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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.
