Capecitabine 150mg
Generic: CAPECITABINE
Basic Information
Manufacturer
Armas Pharmaceuticals Inc.
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
ORAL
FDA Set ID
7f555b6b-60db-45e2-a61e-537e57f43fdc
Indications & Usage
1 INDICATIONS AND USAGE Capecitabine tablets are a nucleoside metabolic inhibitor with antineoplastic activity indicated for: • Adjuvant Colon Cancer (1.1) – Patients with Dukes' C colon cancer • Metastatic Colorectal Cancer (1.1) – First-line as monotherapy when treatment with fluoropyrimidine therapy alone is preferred • Metastatic Breast Cancer (1.2) – In combination with docetaxel after failure of prior anthracycline containing therapy – As monotherapy in patients resistant to both paclitaxel and an anthracycline-containing regimen 1.1 Colorectal Cancer Capecitabine tablets are indicated as a single agent for adjuvant treatment in patients with Dukes' C colon cancer who have undergone complete resection of the primary tumor when treatment with fluoropyrimidine therapy alone is preferred.
Capecitabine tablets are non-inferior to 5-fluorouracil and leucovorin (5-FU/LV) for disease-free survival (DFS).
Physicians should consider results of combination chemotherapy trials, which have shown improvement in DFS and OS, when prescribing single-agent capecitabine tablets in the adjuvant treatment of Dukes' C colon cancer.
Capecitabine tablets are indicated as first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred.
Combination chemotherapy has shown a survival benefit compared to 5-FU/LV alone.
A survival benefit over 5-FU/LV has not been demonstrated with capecitabine tablets monotherapy.
Use of capecitabine tablets instead of 5-FU/LV in combinations has not been adequately studied to assure safety or preservation of the survival advantage.
1.2 Breast Cancer Capecitabine tablets in combination with docetaxel is indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.
Capecitabine tablets monotherapy is also indicated for the treatment of patients with 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/m 2 of doxorubicin or doxorubicin equivalents).
Resistance is 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 regimen.
Capecitabine tablets are non-inferior to 5-fluorouracil and leucovorin (5-FU/LV) for disease-free survival (DFS).
Physicians should consider results of combination chemotherapy trials, which have shown improvement in DFS and OS, when prescribing single-agent capecitabine tablets in the adjuvant treatment of Dukes' C colon cancer.
Capecitabine tablets are indicated as first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred.
Combination chemotherapy has shown a survival benefit compared to 5-FU/LV alone.
A survival benefit over 5-FU/LV has not been demonstrated with capecitabine tablets monotherapy.
Use of capecitabine tablets instead of 5-FU/LV in combinations has not been adequately studied to assure safety or preservation of the survival advantage.
1.2 Breast Cancer Capecitabine tablets in combination with docetaxel is indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.
Capecitabine tablets monotherapy is also indicated for the treatment of patients with 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/m 2 of doxorubicin or doxorubicin equivalents).
Resistance is 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 regimen.
Adverse Reactions
6 ADVERSE REACTIONS 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.
Most common adverse reactions (≥30%) were diarrhea, hand-and-foot syndrome, nausea, vomiting, abdominal pain, fatigue/weakness, and hyperbilirubinemia.
Other adverse reactions, including serious adverse reactions, have been reported.
(6) To report SUSPECTED ADVERSE REACTIONS, contact 1-888-557-1212 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Adjuvant Colon Cancer Table 4 shows the adverse reactions occurring in ≥5% of patients from one phase 3 trial in patients with Dukes' C colon cancer who received at least one dose of study medication and had at least one safety assessment.
A total of 995 patients were treated with 1250 mg/m 2 twice a day of capecitabine administered for 2 weeks followed by a 1-week rest period, and 974 patients were administered 5- FU and leucovorin (20 mg/m 2 leucovorin IV followed by 425 mg/m 2 IV bolus 5-FU on days 1-5 every 28 days).
The median duration of treatment was 164 days for capecitabine-treated patients and 145 days for 5-FU/LV-treated patients.
A total of 112 (11%) and 73 (7%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse reactions.
A total of 18 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 8 (0.8%) patients randomized to capecitabine and 10 (1.0%) randomized to 5-FU/LV.
Table 5 shows grade 3/4 laboratory abnormalities occurring in ≥1% of patients from one phase 3 trial in patients with Dukes' C colon cancer who received at least one dose of study medication and had at least one safety assessment.
Table 4 Percent Incidence of Adverse Reactions Reported in ≥5% of Patients Treated With Capecitabine or 5-FU/LV for Colon Cancer in the Adjuvant Setting (Safety Population) Adjuvant Treatment for Colon Cancer (N=1969) Capecitabine (N=995) 5-FU/LV (N=974) Body System/ Adverse Event All Grades Grade 3/4 All Grades Grade 3/4 Gastrointestinal Disorders 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 Constipation 9 - 11 <1 Upper Abdominal Pain 7 <1 7 <1 Dyspepsia 6 <1 5 - Skin and Subcutaneous Tissue Disorders Hand-and-Foot Syndrome 60 17 9 <1 Alopecia 6 - 22 <1 Rash 7 - 8 - Erythema 6 1 5 <1 General Disorders and Administration Site Conditions Fatigue 16 <1 16 1 Pyrexia 7 <1 9 <1 Asthenia 10 <1 10 1 Lethargy 10 <1 9 <1 Nervous System Disorders Dizziness 6 <1 6 - Headache 5 <1 6 <1 Dysgeusia 6 - 9 - Metabolism and Nutrition Disorders Anorexia 9 <1 11 <1 Eye Disorders Conjunctivitis 5 <1 6 <1 Blood and Lymphatic System Disorders Neutropenia 2 <1 8 5 Respiratory Thoracic and Mediastinal Disorders Epistaxis 2 - 5 - Table 5 Percent Incidence of Grade 3/4 Laboratory Abnormalities Reported in ≥1% of Patients Receiving Capecitabine Monotherapy for Adjuvant Treatment of Colon Cancer (Safety Population) Adverse Event Capecitabine (n=995) Grade 3/4 % IV 5-FU/LV (n=974) Grade 3/4 % Increased ALAT (SGPT) Increased calcium Decreased calcium Decreased hemoglobin Decreased lymphocytes Decreased neutrophils The incidence of grade 3/4 white blood cell abnormalities was 1.3% in the capecitabine arm and 4.9% in the IV 5-FU/LV arm.
** It should be noted that grading was according to NCIC CTC Version 1 (May, 1994).
In the NCIC-CTC Version 1, hyperbilirubinemia grade 3 indicates a bilirubin value of 1.5 to 3.0 x upper limit of normal (ULN) range, and grade 4 a value of > 3.0 x ULN.
The NCI CTC Version2 and above define a grade 3 bilirubin value of >3.0 to 10.0 x ULN, and grade 4 values >10.0 x ULN.
Decreased neutrophils/granulocytes Decreased platelets Increased bilirubin ** 1.6 1.1 2.3 1.0 13.0 2.2 2.4 1.0 20 0.6 0.7 2.2 1.2 13.0 26.2 26.4 0.7 6.3 6.2 Metastatic Colorectal Cancer Monotherapy Table 6 shows the adverse reactions occurring in ≥5% of patients from pooling the two phase 3 trials in first line metastatic colorectal cancer.
A total of 596 patients with metastatic colorectal cancer were treated with 1250 mg/m 2 twice a day of capecitabine administered for 2 weeks followed by a 1-week rest period, and 593 patients were administered 5-FU and leucovorin in the Mayo regimen (20 mg/m 2 leucovorin IV followed by 425 mg/m 2 IV bolus 5-FU, on days 1-5, every 28 days).
In the pooled colorectal database the median duration of treatment was 139 days for capecitabine-treated patients and 140 days for 5-FU/LV-treated patients.
A total of 78 (13%) and 63 (11%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse reactions/intercurrent illness.
A total of 82 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 50 (8.4%) patients randomized to capecitabine and 32 (5.4%) randomized to 5-FU/LV.
Table 6 Pooled Phase 3 Colorectal Trials: Percent Incidence of Adverse Reactions in ≥5% of Patients - Not observed * Excluding vertigo NA=NotApplicable Adverse Event Capecitabine (n=596) 5-FU/LV (n=593) Total % Grade 3 % Grade 4 % Total % Grade 3 % Grade 4 % Number of Patients With > One Adverse Event 96 52 9 94 45 9 Body System/Adverse Event GI Diarrhea 55 13 2 61 10 2 Nausea 43 4 – 51 3 <1 Vomiting 27 4 <1 30 4 <1 Stomatitis 25 2 <1 62 14 1 Abdominal Pain 35 9 <1 31 5 – Gastrointestinal Motility Disorder 10 <1 – 7 <1 – Constipation 14 1 <1 17 1 – Oral Discomfort 10 – – 10 – – Upper GI Inflammatory Disorders 8 <1 – 10 1 – Gastrointestinal Hemorrhage 6 1 <1 3 1 – Ileus 6 4 1 5 2 1 Skin and Subcutaneous Hand-and-Foot Syndrome 54 17 NA 6 1 NA Dermatitis 27 1 – 26 1 – Skin Discoloration 7 <1 – 5 – – Alopecia 6 – – 21 <1 – General Fatigue/Weakness 42 4 – 46 4 – Pyrexia 18 1 – 21 2 – Edema 15 1 – 9 1 – Pain 12 1 – 10 1 – Chest Pain 6 1 – 6 1 <1 Neurological Peripheral Sensory Neuropathy 10 – – 4 – – Headache 10 1 – 7 – – Dizziness* 8 <1 – 8 <1 – Insomnia 7 – – 7 – – Taste Disturbance 6 1 – 11 <1 1 Metabolism Appetite Decreased 26 3 <1 31 2 <1 Dehydration 7 2 <1 8 3 1 Eye Eye Irritation 13 – – 10 <1 – Vision Abnormal 5 – – 2 – – Respiratory Dyspnea 14 1 - 10 <1 1 Cough 7 <1 1 8 - - Pharyngeal Disorder 5 - - 5 - - Epistaxis 3 <1 - 6 - - Sore Throat 2 - - 6 - - Musculoskeletal Back Pain 10 2 – 9 <1 – Arthralgia 8 1 – 6 1 – Vascular Venous Thrombosis 8 3 <1 6 2 – Psychiatric Mood Alteration 5 – – 6 <1 – Depression 5 – – 4 <1 – Infections Viral 5 <1 – 5 <1 – Blood and Lymphatic Anemia 80 2 <1 79 1 <1 Neutropenia 13 1 2 46 8 13 Hepatobiliary Hyperbilirubinemia 48 18 5 17 3 3 6.3 Breast Cancer In Combination with Docetaxel The following data are shown for the combination study with capecitabine and docetaxel in patients with metastatic breast cancer in Table 7 and Table 8 .
In the capecitabine and docetaxel combination arm the treatment was capecitabine administered orally 1250 mg/m 2 twice daily as intermittent therapy (2 weeks of treatment followed by 1 week without treatment) for at least 6 weeks and docetaxel administered as a 1-hour intravenous infusion at a dose of 75 mg/m 2 on the first day of each 3-week cycle for at least 6 weeks.
In the monotherapy arm docetaxel was administered as a 1-hour intravenous infusion at a dose of 100 mg/m 2 on the first day of each 3-week cycle for at least 6 weeks.
The mean duration of treatment was 129 days in the combination arm and 98 days in the monotherapy arm.
A total of 66 patients (26%) in the combination arm and 49 (19%) in the monotherapy arm withdrew from the study because of adverse reactions.
The percentage of patients requiring dose reductions due to adverse reactions was 65% in the combination arm and 36% in the monotherapy arm.
The percentage of patients requiring treatment interruptions due to adverse reactions in the combination arm was 79%.
Treatment interruptions were part of the dose modification scheme for the combination therapy arm but not for the docetaxel monotherapy-treated patients.
– Not observed NA = Not Applicable Table 7 Percent Incidence of Adverse Events Considered Related or Unrelated to Treatment in ≥5% of Patients Participating in the Capecitabine and Docetaxel Combination vs Docetaxel Monotherapy Study Adverse Event Capecitabine 1250 mg/m 2 /bid With Docetaxel 75 mg/m 2 /3 weeks (n=251) Docetaxel 100 mg/m 2 /3 weeks (n=255) Total % Grade 3 % Grade 4 % Total % Grade 3 % Grade 4 % Number of Patients With at Least One Adverse Event 99 76.5 29.1 97 57.6 31.8 Body System/Adverse Event GI Diarrhea 67 14 <1 48 5 <1 Stomatitis 67 17 <1 43 5 – Nausea 45 7 – 36 2 – Vomiting 35 4 1 24 2 – Constipation 20 2 – 18 – – Abdominal Pain 30 <3 <1 24 2 – Dyspepsia 14 – – 8 1 – Dry Mouth 6 <1 – 5 – – Skin and Subcutaneous Hand-and-Foot Syndrome 63 24 NA 8 1 NA Alopecia 41 6 – 42 7 – Nail Disorder 14 2 – 15 – – Dermatitis 8 – – 11 1 – Rash Erythematous 9 <1 – 5 – – Nail Discoloration 6 – – 4 <1 – Onycholysis 5 1 – 5 1 – Pruritus 4 – – 5 – – 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 – Lethargy 7 – – 6 2 – Pain 7 <1 – 5 1 – Chest Pain (non-cardiac) 4 <1 – 6 2 – Influenza-like Illness 5 – – 5 – – Neurological Taste Disturbance 16 <1 – 14 <1 – Headache 15 3 – 15 2 – Paresthesia 12 <1 – 16 1 – Dizziness 12 – – 8 <1 – Insomnia 8 – – 10 <1 – Peripheral Neuropathy 6 – – 10 1 – Hypoaesthesia 4 <1 – 8 <1 – Metabolism Anorexia 13 1 – 11 <1 – Appetite Decreased 10 – – 5 – – Weight Decreased 7 – – 5 – – Dehydration 10 2 – 7 <1 <1 Eye Lacrimation Increased 12 – – 7 <1 – Conjunctivitis 5 – – 4 – – Eye Irritation 5 – – 1 – – Musculoskeletal Arthralgia 15 2 – 24 3 – Myalgia 15 2 – 25 2 – Back Pain 12 <1 – 11 3 – Bone Pain 8 <1 – 10 2 – Cardiac Edema 33 <2 – 34 <3 1 Blood Neutropenic Fever 16 3 13 21 5 16 Respiratory Dyspnea 14 2 <1 16 2 – Cough 13 1 – 22 <1 – Sore Throat 12 2 – 11 <1 – Epistaxis 7 <1 – 6 – – Rhinorrhea 5 – – 3 – – Pleural Effusion 2 1 – 7 4 – Infection Oral Candidiasis 7 <1 – 8 <1 – Urinary Tract Infection 6 <1 – 4 – – Upper Respiratory Tract 4 – – 5 1 – Vascular Flushing 5 – – 5 – – Lymphoedema 3 <1 – 5 1 – Psychiatric Depression 5 – – 5 1 – Table 8 Percent of Patients With Laboratory Abnormalities Participating in the Capecitabine and Docetaxel Combination vs Docetaxel Monotherapy Study Adverse Event Capecitabine 1250 mg/m 2 /bid With Docetaxel 75 mg/m 2 /3 weeks (n=251) Docetaxel 100 mg/m 2 /3 weeks (n=255) Body System/Adverse Event Total % Grade 3 % Grade 4 % Total % Grade 3 % Grade 4 % Hematologic Leukopenia 91 37 24 88 42 33 Neutropenia/Granulocytopenia 86 20 49 87 10 66 Thrombocytopenia 41 2 1 23 1 2 Anemia 80 7 3 83 5 <1 Lymphocytopenia 99 48 41 98 44 40 Hepatobiliary Hyperbilirubinemia 20 7 2 6 2 2 Monotherapy The following data are shown for the study in stage IV breast cancer patients who received a dose of 1250 mg/m 2 administered twice daily for 2 weeks followed by a 1-week rest period.
The mean duration of treatment was 114 days.
A total of 13 out of 162 patients (8%) discontinued treatment because of adverse reactions/intercurrent illness.
Table 9 Percent Incidence of Adverse Reactions Considered Remotely, Possibly or Probably Related to Treatment in ≥5% of Patients Participating in the Single Arm Trial in Stage IV Breast Cancer – Not observed NA = Not Applicable Adverse Event Phase 2 Trial in Stage IV Breast Cancer (n=162) Body System/Adverse Event Total % Grade 3 % Grade 4 % GI Diarrhea 57 12 3 Nausea 53 4 – Vomiting 37 4 – Stomatitis 24 7 – Abdominal Pain 20 4 – Constipation 15 1 – Dyspepsia 8 – – Skin and Subcutaneous Hand-and-Foot Syndrome 57 11 NA Dermatitis 37 1 – Nail Disorder 7 – – General Fatigue 41 8 – Pyrexia 12 1 – Pain in Limb 6 1 – Neurological Paresthesia 21 1 – Headache 9 1 – Dizziness 8 – – Insomnia 8 – – Metabolism Anorexia 23 3 – Dehydration 7 4 1 Eye Eye Irritation 15 – – Musculoskeletal Myalgia 9 – – Cardiac Edema 9 1 – Blood Neutropenia 26 2 2 Thrombocytopenia 24 3 1 Anemia 72 3 1 Lymphopenia 94 44 15 Hepatobiliary Hyperbilirubinemia 22 9 2 6.4 Clinically Relevant Adverse Events in <5% of Patients Clinically relevant adverse events reported in <5% of patients treated with capecitabine tablet either as monotherapy or in combination with docetaxol that were considered at least remotely related to treatment are shown below; occurrences of each grade 3 and 4 adverse event are provided in parentheses.
Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer) Gastrointestinal: abdominal distension, dysphagia, proctalgia, ascites (0.1%), gastric ulcer (0.1%), ileus (0.3%), toxic dilation of intestine, gastroenteritis (0.1%) Skin & Subcutan.: nail disorder (0.1%), sweating increased (0.1%), photosensitivity reaction (0.1%), skin ulceration, pruritus, radiation recall syndrome (0.2%) General: chest pain (0.2%), influenza-like illness, hot flushes, pain (0.1%), hoarseness, irritability, difficulty in walking, thirst, chest mass, collapse, fibrosis (0.1%), hemorrhage, edema, sedation Neurological: insomnia, ataxia (0.5%), tremor, dysphasia, encephalopathy (0.1%), abnormal coordination, dysarthria, loss of consciousness (0.2%), impaired balance Metabolism: increased weight, cachexia (0.4%), hypertriglyceridemia (0.1%), hypokalemia, hypomagnesemia Eye: conjunctivitis Respiratory: cough (0.1%), epistaxis (0.1%), asthma (0.2%), hemoptysis, respiratory distress (0.1%), dyspnea Cardiac: tachycardia (0.1%), bradycardia, atrial fibrillation, ventricular extrasystoles, extrasystoles, myocarditis (0.1%), pericardial effusion Infections: laryngitis (1.0%), bronchitis (0.2%), pneumonia (0.2%), bronchopneumonia (0.2%), keratoconjunctivitis, sepsis (0.3%), fungal infections (including candidiasis) (0.2%) Musculoskeletal: myalgia, bone pain (0.1%), arthritis (0.1%), muscle weakness Blood & Lymphatic: leukopenia (0.2%), coagulation disorder (0.1%), bone marrow depression (0.1%), idiopathic thrombocytopenia purpura (1.0%), pancytopenia (0.1%) Vascular: hypotension (0.2%), hypertension (0.1%), lymphoedema (0.1%), pulmonary embolism (0.2%), cerebrovascular accident (0.1%) Psychiatric: depression, confusion (0.1%) Renal: renal impairment (0.6%) Ear: vertigo Hepatobiliary: hepatic fibrosis (0.1%), hepatitis (0.1%), cholestatic hepatitis (0.1%), abnormal liver function tests Immune System: drug hypersensitivity (0.1%) Capecitabine tablet In Combination With Docetaxel (Metastatic Breast Cancer) Gastrointestinal: ileus (0.4%), necrotizing enterocolitis (0.4%), esophageal ulcer (0.4%), hemorrhagic diarrhea (0.8%) Neurological: ataxia (0.4%), syncope (1.2%), taste loss (0.8%), polyneuropathy (0.4%), migraine (0.4%) Cardiac: supraventricular tachycardia (0.4%) Infection: neutropenic sepsis (2.4%), sepsis (0.4%), bronchopneumonia (0.4%) Blood & Lymphatic: agranulocytosis (0.4%), prothrombin decreased (0.4%) Vascular: hypotension (1.2%), venous phlebitis and thrombophlebitis (0.4%), postural hypotension (0.8%) Renal: renal failure (0.4%) Hepatobiliary: jaundice (0.4%), abnormal liver function tests (0.4%), hepatic failure (0.4%), hepatic coma (0.4%), hepatotoxicity (0.4%) Immune System: hypersensitivity (1.2%) 6.5 Postmarketing Experience The following adverse reactions have been observed in the postmarketing setting: hepatic failure, lacrimal duct stenosis, acute renal failure secondary to dehydration including fatal outcome [ see Warnings and Precautions ( 5.5 ) ], cutaneous lupus erythematosus, corneal disorders including keratitis, toxic leukoencephalopathy, severe skin reactions such as Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (TEN) [ see Warnings and Precautions ( 5.7 ) ], persistent or severe handand-foot syndrome can eventually lead to loss of fingerprints [ see Warnings and Precautions ( 5.7 ) ] 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.
Most common adverse reactions (≥30%) were diarrhea, hand-and-foot syndrome, nausea, vomiting, abdominal pain, fatigue/weakness, and hyperbilirubinemia.
Other adverse reactions, including serious adverse reactions, have been reported.
(6) To report SUSPECTED ADVERSE REACTIONS, contact 1-888-557-1212 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Adjuvant Colon Cancer Table 4 shows the adverse reactions occurring in ≥5% of patients from one phase 3 trial in patients with Dukes' C colon cancer who received at least one dose of study medication and had at least one safety assessment.
A total of 995 patients were treated with 1250 mg/m 2 twice a day of capecitabine administered for 2 weeks followed by a 1-week rest period, and 974 patients were administered 5- FU and leucovorin (20 mg/m 2 leucovorin IV followed by 425 mg/m 2 IV bolus 5-FU on days 1-5 every 28 days).
The median duration of treatment was 164 days for capecitabine-treated patients and 145 days for 5-FU/LV-treated patients.
A total of 112 (11%) and 73 (7%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse reactions.
A total of 18 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 8 (0.8%) patients randomized to capecitabine and 10 (1.0%) randomized to 5-FU/LV.
Table 5 shows grade 3/4 laboratory abnormalities occurring in ≥1% of patients from one phase 3 trial in patients with Dukes' C colon cancer who received at least one dose of study medication and had at least one safety assessment.
Table 4 Percent Incidence of Adverse Reactions Reported in ≥5% of Patients Treated With Capecitabine or 5-FU/LV for Colon Cancer in the Adjuvant Setting (Safety Population) Adjuvant Treatment for Colon Cancer (N=1969) Capecitabine (N=995) 5-FU/LV (N=974) Body System/ Adverse Event All Grades Grade 3/4 All Grades Grade 3/4 Gastrointestinal Disorders 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 Constipation 9 - 11 <1 Upper Abdominal Pain 7 <1 7 <1 Dyspepsia 6 <1 5 - Skin and Subcutaneous Tissue Disorders Hand-and-Foot Syndrome 60 17 9 <1 Alopecia 6 - 22 <1 Rash 7 - 8 - Erythema 6 1 5 <1 General Disorders and Administration Site Conditions Fatigue 16 <1 16 1 Pyrexia 7 <1 9 <1 Asthenia 10 <1 10 1 Lethargy 10 <1 9 <1 Nervous System Disorders Dizziness 6 <1 6 - Headache 5 <1 6 <1 Dysgeusia 6 - 9 - Metabolism and Nutrition Disorders Anorexia 9 <1 11 <1 Eye Disorders Conjunctivitis 5 <1 6 <1 Blood and Lymphatic System Disorders Neutropenia 2 <1 8 5 Respiratory Thoracic and Mediastinal Disorders Epistaxis 2 - 5 - Table 5 Percent Incidence of Grade 3/4 Laboratory Abnormalities Reported in ≥1% of Patients Receiving Capecitabine Monotherapy for Adjuvant Treatment of Colon Cancer (Safety Population) Adverse Event Capecitabine (n=995) Grade 3/4 % IV 5-FU/LV (n=974) Grade 3/4 % Increased ALAT (SGPT) Increased calcium Decreased calcium Decreased hemoglobin Decreased lymphocytes Decreased neutrophils The incidence of grade 3/4 white blood cell abnormalities was 1.3% in the capecitabine arm and 4.9% in the IV 5-FU/LV arm.
** It should be noted that grading was according to NCIC CTC Version 1 (May, 1994).
In the NCIC-CTC Version 1, hyperbilirubinemia grade 3 indicates a bilirubin value of 1.5 to 3.0 x upper limit of normal (ULN) range, and grade 4 a value of > 3.0 x ULN.
The NCI CTC Version2 and above define a grade 3 bilirubin value of >3.0 to 10.0 x ULN, and grade 4 values >10.0 x ULN.
Decreased neutrophils/granulocytes Decreased platelets Increased bilirubin ** 1.6 1.1 2.3 1.0 13.0 2.2 2.4 1.0 20 0.6 0.7 2.2 1.2 13.0 26.2 26.4 0.7 6.3 6.2 Metastatic Colorectal Cancer Monotherapy Table 6 shows the adverse reactions occurring in ≥5% of patients from pooling the two phase 3 trials in first line metastatic colorectal cancer.
A total of 596 patients with metastatic colorectal cancer were treated with 1250 mg/m 2 twice a day of capecitabine administered for 2 weeks followed by a 1-week rest period, and 593 patients were administered 5-FU and leucovorin in the Mayo regimen (20 mg/m 2 leucovorin IV followed by 425 mg/m 2 IV bolus 5-FU, on days 1-5, every 28 days).
In the pooled colorectal database the median duration of treatment was 139 days for capecitabine-treated patients and 140 days for 5-FU/LV-treated patients.
A total of 78 (13%) and 63 (11%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse reactions/intercurrent illness.
A total of 82 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 50 (8.4%) patients randomized to capecitabine and 32 (5.4%) randomized to 5-FU/LV.
Table 6 Pooled Phase 3 Colorectal Trials: Percent Incidence of Adverse Reactions in ≥5% of Patients - Not observed * Excluding vertigo NA=NotApplicable Adverse Event Capecitabine (n=596) 5-FU/LV (n=593) Total % Grade 3 % Grade 4 % Total % Grade 3 % Grade 4 % Number of Patients With > One Adverse Event 96 52 9 94 45 9 Body System/Adverse Event GI Diarrhea 55 13 2 61 10 2 Nausea 43 4 – 51 3 <1 Vomiting 27 4 <1 30 4 <1 Stomatitis 25 2 <1 62 14 1 Abdominal Pain 35 9 <1 31 5 – Gastrointestinal Motility Disorder 10 <1 – 7 <1 – Constipation 14 1 <1 17 1 – Oral Discomfort 10 – – 10 – – Upper GI Inflammatory Disorders 8 <1 – 10 1 – Gastrointestinal Hemorrhage 6 1 <1 3 1 – Ileus 6 4 1 5 2 1 Skin and Subcutaneous Hand-and-Foot Syndrome 54 17 NA 6 1 NA Dermatitis 27 1 – 26 1 – Skin Discoloration 7 <1 – 5 – – Alopecia 6 – – 21 <1 – General Fatigue/Weakness 42 4 – 46 4 – Pyrexia 18 1 – 21 2 – Edema 15 1 – 9 1 – Pain 12 1 – 10 1 – Chest Pain 6 1 – 6 1 <1 Neurological Peripheral Sensory Neuropathy 10 – – 4 – – Headache 10 1 – 7 – – Dizziness* 8 <1 – 8 <1 – Insomnia 7 – – 7 – – Taste Disturbance 6 1 – 11 <1 1 Metabolism Appetite Decreased 26 3 <1 31 2 <1 Dehydration 7 2 <1 8 3 1 Eye Eye Irritation 13 – – 10 <1 – Vision Abnormal 5 – – 2 – – Respiratory Dyspnea 14 1 - 10 <1 1 Cough 7 <1 1 8 - - Pharyngeal Disorder 5 - - 5 - - Epistaxis 3 <1 - 6 - - Sore Throat 2 - - 6 - - Musculoskeletal Back Pain 10 2 – 9 <1 – Arthralgia 8 1 – 6 1 – Vascular Venous Thrombosis 8 3 <1 6 2 – Psychiatric Mood Alteration 5 – – 6 <1 – Depression 5 – – 4 <1 – Infections Viral 5 <1 – 5 <1 – Blood and Lymphatic Anemia 80 2 <1 79 1 <1 Neutropenia 13 1 2 46 8 13 Hepatobiliary Hyperbilirubinemia 48 18 5 17 3 3 6.3 Breast Cancer In Combination with Docetaxel The following data are shown for the combination study with capecitabine and docetaxel in patients with metastatic breast cancer in Table 7 and Table 8 .
In the capecitabine and docetaxel combination arm the treatment was capecitabine administered orally 1250 mg/m 2 twice daily as intermittent therapy (2 weeks of treatment followed by 1 week without treatment) for at least 6 weeks and docetaxel administered as a 1-hour intravenous infusion at a dose of 75 mg/m 2 on the first day of each 3-week cycle for at least 6 weeks.
In the monotherapy arm docetaxel was administered as a 1-hour intravenous infusion at a dose of 100 mg/m 2 on the first day of each 3-week cycle for at least 6 weeks.
The mean duration of treatment was 129 days in the combination arm and 98 days in the monotherapy arm.
A total of 66 patients (26%) in the combination arm and 49 (19%) in the monotherapy arm withdrew from the study because of adverse reactions.
The percentage of patients requiring dose reductions due to adverse reactions was 65% in the combination arm and 36% in the monotherapy arm.
The percentage of patients requiring treatment interruptions due to adverse reactions in the combination arm was 79%.
Treatment interruptions were part of the dose modification scheme for the combination therapy arm but not for the docetaxel monotherapy-treated patients.
– Not observed NA = Not Applicable Table 7 Percent Incidence of Adverse Events Considered Related or Unrelated to Treatment in ≥5% of Patients Participating in the Capecitabine and Docetaxel Combination vs Docetaxel Monotherapy Study Adverse Event Capecitabine 1250 mg/m 2 /bid With Docetaxel 75 mg/m 2 /3 weeks (n=251) Docetaxel 100 mg/m 2 /3 weeks (n=255) Total % Grade 3 % Grade 4 % Total % Grade 3 % Grade 4 % Number of Patients With at Least One Adverse Event 99 76.5 29.1 97 57.6 31.8 Body System/Adverse Event GI Diarrhea 67 14 <1 48 5 <1 Stomatitis 67 17 <1 43 5 – Nausea 45 7 – 36 2 – Vomiting 35 4 1 24 2 – Constipation 20 2 – 18 – – Abdominal Pain 30 <3 <1 24 2 – Dyspepsia 14 – – 8 1 – Dry Mouth 6 <1 – 5 – – Skin and Subcutaneous Hand-and-Foot Syndrome 63 24 NA 8 1 NA Alopecia 41 6 – 42 7 – Nail Disorder 14 2 – 15 – – Dermatitis 8 – – 11 1 – Rash Erythematous 9 <1 – 5 – – Nail Discoloration 6 – – 4 <1 – Onycholysis 5 1 – 5 1 – Pruritus 4 – – 5 – – 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 – Lethargy 7 – – 6 2 – Pain 7 <1 – 5 1 – Chest Pain (non-cardiac) 4 <1 – 6 2 – Influenza-like Illness 5 – – 5 – – Neurological Taste Disturbance 16 <1 – 14 <1 – Headache 15 3 – 15 2 – Paresthesia 12 <1 – 16 1 – Dizziness 12 – – 8 <1 – Insomnia 8 – – 10 <1 – Peripheral Neuropathy 6 – – 10 1 – Hypoaesthesia 4 <1 – 8 <1 – Metabolism Anorexia 13 1 – 11 <1 – Appetite Decreased 10 – – 5 – – Weight Decreased 7 – – 5 – – Dehydration 10 2 – 7 <1 <1 Eye Lacrimation Increased 12 – – 7 <1 – Conjunctivitis 5 – – 4 – – Eye Irritation 5 – – 1 – – Musculoskeletal Arthralgia 15 2 – 24 3 – Myalgia 15 2 – 25 2 – Back Pain 12 <1 – 11 3 – Bone Pain 8 <1 – 10 2 – Cardiac Edema 33 <2 – 34 <3 1 Blood Neutropenic Fever 16 3 13 21 5 16 Respiratory Dyspnea 14 2 <1 16 2 – Cough 13 1 – 22 <1 – Sore Throat 12 2 – 11 <1 – Epistaxis 7 <1 – 6 – – Rhinorrhea 5 – – 3 – – Pleural Effusion 2 1 – 7 4 – Infection Oral Candidiasis 7 <1 – 8 <1 – Urinary Tract Infection 6 <1 – 4 – – Upper Respiratory Tract 4 – – 5 1 – Vascular Flushing 5 – – 5 – – Lymphoedema 3 <1 – 5 1 – Psychiatric Depression 5 – – 5 1 – Table 8 Percent of Patients With Laboratory Abnormalities Participating in the Capecitabine and Docetaxel Combination vs Docetaxel Monotherapy Study Adverse Event Capecitabine 1250 mg/m 2 /bid With Docetaxel 75 mg/m 2 /3 weeks (n=251) Docetaxel 100 mg/m 2 /3 weeks (n=255) Body System/Adverse Event Total % Grade 3 % Grade 4 % Total % Grade 3 % Grade 4 % Hematologic Leukopenia 91 37 24 88 42 33 Neutropenia/Granulocytopenia 86 20 49 87 10 66 Thrombocytopenia 41 2 1 23 1 2 Anemia 80 7 3 83 5 <1 Lymphocytopenia 99 48 41 98 44 40 Hepatobiliary Hyperbilirubinemia 20 7 2 6 2 2 Monotherapy The following data are shown for the study in stage IV breast cancer patients who received a dose of 1250 mg/m 2 administered twice daily for 2 weeks followed by a 1-week rest period.
The mean duration of treatment was 114 days.
A total of 13 out of 162 patients (8%) discontinued treatment because of adverse reactions/intercurrent illness.
Table 9 Percent Incidence of Adverse Reactions Considered Remotely, Possibly or Probably Related to Treatment in ≥5% of Patients Participating in the Single Arm Trial in Stage IV Breast Cancer – Not observed NA = Not Applicable Adverse Event Phase 2 Trial in Stage IV Breast Cancer (n=162) Body System/Adverse Event Total % Grade 3 % Grade 4 % GI Diarrhea 57 12 3 Nausea 53 4 – Vomiting 37 4 – Stomatitis 24 7 – Abdominal Pain 20 4 – Constipation 15 1 – Dyspepsia 8 – – Skin and Subcutaneous Hand-and-Foot Syndrome 57 11 NA Dermatitis 37 1 – Nail Disorder 7 – – General Fatigue 41 8 – Pyrexia 12 1 – Pain in Limb 6 1 – Neurological Paresthesia 21 1 – Headache 9 1 – Dizziness 8 – – Insomnia 8 – – Metabolism Anorexia 23 3 – Dehydration 7 4 1 Eye Eye Irritation 15 – – Musculoskeletal Myalgia 9 – – Cardiac Edema 9 1 – Blood Neutropenia 26 2 2 Thrombocytopenia 24 3 1 Anemia 72 3 1 Lymphopenia 94 44 15 Hepatobiliary Hyperbilirubinemia 22 9 2 6.4 Clinically Relevant Adverse Events in <5% of Patients Clinically relevant adverse events reported in <5% of patients treated with capecitabine tablet either as monotherapy or in combination with docetaxol that were considered at least remotely related to treatment are shown below; occurrences of each grade 3 and 4 adverse event are provided in parentheses.
Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer) Gastrointestinal: abdominal distension, dysphagia, proctalgia, ascites (0.1%), gastric ulcer (0.1%), ileus (0.3%), toxic dilation of intestine, gastroenteritis (0.1%) Skin & Subcutan.: nail disorder (0.1%), sweating increased (0.1%), photosensitivity reaction (0.1%), skin ulceration, pruritus, radiation recall syndrome (0.2%) General: chest pain (0.2%), influenza-like illness, hot flushes, pain (0.1%), hoarseness, irritability, difficulty in walking, thirst, chest mass, collapse, fibrosis (0.1%), hemorrhage, edema, sedation Neurological: insomnia, ataxia (0.5%), tremor, dysphasia, encephalopathy (0.1%), abnormal coordination, dysarthria, loss of consciousness (0.2%), impaired balance Metabolism: increased weight, cachexia (0.4%), hypertriglyceridemia (0.1%), hypokalemia, hypomagnesemia Eye: conjunctivitis Respiratory: cough (0.1%), epistaxis (0.1%), asthma (0.2%), hemoptysis, respiratory distress (0.1%), dyspnea Cardiac: tachycardia (0.1%), bradycardia, atrial fibrillation, ventricular extrasystoles, extrasystoles, myocarditis (0.1%), pericardial effusion Infections: laryngitis (1.0%), bronchitis (0.2%), pneumonia (0.2%), bronchopneumonia (0.2%), keratoconjunctivitis, sepsis (0.3%), fungal infections (including candidiasis) (0.2%) Musculoskeletal: myalgia, bone pain (0.1%), arthritis (0.1%), muscle weakness Blood & Lymphatic: leukopenia (0.2%), coagulation disorder (0.1%), bone marrow depression (0.1%), idiopathic thrombocytopenia purpura (1.0%), pancytopenia (0.1%) Vascular: hypotension (0.2%), hypertension (0.1%), lymphoedema (0.1%), pulmonary embolism (0.2%), cerebrovascular accident (0.1%) Psychiatric: depression, confusion (0.1%) Renal: renal impairment (0.6%) Ear: vertigo Hepatobiliary: hepatic fibrosis (0.1%), hepatitis (0.1%), cholestatic hepatitis (0.1%), abnormal liver function tests Immune System: drug hypersensitivity (0.1%) Capecitabine tablet In Combination With Docetaxel (Metastatic Breast Cancer) Gastrointestinal: ileus (0.4%), necrotizing enterocolitis (0.4%), esophageal ulcer (0.4%), hemorrhagic diarrhea (0.8%) Neurological: ataxia (0.4%), syncope (1.2%), taste loss (0.8%), polyneuropathy (0.4%), migraine (0.4%) Cardiac: supraventricular tachycardia (0.4%) Infection: neutropenic sepsis (2.4%), sepsis (0.4%), bronchopneumonia (0.4%) Blood & Lymphatic: agranulocytosis (0.4%), prothrombin decreased (0.4%) Vascular: hypotension (1.2%), venous phlebitis and thrombophlebitis (0.4%), postural hypotension (0.8%) Renal: renal failure (0.4%) Hepatobiliary: jaundice (0.4%), abnormal liver function tests (0.4%), hepatic failure (0.4%), hepatic coma (0.4%), hepatotoxicity (0.4%) Immune System: hypersensitivity (1.2%) 6.5 Postmarketing Experience The following adverse reactions have been observed in the postmarketing setting: hepatic failure, lacrimal duct stenosis, acute renal failure secondary to dehydration including fatal outcome [ see Warnings and Precautions ( 5.5 ) ], cutaneous lupus erythematosus, corneal disorders including keratitis, toxic leukoencephalopathy, severe skin reactions such as Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (TEN) [ see Warnings and Precautions ( 5.7 ) ], persistent or severe handand-foot syndrome can eventually lead to loss of fingerprints [ see Warnings and Precautions ( 5.7 ) ] 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.