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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