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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 Northstar RxLLC at 1-800-206-7821 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 to 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) 1.6 0.6 Increased calcium 1.1 0.7 Decreased calcium 2.3 2.2 Decreased hemoglobin 1.0 1.2 Decreased lymphocytes 13.0 13.0 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. 2.2 26.2 Decreased neutrophils/granulocytes 2.4 26.4 Decreased platelets 1.0 0.7 Increased bilirubin 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 × upper limit of normal (ULN) range, and grade 4 a value of > 3.0 × ULN. The NCI CTC Version 2 and above define a grade 3 bilirubin value of >3.0 to 10.0 × ULN, and grade 4 values >10.0 × ULN. 20 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 to 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 Adverse Event Capecitabine (n=596) 5-FU/LV (n=593) Total % Grade 3 % Grade 4 % Total % Grade 3 % Grade 4 % – Not observed NA = Not Applicable 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 Excluding vertigo 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. 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 % – Not observed NA = Not Applicable 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 Adverse Event Phase 2 Trial in Stage IV Breast Cancer (n=162) Body System/Adverse Event Total % Grade 3 % Grade 4 % – Not observed NA = Not Applicable 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 either as monotherapy or in combination with docetaxel 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 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: angioedema, 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 hand-and-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.