TS-ONE

TS-ONE Capsule 20: An opaque hard-shell capsule with a white cap and white body containing white powder and granules. Black letter "TC442" is printed on the cap and the body.
Each capsule contains Tegafur 20 mg, Gimeracil 5.8 mg and Oteracil potassium 19.6 mg.
TS-ONE Capsule 25: An opaque hard-shell capsule with an orange cap and white body containing white powder and granules. Black letter "TC443" is printed on the cap and the body.
Each capsule contains Tegafur 25 mg, Gimeracil 7.25 mg and Oteracil potassium 24.5 mg.
Tegafur: The chemical name is 5-fluoro-1-[(2RS)-tetrahydrofuran-2-yl]uracil.
Gimeracil: The chemical name is 5-chloro-2,4-dihydroxypyridine.
Oteracil potassium: The chemical name is Monopotassium 1,2,3,4-tetrahydro-2,4-dioxo-1,3,5-triazine-6-carboxylate.
Excipients/Inactive Ingredients: Lactose, magnesium stearate.

Pharmacology: Pharmacodynamics: 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 Tegafur (FT), Gimeracil (CDHP) and Oteracil Potassium (Oxo), and the 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.
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: Summary of Clinical Studies (Based on CSR): For the treatment of adjuvant gastric cancer: In a randomized phase III study of postoperative adjuvant chemotherapy in patients with gastric cancer, 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 postoperative 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% CI: 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. (See Figure 1.)

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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% CI: 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. (See Figure 2.)

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For the treatment of advanced non-small cell lung cancer: In a randomized phase III study in patients with non-small cell lung cancer who have received a platinum-based treatment, the survival benefit of TS-ONE monotherapy (577 patients) was compared to the docetaxel therapy (570 patients) in previously treated non-small cell lung cancer patients. The median survival time for TS-ONE group was 12.75 months (95% CI, 11.53-14.00) and 12.52 months for the docetaxel group (95% CI, 11.14-14.36). The estimated overall survival hazard ratio (TS-ONE/docetaxel) was 0.945 (95% CI, 0.833-1.073), which confirmed the non-inferiority of TS-ONE monotherapy to docetaxel therapy.
For the treatment of advanced pancreatic cancer: In a randomized phase III study (GEST) comparing Gemcitabine (GEM) Versus TS-ONE Versus Gemcitabine Plus TS-ONE, TS-ONE group successfully demonstrated its anti-cancer effect in locally advanced or metastatic pancreatic cancer patients by showing similar median OS of 9.66 months to gemcitabine monotherapy (MST=8.80 months; hazard ratio=0.957; p=0.6310), which was significantly lower than the margin 1.33 (p=0.0003), meaning that TS-ONE monotherapy could be stated as non-inferior to gemcitabine therapy. Moreover, despite that GEM + TS-ONE group has shown an averagely longer OS of 10.05, the overall survival did not differ significantly between the combination therapy group and GEM group (hazard ratio=0.875; p=0.1496). With regards to safety, TS-ONE monotherapy has fewer severe drug-related TEAEs in contrast to gemcitabine monotherapy and the combination therapy.
Summary of Clinical Studies (Based on Published Data): Information on the target population, efficacy, and safety should refer to the original articles or treatment guidelines.
For the treatment of adjuvant and advanced gastric cancer: Advanced Gastric Cancer: In a randomized phase III study (SPIRITS¹) of TS-ONE alone versus TS-ONE plus cisplatin (CDDP), TS-ONE + CDDP arm showed significant superiority in overall survival compared to TS-ONE alone.
In a randomized Phase III study (G-SOX²) comparing TS-ONE plus oxaliplatin (SOX) with cisplatin plus TS-ONE (CS) in chemotherapy-naïve patients, SOX demonstrated noninferiority in progression-free survival compared with CS.
In a randomized phase III study (START³) comparing TS-ONE plus docetaxel with TS-ONE alone as first-line chemotherapy, addition of docetaxel to TS-ONE prolongs survival of patients.
Adjuvant Gastric Cancer: In a randomized phase III study (ARTIST-2⁴) comparing adjuvant single-agent TS-ONE, TS-ONE with oxaliplatin (SOX), and postoperative chemoradiation with TS-ONE and oxaliplatin (SOXRT) in patients with node-positive gastric cancer after D2 resection, adjuvant SOX was effective in prolonging disease-free survival when compared with TS-ONE monotherapy.
A randomized phase III study (START-2⁵) demonstrated the superiority in 3-year relapse-free survival of postoperative TS-ONE plus docetaxel over TS-ONE alone for R0 resection of pathologic stage III gastric cancer.
For the treatment of advanced non-small cell lung cancer: In a randomized Phase III Study (LETS⁶) comparing oral TS-ONE plus carboplatin with Paclitaxel plus carboplatin in chemotherapy-naïve NSCLC patients, the study demonstrates noninferiority of TS-ONE plus carboplatin relative to carboplatin plus paclitaxel in terms of overall survival.
In a randomized phase III study (CATS⁷) of TS-ONE plus cisplatin versus docetaxel plus cisplatin in previously untreated advanced NSCLC patients, TS-ONE plus cisplatin is not inferior to docetaxel plus cisplatin in terms of overall survival.
For the treatment of colorectal cancer (locally advanced or unresectable or metastasis) when given in combination with oxaliplatin as first-line treatment, or in combination with irinotecan as second-line treatment: In a randomized phase II/III study (FIRIS⁸) of irinotecan plus TS-ONE (IRIS) versus fluorouracil and folinic acid plus irinotecan (FOLFIRI) as second-line chemotherapy for metastatic colorectal cancer, progression-free survival with IRIS is not inferior to that with FOLFIRI.
In a randomized Phase III Study (SOX versus CapeOX⁹) of TS-ONE plus oxaliplatin (SOX) versus Capecitabine plus oxaliplatin (CapeOX) for first-line treatment of patients with metastatic colorectal cancer, SOX is non-inferior to the CapeOX in terms of progression-free survival.
For the treatment of adjuvant pancreatic cancer: A randomized phase III study (JASPAC 01¹⁰) demonstrated that postoperative adjuvant chemotherapy with TS-ONE significantly extended both overall and relapse-free survival of Japanese patients with resected pancreatic cancer compared with gemcitabine.
For the treatment of HER-2 negative metastatic breast cancer when given as monotherapy: In a randomized phase III study (SELECT BC¹¹) of taxanes versus TS-ONE as the first-line chemotherapy for metastatic breast cancer, TS-ONE is shown to be non-inferior to taxane with respect to overall survival.
For the treatment of adjuvant and advanced biliary tract cancer: Advanced biliary tract cancer: In a randomized phase III study (KHBO1401-MITSUBA¹²⁾ of gemcitabine, cisplatin plus TS-ONE (GCS) versus gemcitabine, cisplatin (GC), GCS demonstrated superior overall survival over GC.
In a randomized phase III study (FUGA-BT¹³) of combination gemcitabine plus TS-ONE (GS) versus gemcitabine plus cisplatin (GC), GS demonstrated to be non-inferior to GC in terms of overall survival.
Adjuvant biliary tract cancer: When adjuvant TS-ONE is compared with observation in resected biliary tract cancer in a randomized phase III study, adjuvant therapy with TS-ONE led to significantly longer overall survival than observation in Japanese patients (JCOG1202, ASCOT¹⁴).
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 as follows any of the criteria including a WBC count of 3,000/mm³, a hemoglobin level of 8 g/dL, and a platelet count of 7.5 x 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 1.)

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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 2.)

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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 the patients who were administrated initially at the standard dose. (See Table 3.)

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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 4. The amount excreted in the urine within 72 hours after administration accounted for 52.8% of the CDHP, 7.8% of the FT, 2.2% of the Oxo, 11.4% of the metabolite cyanuric acid (CA) and 7.4% of the 5-FU. (See Table 4.)

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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, 6.9 and 2.3 times higher when combined with 5-FU, FT, FT·Ura, 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. 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 5.)

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Phase I study of TS-ONE investigated the pharmacokinetics of its components and metabolites in patients with normal and impaired renal function. Patients with mild renal impairment (CrCl 51 to 80 mL/min) receiving the same monotherapy dose of 30 mg/m² twice daily as patients with normal renal function (CrCl >80 mL/min) had an increase in mean 5-FU AUC_0-inf relative to that of the normal patients. Patients with moderate renal impairment (CrCl 30 to 50 ml/min) who received a reduced dose of 20 mg/m² twice daily showed no significant increase in mean 5-FU AUC_0-inf relative to that of the normal group. Following a reduced dose of TS-ONE 20 mg/m² administered once daily to the severe renal impairment group (CrCl <30 ml/min), the single-dose AUC_0-inf and multiple-dose AUC_0-τ values for 5-FU were approximately 2-fold higher in the severe renal impairment group compared to those observed in the normal renal function group receiving 30 mg/m² twice daily. Therefore, the daily exposure to 5-FU would be expected to be comparable in these groups, since the daily exposure in patients in the severe renal impairment group is based on the administration of TS-ONE once a day, while the daily exposure to 5-FU in the patients with normal renal function is based on the administration of TS-ONE twice daily. However, it is to be noted that the exposure to 5-FU can be variable and unexpectedly higher in patients with severe renal impairment due to the impact of fluctuations in renal function in these patients.
*) Cockcroft-Gault equation: See equation.

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There were no significant differences in AUCs of 5-FU, tegafur, gimeracil, or oteracil after either single or multiple dose administration of TS-ONE 30 mg/m² twice daily in patients with mild, moderate, or severe hepatic impairment compared to those with normal hepatic function. After single dose administration, there was a statistically significant decrease in 5-FU and gimeracil C_max for the severe hepatic impairment group relative to that of the normal group, but this difference was not observed after multiple dose administration.
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).

TS-ONE is indicated in adults: For the treatment of adjuvant and advanced gastric cancer.
For the treatment of advanced non-small cell lung cancer.
For the treatment of colorectal cancer (locally advanced or unresectable or metastasis) when given in combination with oxaliplatin as first-line treatment, or in combination with irinotecan as second-line treatment.
For the treatment of adjuvant and advanced pancreatic cancer.
For the treatment of HER-2 negative metastatic breast cancer when given as monotherapy.
For the treatment of adjuvant and advanced biliary tract cancer.

The initial recommended dose of TS-ONE when given as monotherapy or combination therapy is provided as follows. The dose can be decreased according to the patient's tolerance to the medication. (See Tables 6 and 7.)

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Monotherapy: TS-ONE should be 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. When used for postoperative adjuvant chemotherapy, the maximum treatment duration is 1 year for gastric cancer and 6 months for pancreatic cancer and biliary tract cancer.
Combination Therapy: Gastric Cancer: TS-ONE with cisplatin: TS-ONE is recommended to be administered twice daily, after meals, for 21 consecutive days and 60 mg/m² intravenous infusion of cisplatin on Day 8, followed by a 14-day rest. This treatment is repeated every 5 weeks.
TS-ONE with docetaxel: TS-ONE is recommended to be administered twice daily, after meals, for 14 consecutive days and intravenous infusion of docetaxel (40 mg/m² body surface area) on Day 1, followed by a 7-day rest. This treatment is repeated every 3 weeks.
When used for postoperative adjuvant chemotherapy, administer TS-ONE monotherapy on days 1 to 14 of a 3-week cycle during the first course. During the second to seventh courses, administer TS-ONE in combination with docetaxel. After the eighth course, continue treatment with TS-ONE monotherapy on days 1 to 28 of 6-week cycles for up to 1 year.
TS-ONE with oxaliplatin: TS-ONE is recommended to be administered twice daily, after meals, for 14 consecutive days and intravenous infusion of oxaliplatin (130 mg/m² in the adjuvant setting; 100 mg/m² in the advanced setting) on Day 1, followed by a 7-day rest. This treatment is repeated every 3 weeks.
When used for postoperative adjuvant chemotherapy, the maximum treatment duration is 6 months.
Non-Small Cell Lung Cancer: TS-ONE with carboplatin: TS-ONE is recommended to be administered twice daily, after meals, for 14 consecutive days, in combination with carboplatin (AUC 5) on Day 1, followed by a 7-day rest. This treatment is repeated every 3 weeks.
TS-ONE with cisplatin: TS-ONE is recommended to be administered twice daily, after meals, for 21 consecutive days and 60 mg/m² intravenous infusion of cisplatin on Day 8, followed by a 14-day rest. This treatment is repeated every 5 weeks.
Colorectal Cancer: For first-line treatment, TS-ONE is recommended to be administered twice daily, after meals, for 14 consecutive days, in combination with oxaliplatin 130 mg/m² on Day 1 as a 2-hour intravenous infusion, followed by a 7-day rest. This treatment is repeated every 3 weeks.
For second-line treatment, TS-ONE is recommended to be administered twice daily, after meals, from Day 1 to 14, in combination with irinotecan 125 mg/m² on Days 1 and 15, followed by a 14-day rest. This treatment is repeated every 4 weeks.
Biliary Tract Cancer: TS-ONE with gemcitabine and cisplatin: TS-ONE is recommended to be administered twice daily, after meals, for 7 consecutive days and intravenous infusion of 1,000 mg/m² gemcitabine and 25 mg/m² cisplatin on day 1, followed by a 7-day rest. This treatment is repeated every 2 weeks. Initial TS-ONE dose is as per Table 6.
TS-ONE with gemcitabine: TS-ONE is recommended to be administered twice daily, after meals, for 14 consecutive days and intravenous infusion of 1,000 mg/m² gemcitabine on days 1 and 8, followed by a 7-day rest. This treatment is repeated every 3 weeks. Initial TS-ONE dose is as per Table 7.
Use in the Elderly: Since elderly patients often have decreased physiological functions, TS-ONE should be administered with care.
Pediatric Use: 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.]

The highest single dose of TS-ONE taken was 1400 mg; this patient developed leukopenia (Grade 3). Manifestations of acute overdose reported include nausea, vomiting, diarrhea, mucositis, gastrointestinal irritation, bleeding, bone marrow depression, and respiratory failure. Medical management of overdose should include customary therapeutic and supportive medical interventions aimed at correcting the presenting clinical manifestations and preventing their possible complications.

TS-ONE is contraindicated in the following patients: Patients with a history of 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 anti-cancer 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).

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 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, 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.
In as much 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 anti-cancer 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).
Read this monograph carefully before using TS-ONE. In addition, TS-ONE should be administered in strict conformity with the Dosage and Administration.
Warning (based on the Ministry of Public Health's Announcement): This drug may cause serious harm. It should be used under the supervision of a physician.

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 8.)

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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.
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, or discontinuing administration of TS-ONE. Laboratory tests should be performed frequently, particularly when one course of the regimen is conducted and the dose is increased (See Pharmacology: Pharmacodynamics: 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; therefore, TS-ONE should be administered after meals.
Efficacy and safety of combination therapy with TS-ONE and chest or abdominal radiation have not yet been established.
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 under Dosage & Administration).
Patients with varicella [Fatal systemic damage may occur].
Important Precautions: A minimum washout period of 7 days must be provided when other fluoropyrimidine-group anti-cancer drugs or the antifungal agent flucytosine are used after withdrawal of TS-ONE (See Interactions).
If dehydration secondary to severe enteritis occurs, take proper measure such as fluid replacement. (See Clinically significant adverse reactions under Adverse Reactions).
An appropriate washout period must be provided when TS-ONE is used after withdrawal of other fluoropyrimidine-group anti-cancer 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 patients with reproductive potential 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 condition (in dogs) and its relief effect on the gastrointestinal toxicity 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.
Effect on ability to drive and use machine: TS-ONE has a moderate influence on the ability to drive and use machines as fatigue, dizziness, blurred vision, and nausea are common adverse reactions of TS-ONE in combination with cisplatin.

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.]

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 anti-cancer 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.
The results of analysis regarding time of onset of the adverse reactions and the period of recovery will be described later as follows (See Pharmacology: Pharmacodynamics: Clinical Studies under Actions). (See Table 9.)

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For the post-operative adjuvant treatment of locally advanced gastric cancer: The following table shows the frequency of 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 10.)

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For the treatment of non-small cell lung cancer in patients who have received a platinum-based treatment: The following table shows the frequency of most common adverse events and laboratory abnormalities (>10% in incidence) reported in the randomized, controlled study to establish the non-inferiority of TS-ONE to the standard treatment of docetaxel therapy in previously-treated non-small cell lung cancer patients. (See Table 11.)

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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 (when indications are added). (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.
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 and 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 hepatitis (including reactivation of hepatitis B virus) (incidence unknown) may occur, the 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. (See Table 13.)

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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.

Contraindications for coadministration (TS-ONE should not be coadministered with the following drugs): See Table 14.

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Precautions for coadministration (TS-ONE should be administered with care when coadministered 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.]
Incompatibilities: It has not been systematically evaluated.

Shelf-life: 3 years.
Special precaution for storage: Store below 30°C.

Cytotoxic Chemotherapy

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

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