CAPECITABINE: 63,506 Adverse Event Reports & Safety Profile

Capecitabine tablets USP are 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, USP is 5'-deoxy-5-fluoro-N-[(pentyloxy) carbonyl]-cytidine and has a molecular weight of 359.35. Capecitabine has the following structural formula: Capecitabine, USP is a white to off-white crystalline powder with an aqueous solubility of 26 mg/mL at 20ºC. Capecitabine tablets USP are supplied as capsule shaped, biconvex film coated tablets for oral administration. Each light pink-colored tablet contains 150 mg capecitabine and each dark pink-colored tablet contains 500 mg capecitabine. The inactive ingredients in Capecitabine tablets USP include: anhydrous lactose, croscarmellose sodium, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium stearate and purified water. The light or dark pink film coating contains hydroxypropyl methylcellulose, talc, titanium dioxide, yellow iron oxide, and red iron oxide.

Structural

Formula

AND USAGE Capecitabine is a nucleoside metabolic inhibitor indicated for: Colorectal Cancer

• adjuvant treatment of patients with Stage III colon cancer as a single agent or as a component of a combination chemotherapy regimen. ( 1.1 )
• perioperative treatment of adults with locally advanced rectal cancer as a component of chemoradiotherapy.( 1.1 )
• treatment of patients with unresectable or metastatic colorectal cancer as a single agent or as a component of a combination chemotherapy regimen. ( 1.1 )

Breast

Cancer

• treatment of patients with advanced or metastatic breast cancer as a single agent if an anthracycline- or taxane-containing chemotherapy is not indicated. ( 1.2 )
• treatment of patients with advanced or metastatic breast cancer in combination with docetaxel after disease progression on prior anthracycline-containing chemotherapy. ( 1.2 ) Gastric, Esophageal, or Gastroesophageal Junction Cancer
• treatment of adults with unresectable or metastatic gastric, esophageal, or gastroesophageal junction cancer as a component of a combination chemotherapy regimen. ( 1.3 )
• 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. ( 1.3 )

Pancreatic

Cancer

• adjuvant treatment of adults with pancreatic adenocarcinoma as a component of a combination chemotherapy regimen. ( 1.4 )

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

AND ADMINISTRATION Adjuvant Treatment of Colon Cancer Single agent: 1,250 mg/m 2 twice daily orally for the first 14 days of each 21-day cycle for a maximum of 8 cycles. ( 2.1 ) In combination with Oxaliplatin-Containing Regimens: 1,000 mg/m 2 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/m 2 administered intravenously on day 1 of each cycle. ( 2.2 )

Perioperative

Treatment of Rectal Cancer With Concomitant Radiation Therapy: 825 mg/m 2 orally twice daily ( 2.2 )

Without Radiation

Therapy: 1,250 mg/m 2 orally twice daily ( 2.2 ) Unresectable or Metastatic Colorectal Cancer: Single agent: 1,250 mg/m 2 twice daily orally for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity. ( 2.2 )

In

Combination with Oxaliplatin: 1,000 mg/m 2 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/m 2 administered intravenously on day 1 of each cycle. ( 2.2 ) Advanced or Metastatic Breast Cancer: Single agent: 1,000 mg/m 2 or 1,250 mg/m 2 twice daily orally for the first 14 days of each 21-day cycle until disease progression or unacceptable toxicity. ( 2.3 ) In combination with docetaxel: 1,000 mg/m 2 or 1,250 mg/m 2 orally twice daily for the first 14 days of a 21-day cycle, until disease progression or unacceptable toxicity in combination with docetaxel at 75 mg/m 2 administered intravenously on day 1 of each cycle ( 2.3 ) Unresectable or Metastatic Gastric, Esophageal, or Gastroesophageal Junction Cancer 625 mg/m 2 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. ( 2.4 )OR 850 mg/m 2 or 1,000 mg/m 2 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/m 2 administered intravenously on day 1 of each cycle. ( 2.4 ) HER2-overexpressing metastatic adenocarcinoma of the gastroesophageal junction or stomach 1,000 mg/m 2 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. ( 2.4 ) Pancreatic cancer 830 mg/m 2 orally twice daily for the first 21 days of each 28-day cycle for maximum of 6 cycles in combination with gemcitabine 1,000 mg/m 2 administered intravenously on days 1, 8, and 15 of each cycle. ( 2.5 ) Refer to Sections 2.5 and 2.6 for information related to dosage modifications for adverse reactions and renal impairment ( 2.5 and 2.6 ).

2.1 Evaluation and Testing for DPD Deficiency Before Initiating Capecitabine Tablets Prior to initiating capecitabine tablets, test patients for genetic variants of the DPYD gene unless immediate treatment is necessary. An FDA-authorized test for the detection of the DPYD gene to identify patients at risk of serious adverse reactions with capecitabine tablet is 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). Avoid use of capecitabine tablets in patients known to have certain homozygous or compound heterozygous DPYD variants that result in complete DPD deficiency. No capecitabine tablets dose has been proven safe for patients with complete DPD deficiency. For patients with partial DPD deficiency, individualize the dosage and modify based on tolerability and intent of treatment <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span>.

2.2 Recommended Dosage for Colorectal Cancer Adjuvant Treatment of Colon Cancer Single Agent The recommended dosage of capecitabine tablet is 1,250 mg/m 2 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/m 2 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/m 2 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/m 2 orally twice daily when administered with concomitant radiation therapy and 1,250 mg/m 2 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/m 2 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/m 2 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/m 2 administered intravenously on day 1 of each cycle. Refer to the Prescribing Information for oxaliplatin for additional dosing information as appropriate.

2.3 Recommended Dosage for Breast Cancer Advanced or Metastatic Breast Cancer Single Agent The recommended dosage of capecitabine tablet is 1,000 mg/m 2 or 1,250 mg/m 2 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/m 2 or 1,250 mg/m 2 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/m 2 administered intravenously on day 1 of each cycle. Refer to the Prescribing Information for docetaxel for additional dosing information as appropriate.

2.4 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/m 2 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/m 2 or 1,000 mg/m 2 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/m 2 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/m 2 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.

2.5 Recommended Dosage for Pancreatic Cancer The recommended dosage of capecitabine tablet is 830 mg/m 2 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/m 2 administered intravenously on days 1, 8, and 15 of each cycle. Refer to Prescribing Information for gemcitabine for additional dosing information as appropriate.

2.6 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 Severity Dosage Modification Resume at Same or Reduced Dose (Percent of Current Dose)

Grade

2 1st appearance Withhold until resolved to grade 0 to 1. 100% 2nd appearance 75% 3rd appearance 50% 4th appearance Permanently discontinue. - Grade 3 1st appearance Withhold until resolved to grade 0 to 1. 75% 2nd appearance 50% 3rd appearance Permanently discontinue. - Grade 4 1st appearance Permanently discontinue OR Withhold until resolved to grade 0 to 1. 50% 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 )].

2.7 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 &lt;30 mL/min) <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.6 )]</span> .

2.8 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.12 )]</span>. 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

Severe Renal Impairment (4.1) Hypersensitivity (4.2)

4.1 Severe Renal Impairment Capecitabine tablets are contraindicated in patients with severe renal impairment (creatinine clearance below 30 mL/min [Cockroft and Gault]) <span class="opacity-50 text-xs">[see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ]</span> .

4.2 Hypersensitivity Capecitabine tablets are contraindicated in patients with known hypersensitivity to capecitabine or to any of its components. Capecitabine tablets are contraindicated in patients who have a known hypersensitivity to 5-fluorouracil.

REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Cardiotoxicity [see Warnings and Precautions ( 5.3 )] Diarrhea [see Warnings and Precautions ( 5.4 )] Dehydration [see Warnings and Precautions ( 5.5 )]

Renal

Toxicity [see Warnings and Precautions ( 5.6 )]

Serious Skin

Toxicities [see Warnings and Precautions ( 5.7 )] Palmar-Plantar Erythrodysesthesia Syndrome [see Warnings and Precautions ( 5.8 )] Myelosuppression [see Warnings and Precautions ( 5.9 )] Hyperbilirubinemia [see Warnings and Precautions ( 5.10 )] Most common adverse reactions in patients who received capecitabine tablets as a single agent for the adjuvant treatment for colon cancer ( > 30%) were palmar-plantar erythrodysesthesia syndrome, diarrhea, and nausea. ( 6.1 ) Most common adverse reactions ( > 30%) in patients with metastatic colorectal cancer who received capecitabine tablets as a single agent were anemia, diarrhea, palmar-plantar erythrodysesthesia syndrome, hyperbilirubinemia, nausea, fatigue, and abdominal pain. ( 6.1 ) Most common adverse reactions ( > 30%) in patients with metastatic breast cancer who received capecitabine tablets with docetaxel were diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, nausea, alopecia, vomiting, edema, and abdominal pain. ( 6.1 ) Most common adverse reactions ( > 30%) in patients with metastatic breast cancer who received capecitabine tablets as a single agent were lymphopenia, anemia, diarrhea, hand-and-foot syndrome, nausea, fatigue, vomiting, and dermatitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ascend Laboratories, LLC at 1-877-272-7901 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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/m 2 orally twice daily for the first 14 days of a 21-day cycle (N=995) or leucovorin 20 mg/m 2 intravenously followed by fluorouracil 425 mg/m 2 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 Adverse Reaction Capecitabine Tablets (N=995) Fluorouracil + Leucovorin (N=974)

All

Grades (%)

Grade

3 or 4 (%)

All

Grades (%)

Grade

3 or 4 (%) Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia syndrome 60 17 9 <1 Gastrointestinal Diarrhea 47 12 65 14 Nausea 34 2 47 2 Stomatitis 22 2 60 14 Vomiting 15 2 21 2 Abdominal pain 14 3 16 2 General Fatigue 16 <1 16 1 Asthenia 10 <1 10 1 Lethargy 10 <1 9 <1 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 Laboratory Abnormality CapecitabineTablets (N=995) Fluorouracil + Leucovorin (N=974)

Grade

3 or 4 (%)

Grade

3 or 4 (%) Bilirubin increased 20 6 Lymphocytes decreased 13 13 Neutrophils/granulocytes decreased 2.4 26 Calcium decreased 2.3

2.2 Neutrophils decreased 2.2 26 ALT increased 1.6

0.6 Calcium increased 1.1

0.7 Hemoglobin decreased 1

1.2 Platelets decreased 1

0.7 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 <span class="opacity-50 text-xs">[see Clinical Studies ( 14.1 )]</span>. 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/m 2 orally twice a day for the first 14 days of a 21-day cycle (N=596) or leucovorin 20 mg/m 2 intravenously followed by fluorouracil 425 mg/m 2 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)

Adverse Reaction Capecitabine

Tablets (N=596) Fluorouracil + Leucovorin (N=593)

All

Grades (%)

Grade

3 (%)

Grade

4 (%)

All

Grades (%)

Grade

3 (%)

Grade

4 (%) Blood and Lymphatic System Anemia 80 2 <1 79 1 <1 Neutropenia 13 1 2 46 8 13 Gastrointestinal Diarrhea 55 13 2 61 10 2 Nausea 43 4 – 51 3 <1 Abdominal pain 35 9 <1 31 5 – Vomiting 27 4 <1 30 4 <1 Stomatitis 25 2 <1 62 14 1 Constipation 14 1 <1 17 1 – Gastrointestinal motility disorder 10 <1 – 7 <1 – Oral discomfort 10 – – 10 – – Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia syndrome 54 17 NA 6 1 NA Dermatitis 27 1 – 26 1 – Hepatobiliary Hyperbilirubinemia 48 18 5 17 3 3 General Fatigue * 42 4 – 46 4 – Pyrexia 18 1 – 21 2 – Edema 15 1 – 9 1 – Pain 12 1 – 10 1 – Metabolism and Nutrition Decreased appetite 26 3 <1 31 2 <1 Respiratory Thoracic and Mediastinal Dyspnea 14 1 – 10 <1 1 Eye Eye irritation 13 – – 10 <1 – Nervous System Peripheral sensory neuropathy 10 – – 4 – – Headache 10 1 – 7 – – Musculoskeletal Back pain 10 2 – 9 <1 – – 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/m 2 orally twice daily for the first 14 days of a 21-day cycle with docetaxel 75 mg/m 2 as 1- hour intravenous infusion on day 1 of each 21-day cycle for at least 6 weeks or docetaxel 100 mg/m 2 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 Adverse Reaction Capecitabine Tablets with Docetaxel (N=251) Docetaxel (N=255)

All

Grades (%)

Grade

3 (%)

Grade

4 (%)

All

Grades (%)

Grade

3 (%)

Grade

4 (%)

Gastrointestinal Diarrhea

67 14 <1 48 5 <1 Stomatitis 67 17 <1 43 5 – Nausea 45 7 – 36 2 – Vomiting 35 4 1 24 2 – Abdominal pain 30 3 <1 24 2 – Constipation 20 2 – 18 – – Dyspepsia 14 – – 8 1 – Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia syndrome 63 24 NA 8 1 NA Alopecia 41 6 – 42 7 – Nail disorder 14 2 – 15 – – Cardiac Edema 33 <2 – 34 <3 1 General Pyrexia 28 2 – 34 2 – Asthenia 26 4 <1 25 6 – Fatigue 22 4 – 27 6 – Weakness 16 2 – 11 2 – Pain in Limb 13 <1 – 13 2 – Blood and Lymphatic System Neutropenic fever 16 3 13 21 5 16 Nervous System Taste disturbance 16 <1 – 14 <1 – Headache 15 3 – 15 2 – Paresthesia 12 <1 – 16 1 – Dizziness 12 – – 8 <1 – Musculoskeletal and Connective Tissue Arthralgia 15 2 – 24 3 – Myalgia 15 2 – 25 2 – Back Pain 12 <1 – 11 3 – Respiratory, Thoracic and Mediastinal Dyspnea 14 2 <1 16 2 – Cough 13 1 – 22 <1 – Sore Throat 12 2 – 11 <1 – Metabolism and Nutrition Anorexia 13 <1 – 11 <1 – Appetite decreased 10 – – 5 – – Dehydration 10 2 – 7 <1 <1 Eye Lacrimation increased 12 – – 7 <1 – – 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 Laboratory Abnormality Capecitabine Tablets with Docetaxel (N=251) Docetaxel (N=255)

All

Grades (%)

Grade

3 (%)

Grade

4 (%)

All

Grades (%)

Grade

3 (%)

Grade

4 (%)

Hematologic Lymphocytopenia

99 48 41 98 44 40 Leukopenia 91 37 24 88 42 33 Neutropenia 86 20 49 87 10 66 Anemia 80 7 3 83 5 <1 Thrombocytopenia 41 2 1 23 1 2 Hepatobiliary Hyperbilirubinemia 20 7 2 6 2 2 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/m 2 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 Adverse Reaction Capecitabine Tablets (n=162)

All

Grades (%)

Grade

3 (%)

Grade

4 (%) Blood and Lymphatic System Lymphopenia 94 44 15 Anemia 72 3 1 Neutropenia 26 2 2 Thrombocytopenia 24 3 1 Gastrointestinal Diarrhea 57 12 3 Nausea 53 4 – Vomiting 37 4 – Stomatitis 24 7 – Abdominal pain 20 4 – Constipation 15 1 – Skin and Subcutaneous Tissue Hand-and-foot syndrome 57 11 NA Dermatitis 37 1 – General Fatigue 41 8 – Pyrexia 12 1 – Metabolism and Nutrition Anorexia 23 3 – Hepatobiliary Hyperbilirubinemia 22 9 2 Nervous System Paresthesia 21 1 – Eye Eye irritation 15 – – – = 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 &amp; Urinary: acute renal failure secondary to dehydration including fatal outcome Skin &amp; 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

AND PRECAUTIONS Coagulopathy: May result in bleeding, death. Monitor anticoagulant response (e.g., INR) and adjust anticoagulant dose accordingly. (5.1) Diarrhea: May be severe.

Interrupt

Capecitabine tablets treatment immediately until diarrhea resolves or decreases to grade 1. Recommend standard antidiarrheal treatments. (5.2) Cardiotoxicity: Common in patients with a prior history of coronary artery disease. (5.3)

Increased

Risk of Severe or Fatal Adverse Reactions in Patients with Lo w or Absent Dihydropyrimidine Dehydrogenase (DPD) Activity: Withhold or permanently discontinue Capecitabine tablets in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of DPD activity.

No

Capecitabine tablets dose has been proven safe in patients with absent DPD activity. ( 5.4 ) Dehydration and Renal Failure: Interrupt Capecitabine tablets treatment until dehydration is corrected. Potential risk of acute renal failure secondary to dehydration. Monitor and correct dehydration. (5.5) . Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. (5.6 , 8.1, 8.3) Mucocutaneous and Dermatologic Toxicity: Severe mucocutaneous reactions, Steven-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), have been reported. Capecitabine tablets should be permanently discontinued in patients who experience a severe mucocutaneous reaction during treatment. Capecitabine tablets may induce hand-and-foot syndrome. Persistent or severe hand-and-foot syndrome can lead to loss of fingerprints which could impact patient identification.

In Interrupt

Capecitabine tablets treatment until the hand-and-foot syndrome event resolves or decreases in intensity. (5.7) Hyperbilirubinemia: Interrupt capecitabine tablet treatment immediately until the hyperbilirubinemia resolves or decreases in intensity. (5.8) Hematologic: Do not treat patients with neutrophil counts <1.5 x 10 9 /L or thrombocyte counts <100 x 10 9 /L. If grade 3-4 neutropenia or thrombocytopenia occurs, stop therapy until condition resolves. (5.9)

5.1 Coagulopathy Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored closely with great frequency and the anticoagulant dose should be adjusted accordingly <span class="opacity-50 text-xs">[see Boxed Warning and Drug Interactions (7.1) ]</span>

5.2 Diarrhea Capecitabine can induce diarrhea, sometimes severe. Patients with severe diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated.

In

875 patients with either metastatic breast or colorectal cancer who received capecitabine monotherapy, the median time to first occurrence of grade 2 to 4 diarrhea was 34 days (range from 1 to 369 days). The median duration of grade 3 to 4 diarrhea was 5 days.

National Cancer

Institute of Canada (NCIC) grade 2 diarrhea is defined as an increase of 4 to 6 stools/day or nocturnal stools, grade 3 diarrhea as an increase of 7 to 9 stools/day or incontinence and malabsorption, and grade 4 diarrhea as an increase of ≥10 stools/day or grossly bloody diarrhea or the need for parenteral support. If grade 2, 3 or 4 diarrhea occurs, administration of capecitabine should be immediately interrupted until the diarrhea resolves or decreases in intensity to grade 1. [see Dosage and Administration (2.3) ] . Standard antidiarrheal treatments (eg, loperamide) are recommended. Necrotizing enterocolitis (typhlitis) has been reported.

5.3 Cardiotoxicity The cardiotoxicity observed with capecitabine tablets includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy. These adverse reactions may be more common in patients with a prior history of coronary artery disease.

5.4 Dihydropyrimidine Dehydrogenase Deficiency Based on post marketing reports, patients with certain homozygous or certain compound heterozygous mutations in the DPD gene that result in complete or near complete absence of DPD activity are at increased risk for acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions caused by capecitabine (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity). Patients with partial DPD activity may also have increased risk of severe, life-threatening, or fatal adverse reactions caused by capecitabine. Withhold or permanently discontinue capecitabine based on clinical assessment of the onset, duration and severity of the observed toxicities in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of DPD activity. No capecitabine dose has been proven safe for patients with complete absence of DPD activity. There is insufficient data to recommend a specific dose in patients with partial DPD activity as measured by any specific test.

5.5 Dehydration and Renal Failure Dehydration has been observed and may cause acute renal failure which can be fatal. Patients with pre-existing compromised renal function or who are receiving concomitant Capecitabine with known nephrotoxic agents are at higher risk. Patients with anorexia, asthenia, nausea, vomiting or diarrhea may rapidly become dehydrated. Monitor patients when Capecitabine is administered to prevent and correct dehydration at the onset. If grade 2 (or higher) dehydration occurs, Capecitabine treatment should be immediately interrupted and the dehydration corrected. Treatment should not be restarted until the patient is rehydrated and any precipitating causes have been corrected or controlled. Dose modifications should be applied for the precipitating adverse event as necessary <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> . Patients with moderate renal impairment at baseline require dose reduction <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span> . Patients with mild and moderate renal impairment at baseline should be carefully monitored for adverse reactions. Prompt interruption of therapy with subsequent dose adjustments is recommended if a patient develops a grade 2 to 4 adverse event as outlined in Table 2 <span class="opacity-50 text-xs">[see Dosage and Administration (2.3 ) , Use in Specific Populations (8.7) , and Clinical Pharmacology (12.3)]</span> .

5.6 Embryo Fetal Toxicity Based on findings from animal reproduction studies and its mechanism of action, capecitabine tablets may cause fetal harm when given to a pregnant woman <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.1) ]</span> . Limited available data are not sufficient to inform use of capecitabine in pregnant women. In animal reproduction studies, administration of capecitabine to pregnant animals during the period of organogenesis cause 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 respectively <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1) ]</span> . Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of capecitabine <span class="opacity-50 text-xs">[see Use in Specific Populations (8.3) ]</span>

5.7 Mucocutaneous and Dermatologic Toxicity Severe mucocutaneous reactions, some with fatal outcome, such as Stevens-Johnson syndrome and Toxic Epidermal Necrolysis (TEN) can occur in patients treated with Capecitabine <span class="opacity-50 text-xs">[see Adverse Reactions (6.4)]</span> . Capecitabine should be permanently discontinued in patients who experience a severe mucocutaneous reaction possibly attributable to Capecitabine treatment. Hand-and-foot syndrome (palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema) is a cutaneous toxicity. Median time to onset was 79 days (range from 11 to 360 days) with a severity range of grades 1 to 3 for patients receiving capecitabine tablets monotherapy in the metastatic setting.

Grade

1 is characterized by any of the following: numbness, dysesthesia/paresthesia, tingling, painless swelling or erythema of the hands and/or feet and/or discomfort which does not disrupt normal activities.

Grade

2 hand-and-foot syndrome is defined as painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patient's activities of daily living.

Grade

3 hand-and-foot syndrome is defined as moist desquamation, ulceration, blistering or severe pain of the hands and/or feet and/or severe discomfort that causes the patient to be unable to work or perform activities of daily living. Persistent or severe hand-and-foot syndrome (grade 2 and above can eventually lead to loss of fingerprints which could impact patient identification. If grade 2 or 3 hand-and-foot syndrome occurs, administration of capecitabine should be interrupted until the event resolves or decreases in intensity to grade 1. Following grade 3 hand-and-foot syndrome, subsequent doses of capecitabine tablets should be decreased [see Dosage and Administration (2.3) ] .

5.8 Hyperbilirubinemia In 875 patients with either metastatic breast or colorectal cancer who received at least one dose of capecitabine 1250 mg/m 2 twice daily as monotherapy for 2 weeks followed by a 1-week rest period, grade 3 (1.5-3 x ULN) hyperbilirubinemia occurred in 15.2% (n=133) of patients and grade 4 (&gt;3 x ULN) hyperbilirubinemia occurred in 3.9% (n=34) of patients.

Of

566 patients who had hepatic metastases at baseline and 309 patients without hepatic metastases at baseline, grade 3 or 4 hyperbilirubinemia occurred in 22.8% and 12.3%, respectively. Of the 167 patients with grade 3 or 4 hyperbilirubinemia, 18.6% (n=31) also had postbaseline elevations (grades 1 to 4, without elevations at baseline) in alkaline phosphatase and 27.5% (n=46) had postbaseline elevations in transaminases at any time (not necessarily concurrent). The majority of these patients, 64.5% (n=20) and 71.7% (n=33), had liver metastases at baseline. In addition, 57.5% (n=96) and 35.3% (n=59) of the 167 patients had elevations (grades 1 to 4) at both prebaseline and postbaseline in alkaline phosphatase or transaminases, respectively.

Only

7.8% (n=13) and 3.0% (n=5) had grade 3 or 4 elevations in alkaline phosphatase or transaminases. In the 596 patients treated with capecitabine as first-line therapy for metastatic colorectal cancer, the incidence of grade 3 or 4 hyperbilirubinemia was similar to the overall clinical trial safety database of capecitabine monotherapy. The median time to onset for grade 3 or 4 hyperbilirubinemia in the colorectal cancer population was 64 days and median total bilirubin increased from 8 μm/L at baseline to 13 μm/L during treatment with capecitabine. Of the 136 colorectal cancer 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

251 patients with metastatic breast cancer who received a combination of capecitabine and docetaxel, grade 3 (1.5 to 3 x ULN) hyperbilirubinemia occurred in 7% (n=17) and grade 4 (>3 x ULN) hyperbilirubinemia occurred in 2% (n=5). If drug-related grade 3 to 4 elevations in bilirubin occur, administration of capecitabine tablets should be immediately interrupted until the hyperbilirubinemia decreases to ≤3.0 X ULN [ see recommended dose modifications under Dosage and Administration (2.3) ] .

5.9 Hematologic In 875 patients with either metastatic breast or colorectal cancer who received a dose of 1250 mg/m 2 administered twice daily as monotherapy for 2 weeks followed by a 1-week rest period, 3.2%, 1.7%, and 2.4% of patients had grade 3 or 4 neutropenia, thrombocytopenia or decreases in hemoglobin, respectively.

In

251 patients with metastatic breast cancer who received a dose of capecitabine in combination with docetaxel, 68% had grade 3 or 4 neutropenia, 2.8% had grade 3 or 4 thrombocytopenia, and 9.6% had grade 3 or 4 anemia. Patients with baseline neutrophil counts of <1.5 x 10 9 /L and/or thrombocyte counts of <100 x 10 9 /L should not be treated with capecitabine. If unscheduled laboratory assessments during a treatment cycle show grade 3 or 4 hematologic toxicity, treatment with capecitabine should be interrupted.

5.10 Geriatric Patients Patients ≥80 years old may experience a greater incidence of grade 3 or 4 adverse reactions.

In

875 patients with either metastatic breast or colorectal cancer who received capecitabine monotherapy, 62% of the 21 patients ≥80 years of age treated with capecitabine experienced a treatment-related grade 3 or 4 adverse event: diarrhea in 6 (28.6%), nausea in 3 (14.3%), hand-and-foot syndrome in 3 (14.3%), and vomiting in 2 (9.5%) patients. Among the 10 patients 70 years of age and greater (no patients were >80 years of age) treated with capecitabine in combination with docetaxel, 30% (3 out of 10) of patients experienced grade 3 or 4 diarrhea and stomatitis, and 40% (4 out of 10) experienced grade 3 hand-and-foot syndrome. Among the 67 patients ≥60 years of age receiving capecitabine in combination with docetaxel, the incidence of grade 3 or 4 treatment-related adverse reactions, treatment-related serious adverse reactions, withdrawals due to adverse reactions, treatment discontinuations due to adverse reactions and treatment discontinuations within the first two treatment cycles was higher than in the <60 years of age patient group.

In

995 patients receiving capecitabine as adjuvant therapy for Dukes' C colon cancer after resection of the primary tumor, 41% of the 398 patients ≥65 years of age treated with capecitabine experienced a treatment-related grade 3 or 4 adverse event: hand-and-foot syndrome in 75 (18.8%), diarrhea in 52 (13.1%), stomatitis in 12 (3.0%), neutropenia/granulocytopenia in 11 (2.8%), vomiting in 6 (1.5%), and nausea in 5 (1.3%) patients. In patients ≥65 years of age (all randomized population; capecitabine 188 patients, 5-FU/LV 208 patients) treated for Dukes' C colon cancer after resection of the primary tumor, the hazard ratios for disease-free survival and overall survival for capecitabine compared to 5-FU/LV were 1.01 (95% C.I. 0.80 – 1.27) and 1.04 (95% C.I. 0.79 – 1.37), respectively.

5.11 Hepatic Insufficiency Patients with mild to moderate hepatic dysfunction due to liver metastases should be carefully monitored when capecitabine is administered. The effect of severe hepatic dysfunction on the disposition of capecitabine is not known <span class="opacity-50 text-xs">[see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3 )]</span> .

5.12 Combination With Other Drugs Use of capecitabine in combination with irinotecan has not been adequately studied.

INTERACTIONS

• Allopurinol: Avoid concomitant use of allopurinol with capecitabine. ( 7.1 )
• Leucovorin: Closely monitor for toxicities when capecitabine is coadministered with leucovorin. ( 7.1 )
• CYP2C9 substrates: Closely monitor for adverse reactions when CYP2C9 substrates are coadministered with capecitabine. ( 7.2 )
• Vitamin K antagonists: Monitor INR more frequently and dose adjust oral vitamin K antagonist as appropriate
• Phenytoin: Closely monitor phenytoin levels in patients taking capecitabine concomitantly with phenytoin and adjust the phenytoin dose as appropriate. ( 7.2 )
• Nephrotoxic drugs: Closely monitor for signs of renal toxicity when capecitabine is used concomitantly with nephrotoxic drugs. ( 7.3 )

7.1 Effect of Other Drugs on Capecitabine Allopurinol Concomitant use with allopurinol may decrease concentration of capecitabine’s active metabolites <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>, which may decrease efficacy. Avoid concomitant use of allopurinol with capecitabine.

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 on Other Drugs CYP2C9 Substrates Capecitabine increased exposure of CYP2C9 substrates <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>, 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 (e.g., anticoagulants, antidiabetic drugs). Vitamin K Antagonists Capecitabine increases exposure of vitamin K antagonist <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>, which may alter coagulation parameters and/or bleeding and could result in death <span class="opacity-50 text-xs">[see Warning and Precautions ( 5.1 )]</span> . These events may occur within days of treatment initiation and up to 1 month after discontinuation of capecitabine. Monitor INR more frequently and refer to the prescribing information of oral vitamin K antagonist for dosage adjustment, as appropriate, when capecitabine is used concomitantly with vitamin K antagonist.

Phenytoin

Capecitabine 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 is used concomitantly with phenytoin.

7.3 Nephrotoxic Drugs Due of the additive pharmacologic effect, concomitant use of capecitabine with other drugs known to cause renal toxicity may increase the risk of renal toxicity <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.6 )]</span>. Closely monitor for signs of renal toxicity when capecitabine is used concomitantly with nephrotoxic drugs (e.g. platinum salts, irinotecan, methotrexate, intravenous bisphosphonates).

For full Taxotere prescribing information, please refer to Taxotere Package Insert. All trade names drug products are the property of their respective owners. Manufactured By: Intas Pharmaceuticals Limited, Ahmedabad – 380 054, India.

For

BluePoint Laboratories Issued 03/23