Monotherapy: Of 578 patients evaluable for adverse reactions in clinical studies with TS-ONE monotherapy excluding the following patients with pancreatic cancer, the incidence of adverse reactions was 87.2% (504 patients). Also, in patients with pancreatic cancer, the incidence of adverse reactions was high (98.3%) compared to patients with other cancer types. Pancreatic cancer patients showed also high incidences of severe adverse reactions, in particular gastrointestinal disorders such as anorexia, nausea, vomiting, and diarrhea. The following adverse reactions appear to be important clinically.
The results of analysis regarding time of onset of the adverse reactions and the period of recovery will be described as follows (See Pharmacology: Pharmacodynamics: Clinical Studies under Actions). (See Table 8.)
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The following table shows frequency of the adverse events occurring in ≥ 5% of patients reported in the randomized study of post-operative adjuvant chemotherapy with TS-ONE for gastric cancer. The data are shown for 517 evaluable patients in the TS-ONE group and 526 evaluable patients in surgery alone group for adverse events. Frequency of all adverse event was 100% in the TS-ONE group and 93.3% in the surgery alone group respectively. (See Table 9.)
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Combination therapy: Of 55 patients evaluable for adverse reactions in a late phase II clinical study with combination therapy (a 21-day consecutive oral administration of TS-ONE and an administration of cisplatin at 60 mg/m
2 on day 8) for non-small cell lung cancer, some kinds of adverse reactions occurred among all 55 patients. The following adverse reactions appear to be important clinically (When indications are added). (See Table 10.)
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(Incidence rates of interstitial pneumonia and other pulmonary disorders in a drug use investigation in patients with non-small cell lung cancer.)
A post-marketing drug use investigation in patients with non-small cell lung cancer reported incidence rates of 0.7% (11/1669) for interstitial pneumonia and 0.7% (12/1669) for other pulmonary disorders including radiation pneumonitis, dyspnea, and respiratory failure.
Clinically significant adverse reactions: The overall safety profile of TS-ONE is based on data from 751 patients treated with TS-ONE monotherapy in clinical studies for advanced or recurrent cancer and from post-marketing experiences in multiple indications in Japan. The following adverse reaction frequencies were calculated from data for these clinical studies.
Bone marrow depression, hemolytic anemia: Since severe bone marrow depression such as pancytopenia, agranulocytosis (symptoms: fever, sore throat and malaise), leukopenia (46.7%), anemia (40.6%), thrombocytopenia (15.7%) and hemolytic anemia (incidence unknown) may occur, the patient's condition should be monitored closely. If any abnormal findings are observed, appropriate measures should be taken, such as discontinuing administration of TS-ONE.
Disseminated intravascular coagulation (DIC): Since disseminated intravascular coagulation (DIC) (0.4%) may occur, the patient's condition should be monitored closely. If any abnormal findings are observed on blood tests including those for platelet count, serum FDP level and plasma fibrinogen level, TS-ONE administration should be discontinued, and appropriate measures should be taken.
Severe hepatic disorder such as fulminant hepatitis: Since severe hepatic disorders such as fulminant hepatits (including reactivation of hepatitis B virus) (incidence unknown) may occur, patient's condition should be monitored closely by periodic hepatic function tests. If any abnormal findings observed, appropriate measures should be taken, such as discontinuing administration of TS-ONE. (See WARNINGS.)
Dehydration: Since severe diarrhea may occur, and may lead to dehydration (incidence unknown), the patient's condition should be monitored closely. If any such symptoms are observed, TS-ONE administration should be discontinued, and appropriate measures should be taken, such as fluid replacement.
Severe enteritis (0.5%): Since hemorrhagic enterocolitis, ischaemic enterocolitis and necrotising enterocolitis may occur; the patient's condition should be monitored closely. If severe symptoms such as abdominal pain and diarrhea occur, TS-ONE administration should be discontinued, and appropriate measures should be taken.
Interstitial pneumonia: Since interstitial pneumonia (0.3%) (early symptoms: cough, shortness of breath, dyspnea and fever) may occur, the patient's condition should be monitored closely. If any abnormal findings are observed, TS-ONE administration should be discontinued, and appropriate measures should be taken, such as chest X-ray examination and treatment with corticosteroids.
Myocardial infarction, angina pectoris, arrhythmia, cardiac failure: Since myocardial infarction, angina pectoris, arrhythmia (including ventricular tachycardia) and cardiac failure (the incidences of these adverse reactions are unknown) may occur, the patient's condition should be monitored closely. If chest pain, syncope, palpitation, abnormal ECG or breathlessness is observed, TS-ONE administration should be discontinued, and appropriate measures should be taken.
Severe stomatitis, gastrointestinal ulcer, gastrointestinal hemorrhage and gastrointestinal perforation: Since severe stomatitis (incidence unknown), gastrointestinal ulcer (0.5%), gastrointestinal hemorrhage (0.3%) and gastrointestinal perforation (incidence unknown) may occur, the patient's condition should be monitored closely. If any abnormal findings are observed, TS-ONE administration should be discontinued and appropriate measures should be taken, such as examination by abdominal X-ray.
Acute kidney injury and nephrotic syndrome: Since severe renal disorder such as acute kidney injury and nephrotic syndrome (incidence unknown) may occur, the patient's condition should be monitored closely. If any abnormal findings are observed, TS-ONE administration should be discontinued, and appropriate measures should be taken.
Toxic epidermal necrolysis (TEN) and muco-cutaneo-ocular syndrome (Stevens-Johnson syndrome): Since toxic epidermal necrolysis and muco-cutaneo-ocular syndrome (incidence unknown) may occur, the patient's condition should be monitored closely. If any abnormal findings are observed, TS-ONE administration should be discontinued, and appropriate measures should be taken.
Psychoneurologic disorders including leukoencephalopathy or other symptoms: Since leukoencephalopathy (major symptoms include consciousness disturbance, cerebellar ataxia, and dementia-like symptoms), consciousness disturbance, disorientation, somnolence, hypomnesia, extrapyramidal symptoms, speech disorder, quadriplegia, gait disturbance, urinary incontinence, or sensory disturbance (the incidences of these adverse reactions are unknown) may occur, the patient's condition should be monitored closely, and if any such symptoms are observed, TS-ONE administration should be discontinued.
Acute pancreatitis: Since acute pancreatitis (incidence unknown) may occur, the patient's condition should be monitored closely. If abdominal pain or increased serum amylase were observed, TS-ONE administration should be discontinued, and appropriate measures should be taken.
Rhabdomyolysis: Since rhabdomyolysis (incidence unknown) marked by muscle pain, feeling of weakness, increased CK (CPK) and increased myoglobin in the blood or urine may occur, TS-ONE administration should be discontinued, and appropriate measures should be taken. Also, care should be taken to avoid appearance of acute kidney injury due to rhabdomyolysis.
Anosmia: Since dysosmia (0.1%) may occur, and anosmia (incidence unknown) may develop, the patient's condition should be monitored closely. If any abnormal findings are observed, appropriate measures should be taken, such as discontinuing administration of TS-ONE.
Lacrimal duct obstruction: Lacrimal duct obstruction (incidence unknown) may occur, and some patients have been reported to undergo surgical procedures. If any symptoms such as lacrimation are observed, appropriate measures should be taken, such as ophthalmic examination.
Clinically significant adverse reactions (similar drugs): Since the following adverse reactions have been reported to be caused by tegafur, if any abnormal findings are observed, appropriate measures should be taken, such as discontinuing administration of TS-ONE.
Hepatic cirrhosis: prolonged prothrombin time, decreased albumin and decreased cholinesterase.
Other adverse reactions: Since the following adverse reactions may occur, if any abnormal findings are observed, appropriate measures should be taken, such as dose reduction or discontinuing administration of TS-ONE. If hypersensitivity is observed, TS-ONE administration should be discontinued, and appropriate measures should be taken. (See Table 11.)
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In patients who were administered TS-ONE in the randomized study of post-operative adjuvant chemotherapy for gastric cancer, frequency of lacrimation (7.2%) was higher than in the studies for treatment of advanced or recurrent cancer. In patients who were administered TS-ONE in the post-marketing clinical study for unresectable or recurrent gastric cancer, the incidence of lacrimation was high (16.0%).
Other adverse reactions (similar drugs): Since the following adverse reactions have been reported to be caused by tegafur, if any abnormal findings are observed, appropriate measures should be taken, such as dose reduction or discontinuing administration of TS-ONE.
Fatty liver, difficulty in swallowing, tinnitus, excitement, increased serum uric acid, gynecomastia.