Capecitabine (Page 4 of 11)
5.11 Embryo-Fetal Toxicity
Based on findings from animal reproduction studies and its mechanism of action, capecitabine can cause fetal harm when administered to a pregnant woman. Insufficient data is available on capecitabine 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 and for 6 months following the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with capecitabine 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 ADVERSE 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)]
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 as a single agent was evaluated in patients with Stage III colon cancer in X-ACT [see Clinical Studies (14.1)]. Patients received capecitabine 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, the median duration of treatment was 5.4 months.
Deaths due to all causes occurred in 0.8% of patients who received capecitabine 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.
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 for Adjuvant Treatment of Colon Cancer in X-ACT | ||||
Adverse Reaction | Capecitabine (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 as a Single Agent for Adjuvant Treatment of Colon Cancer in X-ACT | ||
Laboratory Abnormality | Capecitabine (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 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 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 as a single agent, with the exception of an increased incidence of neurosensory toxicity.
Perioperative Treatment of Rectal Cancer
The safety of capecitabine 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 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 as a single agent, with the exception of an increased incidence of diarrhea.
Metastatic Colorectal Cancer
Single Agent
The safety of capecitabine 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 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, the median duration of treatment was 4.6 months.
Deaths due to all causes occurred in 8% of patients who received capecitabine 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.
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 in Pooled Metastatic Colorectal Cancer Population (Study SO14695 and Study SO14796) | ||||||
Adverse Reaction | Capecitabine (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 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 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 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 in combination with docetaxel was evaluated in patients with metastatic breast cancer in Study SO14999 [see Clinical Studies (14.2)]. Patients received capecitabine 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, the mean duration of treatment was 4.2 months.
Permanent discontinuation due to an adverse reaction occurred in 26% of patients who received capecitabine. Dosage interruptions due to an adverse reaction occurred in 79% of patients who received capecitabine 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 with Docetaxel for Metastatic Breast Cancer in Study SO14999 | ||||||
Adverse Reaction | Capecitabine 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 with Docetaxel for Metastatic Breast Cancer in Study SO14999 | ||||||
Laboratory Abnormality | Capecitabine 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 as a single agent was evaluated in patients with metastatic breast cancer in Study SO14697 [see Clinical Studies (14.2)]. Patients received capecitabine 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 for Metastatic Breast Cancer in Study SO14697 | |||
Adverse Reaction | Capecitabine (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 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 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 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.
The safety of capecitabine 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 for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma was consistent with the known safety profile of capecitabine.
Pancreatic Cancer
The safety of capecitabine 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 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.
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