Can Capecitabine cause malignant neoplasm progression?

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 )] • 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, handand- foot syndrome, nausea, fatigue, vomiting, and dermatitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories Inc., at 1-888-375-3784 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 receivedcapecitabine 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 C apecitabine 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 erythrodysesthesiasyndrome 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:d izziness, 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 C apecitabine tablets (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 [see Clinical Studies ( 14.1 )]. 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 RectalCancer 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 C apecitabine 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 be

WARNINGS AND PRECAUTIONS • Cardiotoxicity : May be more common in patients with a prior history of coronary artery disease. Withhold capecitabine tablets for cardiotoxicity as appropriate. The safety of resumption of capecitabine tablets in patients with cardiotoxicity that has resolved has not been established. ( 2.5 , 5.3 ) • Diarrhea : Withhold capecitabine tablets and then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence. ( 2.5 , 5.4 ) • Dehydration : Optimize hydration before starting capecitabine tablets. Monitor hydration status and kidney function at baseline and as clinically indicated. Withhold capecitabine tablets and then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence. ( 2.5 , 5.5 ) • Renal Toxicity : Monitor renal function at baseline and as clinically indicated. Optimize hydration before starting capecitabine tablets. Withhold capecitabine tablets and then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence. ( 2.5 , 5.6 ) • Serious Skin Toxicities : Monitor for new or worsening serious skin reactions. Permanently discontinue capecitabine tablets in patients who experience a severe cutaneous adverse reaction. ( 5.7 ) • Palmar-Plantar Erythrodysesthesia Syndrome : Withhold capecitabine tablets then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence. ( 2.5 , 5.8 ) • Myelosuppression : Monitor complete blood count at baseline and before each cycle. capecitabine tablets is not recommended in patients with baseline neutrophil counts <1.5 x 10 9 /L or platelet counts <100 x 10 9 /L. For grade 3 or 4 myelosuppression, withhold capecitabine tablets and then resume at same or reduced dose, or permanently discontinue, based on occurrence. ( 2.5 , 5.9 ) • Hyperbilirubinemia : Patients with Grade 3-4 hyperbilirubinemia may resume treatment once the event is Grade 2 or less (<3 x ULN), using the percent of current dose as shown in column 3 of Table 1 ( 2.5 , 5.10 ) ] • Embryo-Fetal Toxicity : Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.11 , 8.1 , 8.3 ) 5.1 Serious Adverse Reactions or Death from Dihydropyrimidine Dehydrogenase (DPD) Deficiency Patients with certain homozygous or compound heterozygous variants in the DPYD gene known to result in complete or near complete absence of DPD activity (complete DPD deficiency) are at increased risk for acute early-onset toxicity and serious, including fatal, adverse reactions due to capecitabine tablets (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity). Patients with partial DPD activity (partial DPD deficiency) may also have increased risk of serious, or fatal, adverse reactions. Prior to initiating capecitabine tablets, test patients for genetic variants of the DPYD gene unlessimmediate treatment is necessary [see Clinical Pharmacology (12.5)]. Serious adverse reactions may still occur even if no DPYD variants are identified. Avoid use of capecitabine tablets in patients with certain homozygous or compound heterozygous DPYD variants that result in complete DPD deficiency. Withhold or permanently discontinue capecitabine tablets based on clinical assessment of the onset, duration, and severity of adverse reactions in patients with evidence of acute early-onset orunusually severe reactions. 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. An FDA-authorized test for the detection of genetic variants of the DPYD gene to identifypatients at risk of serious adverse reactions with capecitabine tablets treatment 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). 5.2 Increased Risk of Bleeding With Concomitant Use of Vitamin K Antagonists Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking capecitabine tablets concomitantly with vitamin K antagonists, such as warfarin. Clinically significant increases in PT and INR have been reported in patients who were on stable doses of oral vitamin K antagonists at the time capecitabine tablets was introduced. These events occurred within several days and up to several months after initiating capecitabine tablets and, in a few cases, within 1 month after stopping capecitabine tablets. These events occurred in patients with and without liver metastases. Monitor INR more frequently and adjust the dose of the vitamin K antagonist as appropriate [see Drug Interactions (7.1) ]. 5.3 Cardiotoxicity Cardiotoxicity can occur with capecitabine tablets. Myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy have been reported with capecitabine tablets. These adverse reactions may be more common in patients with a prior history of coronary artery disease. Withhold capecitabine tablets for cardiotoxicity as appropriate [see Dosage and Administration ( 2.5 )]. The safety of resumption of capecitabine tablets in patients with cardiotoxicity that has resolved have not been established. 5.4 Diarrhea Diarrhea, sometimes severe, can occur with capecitabine tablets. In 875 patients with metastatic breast or colorectal cancer who received capecitabine tablets as a single agent, the median time to first occurrence of grade 2 to 4 diarrhea was 34 days (range: 1 day to 1 year). The median duration of grade 3 to 4 diarrhea was 5 days.Withhold capecitabine tablets and then resume at same or reduced dose or permanently discontinue based on severity and occurrence [see Dosage and Administration ( 2.5 ) ]. 5.5 Dehydration Dehydration can occur with capecitabine tablets. Patients with anorexia, asthenia, nausea, vomiting, or diarrhea may be at an increased risk of developing dehydration with capecitabine tablets. Optimize hydration before startingcapecitabine tablets. Monitor hydration status and kidney function at baseline and as clinically indicated. Withhold capecitabine tablets and then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence [see Dosage and Administration (2.5) ]. 5.6 Renal Toxicity Serious renal failure, sometimes fatal, can occur with capecitabine tablets. Renal impairment or coadministration of capecitabine tablets with other products known to cause renal toxicity may increase the risk of renal toxicity [see Drug Interactions (7.3)]. Monitor renal function at baseline and as clinically indicated. Optimize hydration before starting capecitabine tablets. Withhold capecitabine tablets and then resume at same or reduced dose, or permanently discontinue, based on severity and occurrence [see Dosage and Administration ( 2.5 )]. 5.7 Serious Skin Toxicities Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson Syndrome and toxic epidermal necrolysis (TEN), which can be fatal, can occur with capecitabine tablets [see Adverse Reactions ( 6.2 )]. Monitor for new or worsening serious skin reactions. Permanently discontinue capecitabine tablets for severe cutaneous adverse reactions. 5.8 Palmar-Plantar Erythrodysesthesia Syndrome Palmar-plantar erythrodysesthesia syndrome (PPES) can occur with capecitabine tablets. In patients with metastatic breast or colorectal cancer who received capecitabine tablets as a single agent, the median time to onset of grades 1 to 3 PPES was 2.6 months (range: 11 days to 1 year). Withhold capecitabine tablets and then resume at same or reduced dose or permanently discontinue based on severity and occurrence [see Dosage and Administration ( 2.5 ) ]. 5.9 Myelosuppression Myelosuppression can occur with capecitabine tablets. In the 875 patients with me