TS-One

Tegafur, oteracil potassium, gimeracil.

See Table 1.

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Physicochemistry: See Table 2.

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Pharmacology: Antitumor activity: TS-ONE has effects to inhibit the growth of tumors such as Yoshida sarcoma, AH-130 hepatoma, Sato lung carcinoma (in rats), Sarcoma-180, Lewis lung carcinoma and Colon-26 (in mice) transplanted subcutaneously. TS-ONE also has effects to inhibit the growth of human cancers such as gastric, colorectal, breast, lung, pancreatic and renal when transplanted subcutaneously to nude rats or nude mice. TS-ONE also has survival effects in the mouse Lewis lung carcinoma and L5178Y metastasis models, and has effects to inhibit the growth of tumors in nude rat models in which human gastric cancer and colorectal cancer cell lines were orthotopically implanted.
Mechanism of action: TS-ONE contains FT, CDHP and Oxo, and antitumor activity of TS-ONE after oral administration is based on 5-FU that appears gradually in the body via the transformation of FT. CDHP increased the concentration of 5-FU, which is converted from FT, by selectively and reversibly inhibiting DPD, a catabolic enzyme of 5-FU, which is particularly distributed in the liver. 5-fluoronucleotides, phosphorylated metabolites of 5-FU, are highly maintained in tumor tissues, thereby enhancing the antitumor activity in proportion to the increase in the concentration of 5-FU in the body. Oxo selectively inhibits the production of 5-fluoronucleotides from 5-FU by distributing in the gastrointestinal tissue as a result of oral administration and selectively and reversibly inhibiting orotate phosphoribosyltransferase. Gastrointestinal toxicity appears to be relieved as a result, without interfering with the antitumor activity of 5-FU.
The main mechanisms of action of 5-FU is the inhibition of DNA synthesis resulting from the antagonistic effect of the active metabolite FdUMP acting upon dUMP to form Ternary complex with thymidylate synthase and the reduced folic acid. RNA function is also thought to be damaged by conversion of 5-FU to FUTP, and its incorporation into RNA molecule.
Clinical Studies: Randomized phase III study of post-operative adjuvant chemotherapy: The survival benefit of TS-ONE monotherapy (one year after surgery, 529 patients) was compared with surgery alone (530 patients) in patients with stage II or III gastric cancer after curative gastrectomy (median post-operative follow-up period: 3 years). TS-ONE reduced the risk of death by 32% compared with surgery alone, with a hazard ratio for death of 0.675 (95% confidence interval: 0.523 - 0.871, p=0.0024 by the log-rank test). The three-year survival rate after surgery was 80.5% in the TS-ONE group and 70.1% in the surgery alone group. TS-ONE reduced the risk of relapse by 38% compared with surgery alone, with a hazard ratio for relapse or death of 0.622 (95% confidence interval: 0.501 - 0.772, p<0.0001 by the log-rank test). The three-year relapse-free survival rate was 72.2% in the TS-ONE group and 60.1% in the surgery alone group.
The three-year survival rate following randomization after surgery was 80.1% in the TS-ONE group and 70.1% in the surgery alone group. The three-year relapse-free survival rate following randomization after surgery was 72.2% in the TS-ONE group and 59.6% in the surgery alone group. (See Figures 1 and 2.)

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Time of occurrence of adverse reactions and period of recovery: The time of occurrence of adverse reactions considered noteworthy as a result of administration of TS-ONE was analyzed in 453 patients enrolled in late clinical phase II studies of TS-ONE for advanced or recurrent cancer in Japan. The results were as follows.
Among abnormal laboratory test results below any of the criteria including a WBC count of 3000/mm³, a hemoglobin level of 8 g/dL, and a platelet count of 7.5 × 10⁴/mm³, the median time to nadir in the cycle where the lowest level in a case was reached was 27 days for WBC count, 25 days for hemoglobin level, and 24 days for platelet count. On the other hand, in patients who were confirmed to have recovered from the previously mentioned criteria, the median between the nadir of these values and recovery from them in the course were 7 days, 5.5 days and 6 days, respectively. (See Table 3.)

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When the time of occurrence of adverse reactions after the start of the first dose of TS-ONE was examined to assess the causality between them, the median until the occurrence of diarrhea, rash and stomatitis, which were judged adverse reactions, were 24.5 days, 21 days, and 28 days, respectively. On the other hand, the median between the highest grade of these adverse reactions and the improvement from them were 9 days for diarrhea, 14 days for rash, and 13.5 days for stomatitis. (See Table 4.)

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Adverse reactions in the presence of renal disorder: In the post-marketing surveys of TS-ONE in patients with gastric cancer, the incidence of adverse reactions was tabulated by the range of creatinine clearance value (Ccr estimate), calculated from serum creatinine value, gender, age and weight using Cockcroft-Gault equation. The results were as follows.
In the patients, as creatinine clearance value decreased, the incidence of adverse reactions increased and the severity of the adverse reactions also increased. Additionally, in the patients who were administrated initially at the lower dose (mostly, one stage lower than the standard), the incidence of adverse reactions was low, compared with patients who were administrated initially at the standard dose. (See Table 5.)

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Pharmacokinetics: Pharmacokinetic parameters obtained from the plasma concentrations of TS-ONE administered to 12 cancer patients in a single oral dose of 32-40 mg/m² after a meal are shown in Table 6. The amount excreted in the urine within 72 hours after administration accounted for 52.8% of gimeracil (CDHP), 7.8% of tegafur (FT), 2.2% of oteracil potassium (Oxo), 11.4% of the metabolite cyanuric acid (CA) and 7.4% of fluorouracil (5-FU). (See Table 6.)

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When TS-ONE was orally administered at a dose of 25-200 mg/body, the AUC and C_max of FT, CDHP, Oxo and 5-FU increased in a dose-dependent manner. When the plasma concentration of TS-ONE was measured 1, 7, 14 and 28 days after administration of 32-40 mg/m² of TS-ONE twice a day for 28 consecutive days, it rapidly reached a constant level. Endogenous uracil (Ura) rapidly decreased even after consecutive administration of TS-ONE, and the CDHP-induced DPD inhibition was reversible, and no enhancing effect was observed.
TS-ONE, alone or in combination with other fluoropyrimidine-group drugs, was orally administered to rats for 7 consecutive days, and the plasma concentration of 5-FU was measured 2 hours after the final dose. It was found to be 4.1, 8.1, 2.8, 5.7, 6.9 and 2.3 times higher when combined with 5-FU, FT, FT-Ura, carmofur, doxifluridine and flucytosine, respectively, than when administered alone. This suggests that the combined use of TS-ONE and other fluoropyrimidine-group drugs may enhance adverse reactions.
When TS-ONE was administered to a renal dysfunction rabbit, CDHP renal clearance was found to be decreased, and the blood concentration of 5-FU was markedly increased compared to control animal. These suggest that adverse reactions may be enhanced.
Creatinine clearance value (Ccr estimate) was calculated from serum creatinine value, gender, age, and weight using the Cockcroft-Gault equation* for the clinical study patients for whom pharmacokinetics were examined in detail (clinical pharmacology, pancreatic cancer, biliary tract cancer). The AUCs of two patient groups with normal and slightly impaired renal function were tabulated by range of creatinine clearance value (Ccr estimate). (See Table 7.)

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* Cockcroft-Gault equation: See equation.

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Protein binding: The rates of protein binding of each component and 5-FU in human serum were 49-56% for FT, 32-33% for CDHP, 7-10% for Oxo and 17-20% for 5-FU (in vitro).
Metabolic enzyme: It has been reported that CYP2A6 is the major cytochrome P450 isoenzymes in human liver microsomes involved in the metabolic transformation of FT to 5-FU (in vitro).

Post-operative adjuvant chemotherapy for locally advanced stage II (excluding T1), IIIA or IIIB gastric cancer.

Usually, the following standard doses are defined as the initial dose (single dose) for adults according to body surface area. TS-ONE is administered twice daily, after breakfast and after the evening meal, for 28 consecutive days, followed by a 14-day rest. This is regarded as one course of the regimen. (See Table 8.)

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The initial dose can be decreased according to the patient's condition. The doses are staged thus: 40 mg, 50 mg, 60 mg. The dose can be decreased by one stage, and the lower limit is 40 mg.
Precautions on Dosage and Administration: When the dose is decreased according to the patient's condition, the following standard doses should be referenced. (See Table 9.)

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If a drug rest period therapeutically needs to be shortened, it should be implemented after confirming that no drug-induced abnormalities in laboratory findings (hematological tests, liver and renal function tests) and no gastrointestinal symptoms occur, i.e., the drug is not problematic in terms of safety. A minimum drug rest period of 7 days must be provided. Also, safety in the case of the shortened drug rest period with inoperable or recurrent breast cancer have not yet been established (there is no clinical data).
To avoid serious adverse reactions such as bone marrow depression and fulminant hepatitis, the patient's condition should be monitored thoroughly by performing laboratory tests (hematological tests, liver and renal function tests) before the start of each course and at least once every 2 weeks during dosing. If any abnormal findings are observed, appropriate measures should be taken, such as prolongation of the drug rest period, dosage reduction according to the previously mentioned standard doses, or discontinuing administration of TS-ONE. Laboratory tests should be performed frequently, particularly when one course of the regimen is conducted (see Pharmacology: Clinical Studies under Actions).
Since basic investigations (rats) have revealed that the bioavailability of oteracil potassium changes when the drug is administered in the fasting state, it is speculated that phosphorylation of fluorouracil is inhibited and that its antitumor effect is reduced, TS-ONE should be administered after meals.
The recommended treatment course for post-operative adjuvant chemotherapy for gastric cancer is one year after surgery. Treatment with TS-ONE beyond one year after surgery has not been studied.

TS-ONE is contraindicated in the following patients.
Patients with a history of severe hypersensitivity to the ingredients of TS-ONE.
Patients with severe bone marrow depression: Bone marrow depression may be aggravated.
Patients with severe renal disorder: The urinary excretion of gimeracil, a catabolic enzyme inhibitor of fluorouracil (5-FU), is markedly decreased, thereby the blood concentration of 5-FU is increased. These suggest that adverse reactions such as bone marrow depression may be enhanced (see Pharmacology: Pharmacokinetics under Actions).
Patients with severe hepatic disorder: Hepatic disorder may be aggravated.
Patients receiving treatment with other fluoropyrimidine-group anticancer drugs including combination therapies with them (see Interactions).
Patients receiving treatment with flucytosine (see Interactions).
Pregnant women or women suspected of being pregnant (see Use in Pregnancy & Lactation).
Patients with known complete dihydropyrimidine dehydrogenase (DPD) deficiency (see Precautions).

Cancer chemotherapy with TS-ONE, as a single drug or in combination, should be administered only to patients for whom treatment with TS-ONE has been judged appropriate, under the supervision of experienced physicians who are familiar with cancer chemotherapy and who are based in medical institutions with adequate emergency facilities. A patient who will receive chemotherapy that includes TS-ONE should be carefully selected with reference to the package insert of each concomitant drug. TS-ONE should only be administered after the effectiveness and risks have been explained, and informed consent has been given by the patient or by the patient's guardian before chemotherapy is started.
Since the dose-limiting toxicity (DLT) of TS-ONE is bone marrow depression (see Adverse Reactions), in which is different from conventional oral fluorouracil-group drugs, it is necessary to pay attention for changes in the laboratory data. Laboratory tests should be conducted frequently.
Inasmuch as there may occur severe hepatic disorders, such as fulminant hepatitis, the patient's hepatic functions should be monitored closely by periodic hepatic function tests to detect hepatic disorder early. Close monitoring should be given to detect possible malaise accompanied by anorexia, in which is thought to be a sign or subjective symptom of hepatic disorder. If jaundice (yellow ocular coloring) appears, TS-ONE should be discontinued immediately, and appropriate measures should be taken.
TS-ONE should not be combined with other fluoropyrimidine-group anticancer drugs, combination therapies with them (such as folinate plus tegafur-uracil combination therapy), or the antifungal agent flucytosine because there is a possibility that combination with these drugs may cause adverse reactions such as serious blood dyscrasia (see Interactions).
TS-ONE should be administered in strict conformity with Dosage & Administration.

Dose-limiting toxicities include diarrhea and dehydration. Most adverse reactions are reversible and can be managed by symptomatic therapy, dose interruptions and dose reductions.
Bone marrow suppression: Patients with low white blood cell counts should be monitored carefully for infection and risk of other complications of neutropenia and treated as medically indicated (e.g., with antibiotics, granulocyte-colony stimulating factor [G-CSF]). Patients with low platelet counts are at increased risk for bleeding and should be monitored carefully.
Diarrhea: Patients with diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. Prophylactic treatment for diarrhea should be administered as indicated. Standard antidiarrheal therapy (e.g., loperamide) and intravenous fluids/electrolytes should be initiated early when diarrhea develops. Dose suspension/adjustment should be implemented with the occurrence of Grade 2 or higher diarrhea if symptoms persist despite adequate treatment.
Dehydration: Dehydration and any associated electrolyte disturbances should be prevented or corrected at onset. Patients with anorexia, asthenia, nausea, vomiting, diarrhea, stomatitis, and gastrointestinal obstruction should be monitored closely for signs of dehydration. Dehydration should be managed aggressively with rehydration and other appropriate measures. If Grade 2 (or higher) dehydration occurs, treatment should be immediately suspended and the dehydration corrected. Treatment should not be resumed until dehydration and its underlying causes are corrected or adequately controlled.
Renal toxicity: To detect early changes in renal function during treatment, renal parameters should be closely monitored (e.g., serum creatinine, CrCl).
Gimeracil increases 5-fluorouracil (5-FU) exposure by inhibiting DPD, the primary enzyme for metabolizing 5-FU. Gimeracil is primarily cleared by kidney; so, in patients with renal insufficiency gimeracil renal clearance is decreased and 5-FU exposure thus increased. Treatment-related toxicities can be expected to increase as 5-FU exposure increases.
Ocular toxicity: Most ocular reactions will resolve or improve with suspension of medicinal product and proper treatment (instillation of artificial tears, antibiotic eye drops, implantation of glass or silicone tubes in lacrimal punctas or canaliculi, and/or use of spectacles rather than contact lenses). Efforts should be made to ensure early detection of ocular reactions, including an early ophthalmologic consultation in the event of any persistent or vision-reducing ocular symptoms such as lacrimation or corneal symptoms.
Coumarin-derivative anticoagulant: Patients receiving oral coumarin-derivative anticoagulant therapy must have their anticoagulant response (International Normalized Ratio for prothrombin time [INR] or prothrombin time [PT]) monitored closely and the anticoagulant dose adjusted accordingly. The use of coumarin-derivative anticoagulant in clinical trials has been associated with elevated INR and gastrointestinal bleeding, bleeding tendency, haematuria, and anaemia in patients receiving TS-ONE therapy.
Glucose/galactose intolerance/malabsorption: This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose/galactose malabsorption should not take this medicinal product.
Dihydropyrimidine dehydrogenase (DPD) deficiency: DPD activity is rate-limiting in the catabolism of fluorouracil. Patients with DPD deficiency are therefore at increased risk of fluoropyrimidine-related toxicity, including for example stomatitis, diarrhea, mucosal inflammation, neutropenia and neurotoxicity.
DPD-deficiency related toxicity usually occurs during the first cycle of treatment or after dose increase.
Complete DPD deficiency: Complete DPD deficiency is rare (0.01-0.5% of Caucasians). Patients with complete DPD deficiency are at high risk of life-threatening or fatal toxicity and must not be treated with TS-ONE.
Partial DPD deficiency: Partial DPD deficiency is estimated to affect 3-9% of the Caucasian population. Patients with partial DPD deficiency are at increased risk of severe and potentially life-threatening toxicity. A reduced starting dose should be considered to limit this toxicity. DPD deficiency should be considered as a parameter to be taken into account in conjunction with other routine measures for dose reduction. Initial dose reduction may impact the efficacy of treatment. In the absence of serious toxicity, subsequent doses may be increased with careful monitoring.
Testing for DPD deficiency: Phenotype and/or genotype testing prior to the initiation of treatment with TS-ONE is recommended despite uncertainties regarding optimal pre-treatment testing methodologies. Consideration should be given to applicable clinical guidelines.
Genotypic characterisation of DPD deficiency: Pre-treatment testing for rare mutations of the DPYD gene can identify patients with DPD deficiency.
The four DPYD variants c.1905+1G>A [also known as DPYD*2A], c.1679T>G [DPYD*13], c.2846A>T and c.1236G>A/HapB3 can cause complete absence or reduction of DPD enzymatic activity. Other rare variants may also be associated with an increased risk of severe or life-threatening toxicity.
Certain homozygous and compound heterozygous mutations in the DPYD gene locus (e.g. combinations of the four variants with at least one allele of c.1905+1G>A or c.1679T>G) are known to cause complete or near complete absence of DPD enzymatic activity.
Patients with certain heterozygous DPYD variants (including c.1905+1G>A, c.1679T>G, c.2846A>T and c.1236G>A/HapB3 variants) have increased risk of severe toxicity when treated with fluoropyrimidines.
The frequency of the heterozygous c.1905+1G>A genotype in the DPYD gene in Caucasian patients is around 1%, 1.1% for c.2846A>T, 2.6-6.3% for c.1236G>A/HapB3 variants and 0.07 to 0.1% for c.1679T>G.
Data on the frequency of the four DPYD variants in other populations than Caucasian is limited. At the present, the four DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T and c.1236G>A/HapB3) are considered virtually absent in populations of African (-American) or Asian origin.
Phenotypic characterisation of DPD deficiency: For phenotypic characterisation of DPD deficiency, the measurement of pre-therapeutic blood levels of the endogenous DPD substrate uracil (U) in plasma is recommended.
Elevated pre-treatment uracil concentrations are associated with an increased risk of toxicity. Despite uncertainties on uracil thresholds defining complete and partial DPD deficiency, a blood uracil level ≥16 ng/ml and <150 ng/ml should be considered indicative of partial DPD deficiency and associated with an increased risk for fluoropyrimidine toxicity. A blood uracil level ≥150 ng/ml should be considered indicative of complete DPD deficiency and associated with a risk for life-threatening or fatal fluoropyrimidine toxicity.
Careful Administration: TS-ONE should be administered with care in the following patients.
Patients with bone marrow depression: Bone marrow depression may be aggravated.
Patients with renal disorder: The urinary excretion of gimeracil, a catabolic enzyme inhibitor of fluorouracil (5-FU), is markedly decreased, thereby the blood concentration of 5-FU is increased. These suggest that adverse reactions such as bone marrow depression may be enhanced (see Pharmacology: Pharmacokinetics under Actions).
Patients with hepatic disorder: Hepatic disorder may be aggravated.
Patients having infectious disease: Infectious disease may be aggravated as a result of bone marrow depression.
Patients with abnormal glucose tolerance: Abnormal glucose tolerance may be aggravated.
Patients with a current or previous history of interstitial pneumonia: Interstitial pneumonia may be aggravated or may develop.
Patients with a current or previous history of heart disease: Symptoms may be aggravated.
Patients with gastrointestinal ulcer or hemorrhage: Symptoms may be aggravated.
Elderly patients: See Use in the Elderly as follows.
Important Precautions: A minimum washout period of 7 days must be provided when other fluoropyrimidine-group anticancer drugs or the antifungal agent flucytosine are used after withdrawal of TS-ONE (see Interactions).
An appropriate washout period must be provided when TS-ONE is used after withdrawal of other fluoropyrimidine-group anticancer drugs or the antifungal agent flucytosine in consideration of the influence of these prior agents (see Interactions).
Since patients who have died of septic shock or disseminated intravascular coagulation due to serious infectious disease (septicemia) caused by bone marrow depression have been reported, care should be taken to avoid the appearance or aggravation of infection or bleeding tendency.
Administration to reproducible patients should be performed with consideration of potential gonadic effects.
TS-ONE may cause or aggravate interstitial pneumonia with a possible fatal outcome. Therefore, patients must be examined for the presence of interstitial pneumonia before receiving TS-ONE, and be properly monitored for respiratory status and the onset of symptoms such as cough and fever while receiving TS-ONE. Monitoring should include chest X-ray examination. If the onset or progression of interstitial pneumonia is observed, TS-ONE should be discontinued, and appropriate measures should be taken. Pulmonary disorders including interstitial pneumonia are more likely to occur in patients with non-small cell lung cancer than in patients with other cancers (see Adverse Reactions).
Since administration of TS-ONE in hepatitis B virus carriers, HBs antigen negative and HBc antibody positive patients, or HBs antigen negative and HBs antibody positive patients may result in reactivation of hepatitis B, the status of previous exposure to hepatitis infection should be confirmed, and appropriate measures should be taken before administration. Following administration of TS-ONE, it is necessary to pay attention to signs or symptoms of the reactivation of hepatitis B, and follow-up monitoring for hepatic function tests or viral markers are recommended.
Other Precautions: It has been reported that acute leukemia (in some cases accompanied with preleukemic phase) or myelodysplastic syndrome (MDS) have occurred in patients treated with TS-ONE.
It has been reported that deficiency of dihydropyrimidine dehydrogenase (DPD), a catabolic enzyme of fluorouracil, exists in extremely rare patients, and if fluorouracil-group drugs are administered to such patients, serious adverse reactions (such as stomatitis, diarrhea, blood dyscrasia and neuropathy) may occur in the early stages of administration.
Although the causality of TS-ONE was unknown, it has been reported that cerebral infarction has occurred.
It has been reported that a remarkable decrease in gastric pH may induce diarrhea, because oteracil potassium is labile to decompose in the gastric fluid under a hyper-acid condition (in dogs) and its relief effect on the gastrointestinal toxicity is reduced when its composition ratio is decreased (in rats).
Repeated administration of TS-ONE to dogs has been reported to cause bulbar conjunctival and scleral pigmentation and nebula.
Use in the Elderly: Since elderly patients often have decreased physiological functions, TS-ONE should be administered with care.
Use in Children: The safety of TS-ONE in low birth weight infants, neonates, infants or children has not been established. There is no clinical data. When TS-ONE must be administered to children, special attention must be paid to the development of adverse reactions, taking the effect of TS-ONE on the gonads into account.

TS-ONE is contraindicated in patients who are or may be pregnant. It has been reported that pregnant women treated with tegafur/uracil have delivered neonates with malformation.
Teratogenicity is also reported in animal experiments. Consecutive oral administration of TS-ONE (corresponding to 7 mg/kg and 1.5 mg/kg as tegafur) to pregnant rats and rabbits has been observed to have fetal visceral anomalies, skeletal anomalies and retarded ossification.
When TS-ONE is administered to nursing mothers, breastfeeding should be discontinued. There is no clinical data. Excretion to milk has been reported in animal (rats) experiments.

Clinically significant adverse reactions: 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%) and 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 hepatitis (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 are 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 are 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. Also, in case of previously-treated breast cancer, the incidence of hand-foot syndrome was high (21.8%). 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%). (See Table 10.)

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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.
Adverse reactions from other clinical studies in Japan (Reference from Japan Package Insert): Monotherapy: Of 578 patients evaluable for adverse reactions in clinical studies with TS-ONE monotherapy excluding the following patients with previously-treated breast cancer, pancreatic cancer, and biliary tract cancer, the incidence of adverse reactions was 87.2% (504 patients). Also, in patients with inoperable or recurrent breast cancer previously treated with taxane-group anticancer drugs, pancreatic cancer, and biliary tract cancer, the incidence of adverse reactions was high (96.4%, 98.3% and 94.9%, respectively) 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. (See Table 11.)
The results of analysis regarding time of onset of the adverse reactions and the period of recovery are described in Clinical Studies (see Pharmacology: Clinical Studies under Actions).

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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/m² 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. (See Table 12.)

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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.
Studies in Europe/United States of America (EU/USA) of patients treated with TS-ONE in combination with cisplatin (Reference from EU SmPC): The following headings are used to rank the adverse reactions by frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from the available data). The frequencies of very common, common, and uncommon adverse reactions are from 593 patients treated with TS-ONE in combination with cisplatin in clinical trials. The frequencies of medically relevant rare and very rare adverse reactions are estimated from post-marketing surveillance of 866,000 patients in Asia (mostly Japanese) treated with TS-ONE-based therapy. Each term is presented in its most common category only and within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Adverse reactions reported by decreasing seriousness in each frequency grouping: See Tables 13a and 13b.

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Contraindications for co-administration: TS-ONE should not be co-administered with the following drugs. (See Table 14.)

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Precautions for co-administration: TS-ONE should be administered with care when co-administered with the following drugs. (See Table 15.)

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Precautions concerning use: Precaution in giving the drug to patients: For drugs that are dispensed in a press-through package (PTP), instruct the patient to remove the drug from the package prior to use. It has been reported that, if the PTP sheet is swallowed, the sharp corners of the sheet may puncture the esophageal mucosa, resulting in severe complications such as mediastinitis.

Cytotoxic Chemotherapy

L01BC53 - tegafur, combinations ; Belongs to the class of antimetabolites, pyrimidine analogues. Used in the treatment of cancer.

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