for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma was consistent with the known safety profile of capecitabine tablets.

Pancreatic Cancer

The safety of capecitabine tablets for the adjuvant treatment of adults with pancreatic adenocarcinoma as a component of a combination chemotherapy regimen was derived from the published literature [see Clinical Studies (14.4)]. The safety of capecitabine tablets for the adjuvant treatment of adults with pancreatic adenocarcinoma as a component of a combination chemotherapy regimen was consistent with the known safety profile of capecitabine tablets.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of capecitabine tablets.         Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Eye: lacrimal duct stenosis, corneal disorders including keratitis

Hepatobiliary: hepatic failure

Immune System Disorders: angioedema

Nervous System: toxic leukoencephalopathy

Renal & Urinary: acute renal failure secondary to dehydration including fatal outcome

Skin & Subcutaneous Tissue: cutaneous lupus erythematosus, severe skin reactions such as Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (TEN), persistent or severe PPES can eventually lead to loss of fingerprints

7.1 Effect of Other Drugs on Capecitabine Tablets

Allopurinol

Concomitant use with allopurinol may decrease concentration of capecitabine’s active  metabolites [see Clinical Pharmacology (12.3)], which may decrease efficacy. Avoid concomitant use of allopurinol with capecitabine tablets.

Leucovorin

The concentration of fluorouracil is increased and its toxicity may be enhanced by leucovorin, folic acid, or folate analog products. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil.

Instruct patients not to take products containing folic acid or folate analog products unless directed to do so by their healthcare provider.

7.2 Effect of Capecitabine Tablets on Other Drugs

CYP2C9 Substrates

Capecitabine tablets increased exposure of CYP2C9 substrates [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to these substrates. Closely monitor for adverse reactions of CYP2C9 substrates where minimal concentration changes may lead to serious adverse reactions when used concomitantly with capecitabine tablets (e.g., anticoagulants, antidiabetic  drugs).

Vitamin K Antagonists

Capecitabine tablets increases exposure of vitamin K antagonist [see Clinical Pharmacology (12.3)], which may alter coagulation parameters and/or bleeding and could result in death [see Warning and Precautions (5.1)]. These events may occur within days of treatment initiation and up to 1 month after discontinuation of capecitabine tablets.

Monitor INR more frequently and refer to the prescribing information of oral vitamin K antagonist for dosage adjustment, as appropriate, when capecitabine tablets are used concomitantly with vitamin K antagonist.

Phenytoin

Capecitabine tablets may increases exposure of phenytoin, which may increase the risk of adverse reactions related to phenytoin. Closely monitor phenytoin levels and refer to the prescribing information of phenytoin for dosage adjustment, as appropriate, when capecitabine tablets are used concomitantly with phenytoin.

7.3 Nephrotoxic Drugs

Due of the additive pharmacologic effect, concomitant use of capecitabine tablets with other drugs known to cause renal toxicity may increase the risk of renal toxicity [see Warnings and Precautions (5.6)]. Closely monitor for signs of renal toxicity when capecitabine tablets are used concomitantly with nephrotoxic drugs (e.g. platinum salts, irinotecan, methotrexate, intravenous bisphosphonates).

8.1 Pregnancy

Risk Summary

Based on findings in animal reproduction studies and its mechanism of action [see Clinical Pharmacology (12.1)], capecitabine tablets can cause fetal harm when administered to a pregnant woman. Available human data with capecitabine tablets use in pregnant women is not sufficient to inform the drug-associated risk. In animal reproduction studies, administration of capecitabine to pregnant animals during the period of organogenesis caused embryolethality and teratogenicity in mice and embryolethality in monkeys at 0.2 and 0.6 times the exposure (AUC) in patients receiving the recommended dose of 1,250 mg/m2 twice daily, respectively (see Data). Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

Oral administration of capecitabine to pregnant mice during the period of organogenesis at a dose of 198 mg/kg/day caused malformations and embryo lethality. In separate pharmacokinetic studies, this dose in mice produced 5’-DFUR AUC values that were approximately 0.2 times the AUC values in patients administered the recommended daily dose. Malformations in mice included cleft palate, anophthalmia, microphthalmia, oligodactyly, polydactyly, syndactyly, kinky tail and dilation of cerebral ventricles. Oral administration of capecitabine to pregnant monkeys during the period of organogenesis at a dose of 90 mg/kg/day, caused fetal lethality.

This dose produced 5’-DFUR AUC values that were approximately 0.6 times the AUC values in patients administered the recommended daily dose.

8.2 Lactation

Risk Summary

There is no information regarding the presence of capecitabine or its metabolites in human milk, or on its effects on milk production or the breastfed child. Capecitabine metabolites were present in the milk of lactating mice (see Data). Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with capecitabine tablets and for 1 week after the last dose.

Data

Lactating mice given a single oral dose of capecitabine excreted significant amounts of capecitabine metabolites into the milk.

8.3 Females and Males of Reproductive Potential

Capecitabine tablets can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating capecitabine tablets.

 Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with capecitabine tablets and for 6 months after the last dose.

Males

Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with capecitabine tablets and for 3 months after the last dose [see Nonclinical Toxicology (13.1)].

Infertility

Based on animal studies, capecitabine tablets may impair fertility in females and males of reproductive potential [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of capecitabine tablets in pediatric patients have not been established.

Safety and effectiveness were assessed, but not established in two single arm studies in 56 pediatric patients aged 3 months to <17 years with newly diagnosed gliomas. In both trials, pediatric patients received an investigational pediatric formulation of capecitabine concomitantly with and following completion of radiation therapy (total dose of 5,580 cGy in 180 cGy fractions). The relative bioavailability of the investigational formulation to capecitabine tablets was similar.

The adverse reaction profile was consistent with that of adults, with the exception of laboratory abnormalities which occurred more commonly in pediatric patients. The most frequently reported laboratory abnormalities (per-patient incidence ≥ 40%) were increased ALT (75%), lymphocytopenia (73%), hypokalemia (68%), thrombocytopenia (57%), hypoalbuminemia (55%), neutropenia (50%), low hematocrit (50%), hypocalcemia (48%), hypophosphatemia (45%) and hyponatremia (45%).

8.5 Geriatric Use

Of 7,938 patients with colorectal cancer who were treated with capecitabine tablets, 33% were older than 65 years. Of the 4,536 patients with metastatic breast cancer who were treated with capecitabine tablets, 18% were older than 65 years.

Of 1,951 patients with gastric, esophageal, or gastrointestinal junction cancer who were treated with capecitabine tablets, 26% were older than 65 years.

Of 364 patients with pancreatic cancer who received adjuvant treatment with capecitabine tablets, 47% were 65 years or older.

No overall differences in efficacy were observed comparing older versus younger patients with colorectal cancer, gastric, esophageal or gastrointestinal junction cancer, or pancreatic cancer using the approved recommended dosages and treatment regimens.

Older patients experience increased gastrointestinal toxicity due to capecitabine tablets compared to younger patients. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil [see Drug Interactions (7.1)].

8.6 Renal Impairment

The exposure of capecitabine and its inactive metabolites (5-DFUR and FBAL) increases in patients with CLcr <50 mL/min as determined by Cockcroft-Gault [see Clinical Pharmacology (12.3)]. Reduce the dosage for patients with CLcr of 30 to 50 mL/min [see Dosage and Administration (2.6)]. There is limited experience with capecitabine tablets in patients with CLcr <30 mL/min, and a dosage has not been established in those patients. If no treatment alternative exists, capecitabine tablets could be administered to such patients on an individual basis applying a reduced starting dose, close monitoring of a patient's clinical and biochemical data and dose modifications guided by observed adverse reactions.

8.7 Hepatic Impairment

The exposure of capecitabine increases in patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on the safety and pharmacokinetics of capecitabine tablets are unknown [see Clinical Pharmacology (12.3)]. Monitor patients with hepatic impairment more frequently for adverse reactions.

12.1 Mechanism of Action

Capecitabine is metabolized to fluorouracil in vivo. Both normal and tumor cells metabolize fluorouracil 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, N5-10-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.

12.2 Pharmacodynamics

Population-based exposure-effect analyses demonstrated a positive association between AUC of                                     fluorouracil and grade 3 to 4 hyperbilirubinemia.

12.3 Pharmacokinetics

The AUC of capecitabine and its metabolite 5’-DFCR increases proportionally over a dosage range of 500 mg/m2/day to 3,500 mg/m2/day (0.2 to 1.4 times the approved recommended dosage). The AUC of capecitabine’s metabolites 5’-DFUR and fluorouracil increased greater than proportional to the dose. The interpatient variability in the Cmax and AUC of fluorouracil was greater than 85%.

Absorption

Following oral administration of capecitabine tablets 1,255 mg/m2 orally twice daily (the recommended dosage when used as single agent), the median Tmax of capecitabine and its metabolite fluorouracil was approximately 1.5 hours and 2 hours, respectively.

Effect of Food

Following administration of a meal (breakfast medium-rich in fat and carbohydrates), the mean Cmax and AUC0-INF of capecitabine was decreased by 60% and 34%, respectively. The mean Cmax and AUC0-INF of fluorouracil were also decreased by 37 % and 12%, respectively. The Tmax of both capecitabine and fluorouracil was delayed by 1.5 hours.

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%).

Following oral administration of capecitabine tablets 7 days before surgery in patients with colorectal cancer, the median ratio of concentration for the active metabolite fluorouracil in colorectal        tumors to adjacent tissues was 2.9 (range: 0.9 to 8.0).

Elimination

The elimination half-lives of capecitabine and fluorouracil were approximately 0.75 hour.

Metabolism

Capecitabine undergoes metabolism by carboxylesterase and is hydrolyzed to 5’-DFCR. 5’- DFCR is subsequently converted to 5’-DFUR by cytidine deaminase. 5’-DFUR is then hydrolized by thymidine phosphorylase (dThdPase) enzymes to the active metabolite fluorouracil.

Fluorouracil is subsequently metabolized by dihydropyrimidine dehydrogenase to 5-fluoro-5, 6- dihydro-fluorouracil (FUH2). The pyrimidine ring of FUH2 is cleaved by dihydropyrimidinase to yield 5-fluoro-ureido-propionic acid (FUPA). Finally, FUPA is cleaved by β-ureido-propionase to α-fluoro-β-alanine (FBAL).

Excretion

Following administration of radiolabeled capecitabine, 96% of the administered capecitabine dose was recovered in urine (3% unchanged and 57% as metabolite FBAL) and 2.6% in feces.

Specific Populations

Following therapeutic doses of capecitabine tablets, no clinically meaningful difference in the pharmacokinetics of 5’-DFUR, fluorouracil or FBAL were observed based on sex (202 females and 303 males) and race (455 White, 22 Black, and 28 Other). No clinically meaningful difference on the pharmacokinetics of 5’-DFUR and fluorouracil were observed based on age (range: 27 to 86 years); however, the AUC of FBAL increased by 15% following a 20% increase in age.

Racial or Ethnic Groups

Following administration of capecitabine tablets 825 mg/m2 orally twice daily for 14 days (0.66 times the recommended dosage), the Cmax and AUC of capecitabine decreased by 36% and 24%, respectively in Japanese patients (n=18) compared to White patients (n=22). The Cmax and AUC of FBAL decreased by approximately 25% and 34%, respectively in Japanese patients compared to White patients; however, the clinical significance of these differences is unknown. No clinically significant differences in the pharmacokinetics of 5’-DFCR, 5’-DFUR or fluorouracil were observed.

Patients with Renal Impairment

Table 8 Effect of Renal Impairment on the Pharmacokinetics of Capecitabine, 5’-DFUR, and FBAL

Patients with Hepatic Impairment

AUC0-INF and Cmax of capecitabine’s active principle, fluorouracil, were not affected in patients with mild or moderate hepatic impairment compared to patients with normal hepatic function. The AUC0-INF and Cmax of capecitabine increased by 60%. The effect of severe hepatic impairment on the pharmacokinetics of capecitabine and its metabolites are unknown.

Drug Interaction Studies

Clinical Studies

Effect of Capecitabine on Warfarin: In four patients with cancer, chronic administration of capecitabine tablets 1,250 mg/m2 twice daily with a single dose of warfarin 20 mg 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%.

Effect of Capecitabine on Celecoxib: Concomitant administration of multiple doses of capecitabine (capecitabine tablets 1,000 mg/m2 twice daily for 14 days) increased celecoxib (sensitive CYP2C9 substrate) AUC by 28%, Cmax by 24% and Ctrough by 30%.

Effect of Antacids on Capecitabine: When an aluminum hydroxide- and magnesium hydroxide- containing antacid was administered immediately after a capecitabine tablets dose of 1,250 mg/m2 in patients with cancer, AUC and Cmax 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, fluorouracil, FBAL) of capecitabine tablets.

Effect of Allopurinol on Capecitabine: Concomitant use with allopurinol may decrease conversion of capecitabine to the active metabolites, FdUMP and FUTP.

Effect of Capecitabine on Docetaxel and Effect of Docetaxel on Capecitabine: Capecitabine tablets had no  effect on the pharmacokinetics of docetaxel (Cmax and AUC) and docetaxel has no effect on the pharmacokinetics of capecitabine and the fluorouracil precursor 5’-DFUR.

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: Capecitabine and its metabolites (5’-DFUR, 5’-DFCR, fluorouracil, and FBAL) did not inhibit CYP1A2, CYP2A6, CYP3A4, CYP2C19, CYP2D6, or CYP2E1 in vitro.

12.5 Pharmacogenomics

The DPYD gene encodes the enzyme DPD, which is responsible for the catabolism of >80% of fluorouracil. Approximately 3 to 5% of White populations have partial DPD deficiency and 0.2% of White populations have complete DPD deficiency, which may be due to certain genetic no function or decreased function variants in DPYD resulting in partial to complete or near complete absence of enzyme activity. DPD deficiency is estimated to be more prevalent in Black or African American populations compared to White populations. Insufficient information is available to estimate the prevalence of DPD deficiency in other populations.

Patients who are homozygous or compound heterozygous for no function DPYD variants (i.e., carry two no function DPYD variants) or are compound heterozygous for a no function DPYD            variant plus a decreased function DPYD variant have complete DPD deficiency and are at increased risk for acute early-onset of toxicity and serious life-threatening, or fatal adverse reactions due to increased systemic exposure to capecitabine tablets. Partial DPD deficiency can result from the presence of either two decreased function DPYD variants or one normal function plus either a decreased function or a no function DPYD variant. Patients with partial DPD deficiency may also be at an increased risk for toxicity from capecitabine tablets.

Four DPYD variants have been associated with impaired DPD activity in White populations, especially when present as homozygous or compound heterozygous variants: c.1905+1G>A (DPYD *2A), c.1679T>G (DPYD *13), c.2846A>T, and c.1129-5923C>G (Haplotype B3). DPYD*2A and DPYD*13 are no function variants, and c.2846A>T and c.1129-5923C>G are decreased function variants. The decreased function DPYD variant c.557A>G is observed in individuals of African ancestry. This is not a complete listing of all DPYD variants that may result in DPD deficiency [see Warnings and Precautions (5.2)].

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Adequate studies investigating the carcinogenic potential of capecitabine have not been conducted. Capecitabine was not mutagenic in vitro to bacteria (Ames test) or mammalian cells (Chinese hamster V79/HPRT gene mutation assay). Capecitabine was clastogenic in vitro to human peripheral blood lymphocytes but not clastogenic in vivo to mouse bone marrow (micronucleus test). Fluorouracil causes mutations in bacteria and yeast. Fluorouracil also causes chromosomal abnormalities in the mouse micronucleus test in vivo.

In studies of fertility and general reproductive performance in female mice, oral capecitabine doses of 760 mg/kg/day (about 2,300 mg/m2/day) disturbed estrus and consequently caused a decrease in fertility. In mice that became pregnant, no fetuses survived this dose. The disturbance in estrus was reversible. In males, this dose caused degenerative changes in the testes, including decreases in the number of spermatocytes and spermatids. In separate pharmacokinetic studies, this dose in mice produced 5’-DFUR AUC values about 0.7 times the corresponding values in patients administered the recommended daily dose.

14.1 Colorectal Cancer

Adjuvant Treatment of Colon Cancer

Single Agent

The efficacy of capecitabine tablets was evaluated in X-ACT (NCT00009737), a multicenter, randomized, controlled clinical trial. Eligible patients were between 18 and 75 years of age with histologically-confirmed Dukes’ Stage C colon cancer with at least one positive lymph node and to have undergone (within 8 weeks prior to randomization) complete resection of the primary tumor without macroscopic or microscopic evidence of remaining tumor. Patients were also required to have no prior cytotoxic chemotherapy or immunotherapy (except steroids) and have an ECOG performance status of 0 or 1 (KPS >70%), ANC >1.5x109/L, platelets >100x109/L, serum creatinine <1.5 ULN, total bilirubin <1.5 ULN, AST/ALT <2.5 ULN and CEA within normal limits at time of randomization.

Patients (n=1,987) were randomized to capecitabine tablets 1,250 mg/m2 orally twice daily for the first 14 days of a 21-day cycle for a total of 8 cycles or fluorouracil 425 mg/m2 and leucovorin 20 mg/m2 intravenously on days 1 to 5 of each 28-day cycle for a total of 6 cycles. The capecitabine tablets dose was reduced in patients with baseline CLcr of 30 to 50 mL/min. The major efficacy outcome measure was disease-free survival (DFS).

The baseline demographics are shown in Table 9. The baseline characteristics were well- balanced between arms.

Table 9 Baseline Demographics in X-ACT

Efficacy results are summarized in Table 10 and Figures 1 and 2. The median follow-up at the time of the analysis was 6.9 years. Because the upper 2-sided 95% confidence limit of hazard ratio for DFS was less than 1.20, capecitabine tablets was non-inferior to fluorouracil + leucovorin. The choice of the non-inferiority margin of 1.20 corresponds to the retention of approximately 75% of the fluorouracil + leucovorin effect on DFS. The hazard ratio for capecitabine tablets compared to fluorouracil + leucovorin with respect to overall survival was 0.86 (95% CI 0.74, 1.01). The 5- year overall survival rates were 71% for capecitabine tablets and 68% for fluorouracil + leucovorin.

Table 10 Efficacy Results in X-ACTa (All Randomized Population)

aApproximately 93.4 % had 5-year DFS information

b Based on Kaplan-Meier estimates

c Wald chi-square test

 Figure 1 Kaplan-Meier Estimates of Disease-Free Survival in X-ACT (All Randomized Population)

Figure 2 Kaplan-Meier Estimates of Overall Survival in X-ACT (All Randomized Population)

In Combination with Oxaliplatin-Containing Regimens

The efficacy of capecitabine tablets in combination with oxaliplatin for the adjuvant treatment of patients with Stage III colon cancer as a component of a combination chemotherapy regimen was derived from studies in the published literature, including NO16968 [NCT00069121], a multicenter, open-label, randomized trial, where the major efficacy outcome measure was disease free survival.

Perioperative Treatment of Rectal Cancer

The efficacy of capecitabine tablets for the perioperative treatment of adults with locally advanced rectal cancer as a component of chemoradiotherapy was derived from studies in the published literature, including Rektum-III [NCT01500993], a randomized, open-label, multicenter, non- inferiority trial, where the major efficacy outcome measure was overall survival.

Metastatic Colorectal Cancer

The efficacy of capecitabine tablets as a single agent was evaluated in two open-label, multicenter, randomized, controlled clinical trials (Study SO14695 and Study SO14796). Eligible patients received first-line treatment for metastatic colorectal cancer. Patients were randomized to capecitabine tablets 1,250 mg/m2 twice daily for first 14 days of a 21-day cycle or leucovorin 20 mg/m2 intravenously followed by fluorouracil 425 mg/m2 as an intravenous bolus on days 1 to 5 of each 28-day cycle.

The efficacy outcome measures were overall survival, time to progression and response rate (complete plus partial responses). Responses were defined by the World Health Organization criteria and submitted to a blinded independent review committee (IRC). Differences in assessments between the investigator and IRC were reconciled by the sponsor, blinded to treatment arm, according to a specified algorithm. Survival was assessed based on a non- inferiority analysis.

The baseline demographics are shown in Table 11.

Table 11 Baseline Demographics for Study SO14695 and Study SO14796

Efficacy results for Study SO14695 and Study SO14796 are shown in Table 12 and Table 13.

Table 12 Efficacy Results for First-Line Treatment of Metastatic Colorectal Cancer (Study SO14695)

Table 13 Efficacy Results for First-Line Treatment of Metastatic Colorectal Cancer (Study SO14796)

Efficacy results of the pooled population from Study SO14695 and Study SO14796 are shown in Figure 3. Statistical analyses were performed to determine the percent of the survival effect of fluorouracil + leucovorin that was retained by capecitabine tablets. The estimate of the survival effect of fluorouracil + leucovorin was derived from a meta-analysis of ten randomized studies from the published literature comparing fluorouracil to regimens of fluorouracil + leucovorin that were similar to the control arms used in these Studies SO14695 and SO14796. The method for comparing the treatments was to examine the worst case (95% confidence upper bound) for the difference between fluorouracil + leucovorin and capecitabine tablets, and to show that loss of more than 50% of the fluorouracil + leucovorin survival effect was ruled out. It was demonstrated that the percent of the survival effect of fluorouracil + leucovorin maintained was at least 61% for Study SO14796 and 10% for Study SO14695. The pooled result is consistent with a retention of at least 50% of the effect of fluorouracil + leucovorin. It should be noted that these values for preserved effect are based on the upper bound of the fluorouracil + leucovorin vs capecitabine tablets difference.

Figure 3 Kaplan-Meier Curve for Overall Survival of Pooled Data (Studies SO14695 and SO14796)

In Combination with Oxaliplatin

The efficacy of capecitabine tablets for the treatment of patients with unresectable or metastatic colorectal cancer as a component of a combination chemotherapy regimen was derived from studies in the published literature, including NO16966 [NCT00069095], a randomized, non-inferiority, 2x2 factorial trial, where the major efficacy outcome measure was progression free survival.

14.2 Metastatic Breast Cancer

In Combination With Docetaxel

The efficacy of capecitabine tablets in combination with docetaxel was evaluated in an open-label, multicenter, randomized trial (Study SO14999). Eligible patients had metastatic breast cancer resistant to, or recurring during or after an anthracycline-containing therapy, or relapsing during or recurring within 2 years of completing an anthracycline-containing adjuvant therapy were enrolled. Patients were randomized to capecitabine tablets 1,250 mg/m2 twice daily for the first 14 days of a 21-day cycle and docetaxel 75 mg/m2 as a 1-hour intravenous infusion on day 1 of day of a 21- day cycle or docetaxel 100 mg/m2 as a 1-hour intravenous infusion on day 1 of a 21-day cycle. The efficacy outcome measures were time to disease progression, overall survival, and response  rate.

Patient demographics are provided in Table 14.

Table 14          Baseline Demographics in Metastatic Breast Cancer (Study SO14999)

1Includes 10 patients in combination and 18 patients in single agent arms treated with an anthracenedione

Efficacy results are shown in Table 15, Figure 4 and Figure 5.

Table 15 Efficacy Results in Metastatic Breast Cancer (Study SO14999)

1 The response rate reported represents a reconciliation of the investigator and IRC assessments performed by the sponsor according to a predefined algorithm.

Figure 4 Kaplan-Meier Estimates for Time to Disease Progression in Metastatic Breast Cancer (Study SO14999)

Figure 5 Kaplan-Meier Estimates of Survival in Metastatic Breast Cancer (Study SO14999)

Single Agent

The efficacy of capecitabine tablets as a single agent was evaluated in an open-label single-arm trial (Study SO14697). Eligible patients had metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy is not indicated (e.g., patients who have received cumulative doses of 400 mg/m2 of doxorubicin or doxorubicin equivalents). Resistance was defined as progressive disease while on treatment, with or without an initial response, or relapse within 6 months of completing treatment with an anthracycline-containing adjuvant chemotherapy regimen. Patients received capecitabine tablets 1,255 mg/m2 orally twice daily for first 14-days of a 21-day treatment cycle. The major efficacy outcome measure was tumor response rate in patients with measurable disease, with response defined as a ≥50% decrease in sum of the products of the perpendicular diameters of bidimensionally measurable disease for at least 1 month.

The baseline demographics are shown in Table 16.

Table 16 Baseline Demographics in Metastatic Breast Cancer (Study SO14697)

1Lung, pleura, liver, peritoneum

2Includes 2 patients treated with an anthracenedione

Efficacy for Study SO14697 are shown in Table 17.

Table 17 Efficacy Results in Metastatic Breast Cancer (Study SO14697)

1 Includes 2 patients treated with an anthracenedione

2 From date of first response

For the subgroup of 43 patients who were doubly resistant, the median time to progression was 3.4 months and the median survival was 8.4 months. The objective response rate in this population was supported by a response rate of 18.5% (1 CR, 24 PRs) in the overall population of 135 patients with measurable disease, who were less resistant to chemotherapy (see Table 15). The median time to progression was 3.0 months and the median survival was 10.1 months.

14.3 Gastric, Esophageal, or Gastroesophageal Junction Cancer

The efficacy of capecitabine tablets for treatment of adults with unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer as a component of a combination chemotherapy regimen was derived from studies in the published literature. Capecitabine tablets were evaluated in REAL- 2, a randomized non-inferiority, 2x2 factorial trial, where the major efficacy outcome measure was overall survival, and an additional randomized trial conducted by the North Central Cancer Treatment Group, where the major efficacy outcome measure was objective response rate.

The efficacy of capecitabine tablets for the treatment of adults with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease as a component of a combination regimen was derived from studies in the published literature. Capecitabine tablets were evaluated in the ToGA trial [NCT01041404], an open-label, multicenter, randomized trial where the primary efficacy measure was overall survival.

14.4 Pancreatic Cancer

The efficacy of capecitabine tablets for the adjuvant treatment of adults with pancreatic adenocarcinoma as a component of a combination chemotherapy regimen was derived from a study in the published literature. Capecitabine tablets were evaluated in ESPAC-4 trial, a two-group, open-label, multicenter, randomized trial, where the major efficacy outcome measure was overall survival.