Teysuno (Capsules) Instructions for Use
Marketing Authorization Holder
Nordic Group, BV (Netherlands)
Manufactured By
Taiho Pharmaceutical Co. Ltd. (Japan)
ATC Code
L01BC53 (Tegafur in combination with other drugs)
Dosage Forms
 |
Teysuno | Capsules 15 mg+4.53 mg+11.8 mg: 42, 84 or 126 pcs. |
| Capsules 20 mg+5.8 mg+15.8 mg: 42, 84 or 126 pcs. |
Dosage Form, Packaging, and Composition
Capsules hard gelatin, opaque, size No. 4, cylindrical, with a brown cap and white body, marked with “TS448” in gray ink on the capsule (cap and body); capsule contents – a mixture of white powder and white granules.
| 1 caps. | |
| Tegafur | 15 mg |
| Gimeracil | 4.53 mg |
| Oteracil potassium | 14.7 mg, |
| Equivalent to oteracil content | 11.8 mg |
Excipients: lactose monohydrate – 70.2 mg, magnesium stearate – 0.3 mg.
Shell composition body: gelatin – 19.7752 mg, titanium dioxide – 0.84 mg, sodium lauryl sulfate – 0.0248 mg, talc*; cap: gelatin – 13.4155 mg, titanium dioxide – 0.24 mg, iron oxide red – 0.088 mg, sodium lauryl sulfate – 0.0165 mg, talc*.
Ink composition iron oxide red*, FD&C blue No. 2 aluminum lake (E132)*, carnauba wax*, bleached shellac*, glyceryl monooleate*.
* – present in trace amounts.
14 pcs. – blisters (3) – cardboard packs.
14 pcs. – blisters (6) – cardboard packs.
14 pcs. – blisters (9) – cardboard packs.
Capsules hard gelatin, opaque, size No. 4, cylindrical, with a brown cap and white body, marked with “TS448” in gray ink on the capsule (cap and body); capsule contents – a mixture of white powder and white granules.
| 1 caps. | |
| Tegafur | 20 mg |
| Gimeracil | 5.8 mg |
| Oteracil potassium | 19.6 mg, |
| Equivalent to oteracil content | 15.8 mg |
Excipients: lactose monohydrate – 93.6 mg, titanium dioxide – 0.4 mg.
Shell composition body: gelatin – 19.7752 mg, titanium dioxide – 0.84 mg, sodium lauryl sulfate – 0.0248 mg, talc*; cap: gelatin – 13.1835 mg, titanium dioxide – 0.56 mg, sodium lauryl sulfate – 0.0165 mg, talc*.
Ink composition iron oxide red*, iron oxide yellow*, FD&C blue No. 2 aluminum lake (E132)*, carnauba wax*, bleached shellac*, glyceryl monooleate*.
* – present in trace amounts.
14 pcs. – blisters (3) – cardboard packs.
14 pcs. – blisters (6) – cardboard packs.
14 pcs. – blisters (9) – cardboard packs.
Clinical-Pharmacological Group
Antineoplastic drug
Pharmacotherapeutic Group
Antineoplastic agent, antimetabolite
Pharmacological Action
The drug Teysuno is a combined oral fluoropyrimidine antineoplastic drug, including a fixed combination of 3 active substances – tegafur, gimeracil and oteracil.
After absorption in the gastrointestinal tract, Tegafur is transformed into the active form fluorouracil (FU), which has pronounced antineoplastic activity, without enhancing the toxic effects of FU.
Gimeracil – a competitive inhibitor of dihydropyrimidine dehydrogenase (DPD), its action consists in inhibiting the degradation of FU in the human body.
Oteracil – an inhibitor of orotate phosphoribosyltransferase (OPRT), reduces the severity of the local irritant effect of FU on the intact gastrointestinal mucosa and the severity of inflammatory reactions caused by FU.
The combined drug Teysuno, containing a fixed combination of tegafur, gimeracil and oteracil potassium in a molar ratio of 1:0.4:1, while preserving the antineoplastic activity of FU, has a less pronounced toxic effect compared to FU monotherapy.
Tegafur is a prodrug of FU. When taken orally, Tegafur has high bioavailability. In in vivo studies, under the influence of the cytochrome P450 isoenzyme CYP2A6, Tegafur is gradually transformed into FU. Under the action of hepatic dihydropyrimidine dehydrogenase, FU is metabolized, and within the tumor cell, during phosphorylation, FU is activated and the active metabolite, 5-fluoro-deoxyuridine monophosphate (FdUMP), is formed. In turn, FdUMP and a folic acid derivative bind to thymidylate synthase, and the formed tertiary complex disrupts DNA synthesis. Also, 5-fluoro-deoxyuridine triphosphate (FdUTP) is incorporated into the RNA structure, causing disruption of its function.
Gimeracil prevents the degradation of FU by selective and reversible inhibition of DPD, the main enzyme of FU metabolism, thus, when a low dose of tegafur is taken, a higher level of FU concentration in the blood plasma is achieved. Preclinical studies have shown that after oral administration, oteracil is detected in high concentrations in the gastrointestinal tract, while its concentration in the blood plasma and in the tumor remains relatively low.
The drug Teysuno does not have a cardiotoxic effect (does not affect the process of myocardial repolarization) in patients with advanced gastric cancer. No relationship was established between the dynamics of the QTc interval compared to baseline values and the maximum plasma concentrations of the active substances included in the drug Teysuno.
Overall survival when using the drug Teysuno in combination with cisplatin was comparable to the use of the combination of FU and cisplatin. At the time of assessment, the median overall survival period of patients was 18.3 months.
Pharmacokinetics
Absorption
After oral administration of the drug Teysuno at a dose of 50 mg (determined by tegafur content) in patients (at a dose of 30 mg/m2, determined by body surface area of 1.56-2.10 m2 in patients n=14), the average time to reach maximum plasma concentration (Tmax) of the components of the drug Teysuno, including Tegafur, Gimeracil and oteracil, was 0.5 h, 1 h and 2 h, respectively. The mean values and standard deviations of AUC and Cmax were 14595±4340 ng×h/ml and 1762±279 ng/ml for tegafur, 1884±640 ng×h/ml and 452±102 ng/ml for gimeracil, 556±281 ng×h/ml and 112±52 ng/ml for oteracil. Tmax of FU is 2 h, and the mean values of AUC0-inf and Cmax are 842±252 ng×h/ml and 174±58 ng/ml.
Concentrations of tegafur, gimeracil and oteracil, as well as FU in the blood are determined for 10 hours. After administration of the drug Teysuno at a dose of 30 mg/m2, steady-state concentrations of tegafur, gimeracil and oteracil are reached no later than day 8. After repeated administration of the drug Teysuno (at a dose of 30 mg/m2 2 times/day for 14 days, n=10), the median Tmax time for tegafur, gimeracil and oteracil was 0.8 h, 1 h and 2 h, respectively, and the mean standard deviation of AUC(0-12h) and Cmax values were 19967±6027 ng×h/ml and 2970±852 ng/ml for tegafur, 1483±527 ng×h/ml and 305±116 ng/ml for gimeracil, 692±529 ng×h/ml and 122±82 ng/ml for oteracil, respectively. The median Tmax time for FU was 2 h, and the mean values of AUC(0-12h) and Cmax were 870±405 ng×h/ml and 165±62 ng/ml, respectively.
Administration of the drug Teysuno after a meal is accompanied by a decrease in AUC0-inf of oteracil by approximately 71% and gimeracil by 25% compared to taking the drug on an empty stomach. Concurrent administration of proton pump inhibitors reduces the effect of food intake on the pharmacokinetic profile of oteracil, although it does not completely eliminate it. It was noted that AUC0-inf of FU after a meal decreases by 15%, however, the plasma concentration of tegafur does not change after food intake (no effect of food on tegafur concentration).
The mean values of AUC0-inf and Cmax of FU were almost 3 times higher when taking the drug Teysuno (at a dose of 50 mg based on tegafur) compared to tegafur monotherapy (at a dose of 800 mg), while AUC0-inf and Cmax of the metabolite alpha-fluoro-beta-alanine (FBA) of FU were approximately 15-22 times lower after taking the drug Teysuno compared to the use of tegafur.
Oteracil, which is part of the drug Teysuno, does not affect the pharmacokinetic profiles of FU, tegafur, gimeracil, FBA and uracil. Gimeracil does not change the pharmacokinetic profiles of tegafur.
Linearity/non-linearity of pharmacokinetics
In a dose-finding study of the drug Teysuno, it was shown that the plasma concentrations of tegafur, gimeracil and oteracil increased in direct proportion to the dose value in the range from 25 to 200 mg/kg. A trend towards a more significant increase in FU concentration compared to the increase in tegafur plasma concentration was noted.
Distribution
Oteracil, Gimeracil, FU and Tegafur bind to plasma proteins by 8.4%, 32.2%, 18.4% and 52.3%, respectively. Protein binding is independent of concentration when used in the dose range above 0.1-1.0 µg/ml for oteracil, gimeracil and FU and 1.2-11.8 µg/ml for tegafur.
Despite the lack of data on intravenous administration of the drug Teysuno in clinical studies, the Vd of the drug components, which is 16 l/m2, 17 l/m2 and 23 l/m2 for tegafur, gimeracil and oteracil, respectively, can be approximately estimated from the expected Vd and renal excretion rate.
Metabolism
Tegafur is metabolized in the liver under the influence of the cytochrome P450 isoenzyme CYP2A6, transforming into FU. Gimeracil was stable upon homogenization (S9 fractions) with lithium salt of adenosine-3′-phosphate-5′-phosphosulfate (PAPS; co-factor of sulfotransferase) or nicotinamide adenine dinucleotide phosphate (NADP). In an in vitro study, it was found that oteracil, under the influence of gastric juice and without the participation of enzymes, is partially converted into 5-azauracil (5-AZU), and then into cyanuric acid (CA) in the gastrointestinal tract. Both metabolites of oteracil do not reduce the activity of the enzyme orotate phosphoribosyltransferase (OPRT). Only a small amount of oteracil undergoes metabolism in the liver, due to its low penetrating ability. In an in vitro study on human liver microsomes, it was shown that Tegafur, Gimeracil and oteracil did not inhibit the enzymatic activity of the studied cytochrome P450 isoenzymes (e.g., CYP1A1/2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4). In in vitro studies on primary human liver cell cultures, it was established that Tegafur (0.7-70 µmol), Gimeracil (0.2-25 µmol) and oteracil (0.04-4 µmol) have a weak ability to induce the metabolic activity of the listed isoenzymes CYP1A1/2, CYP2A6 and CYP3A4/5 or do not have such ability at all. Uracil concentration in plasma was determined to assess the activity of dihydropyrimidine dehydrogenase (DPD), and no significant changes in uracil plasma concentration were observed after taking 800 mg of tegafur, however, after taking 50 mg of the drug Teysuno, the uracil plasma concentration significantly increased (due to the DPD inhibitory action of gimeracil). Cmax of uracil, corresponding to DPD inhibition, is observed approximately 4 hours after the start of drug administration, both after a single dose of the drug Teysuno (at a dose of 50 mg) and with repeated use (at a dose of 30 mg/m2 2 times/day). In both administration options, a comparable inhibitory effect is noted. The uracil concentration in the blood returns to baseline approximately 48 hours after drug administration, indicating the reversibility of DPD inhibition by gimeracil.
Excretion
T1/2 of FU after taking the drug Teysuno (containing Tegafur, a prodrug of FU) was longer (about 1.6-1.9 h) compared to T1/2 after intravenous administration of FU (10-20 min). After a single oral administration of the drug Teysuno, T1/2 of tegafur is 6.7-11.3 h, gimeracil – 3.1-4.1 h and oteracil – 1.8-9.5 h.
After a single dose of the drug Teysuno, 3.8-4.2% of the administered dose of tegafur is excreted by the kidneys unchanged, 65-72% – gimeracil and 3.5-3.9% oteracil.
About 9.5-9.7% of the administered dose of tegafur is excreted by the kidneys as FU and 70-77% – as FBA, in total, 83-91% of the administered dose of the drug Teysuno is excreted by the kidneys (together Tegafur+FU+FBA). When compared with the clearance of tegafur in monotherapy, it was shown that Gimeracil does not change the renal clearance of tegafur, FBA and FU when taking the drug Teysuno.
Pharmacokinetics in special patient groups
Studies conducted in special populations
The most significant influence on the plasma concentration of gimeracil and FU is exerted by such a factor as reduced renal function, which is determined by the value of CrCl. A trend of influence on the pharmacokinetics of the drug Teysuno by patient age was noted, since renal function decreases with age, which is also determined by the value of CrCl.
In patients with renal impairment
In a comparative study of the pharmacokinetics of the active substances of the drug Teysuno and their metabolites in patients with normal and reduced renal function, it was shown that in patients with mild renal impairment (CrCl 51-80 ml/min) receiving the same dose of the drug as patients with normal function in monotherapy 30 mg/m2 2 times/day (maximum tolerated dose in monotherapy), as well as in patients with normal renal function (CrCl>80 ml/min), an increase in the AUC0-inf value of FU was observed compared to patients with preserved renal function. In patients with moderate renal impairment (CrCl 30-50 ml/min) receiving a reduced dose of the drug Teysuno of 20 mg/m2 2 times/day, no increase in the AUC0-inf value of 5-FU was noted compared to patients without renal impairment.
The increase in FU plasma concentration in patients with mild renal impairment and the results of population pharmacokinetic analysis suggest that similar values of FU plasma concentration can be achieved both in patients with mild renal impairment when using the drug Teysuno at a dose of 25 mg/m2 2 times/day, and in patients without renal impairment when taking the drug Teysuno at a dose of 30 mg/m2 2 times/day, as well as in patients with moderate renal impairment who receive a drug dose of 20 mg/m2.
After administration of a reduced dose of the drug Teysuno of 20 mg/m2 once/day in patients with severe renal impairment (CrCl<30 ml/min), AUC0-inf of FU after a single dose and AUC0-t of FU after repeated administration of the drug Teysuno increase by 2 times compared to the values in the group of patients with normal renal function receiving the drug Teysuno at a dose of 30 mg/m2 2 times/day. In this regard, the daily exposure to FU should be comparable in both groups, since the daily exposure in patients with severe renal impairment is based on the use of the drug Teysuno once/day, while the daily exposure to FU in patients with normal renal function is based on taking the drug Teysuno 2 times/day. It should be noted that FU exposure may change and may be unexpectedly higher in patients with severe renal impairment due to reduced renal function in these patients.
In patients with hepatic impairment
With single or repeated administration of the drug Teysuno at a dose of 30 mg/m2 2 times/day in patients with mild, moderate and severe hepatic impairment, no significant differences were observed in the plasma concentrations of tegafur, gimeracil and oteracil compared to patients without hepatic impairment.
In patients with severe hepatic impairment compared to patients with normal liver function, a single dose of the drug was accompanied by a statistically significant decrease in Cmax of FU and gimeracil, however, with repeated administration of the drug, these differences were not observed.
In patients of different ethnic groups
In a comparative study of the pharmacokinetics of the drug Teysuno in monotherapy in patients from Asian countries (China, Malaysia) and in Europeans (patients from the USA), it was shown that in Asian patients, due to lower activity of the CYP2A6 isoenzyme, AUC0-12 of tegafur is higher, and T1/2 is longer compared to European patients. AUC0-12 of gimeracil and uracil in both groups were comparable, which may indicate that the inhibitory effects on hepatic DPD in the studied patient groups are similar. FU exposure did not differ statistically in both groups. AUC0-12 of oteracil – is 2 times lower in Asian patients compared to European patients, however, this difference was statistically insignificant, probably due to high interindividual variability.
The pharmacokinetics of the drug Teysuno in children has not been studied.
Indications
- Treatment of advanced gastric cancer in adults in combination with cisplatin.
ICD codes
| ICD-10 code | Indication |
| C16 | Malignant neoplasm of stomach |
| ICD-11 code | Indication |
| 2B72.Z | Malignant neoplasms of stomach, unspecified |
Dosage Regimen
| The method of application and dosage regimen for a specific drug depend on its form of release and other factors. The optimal dosage regimen is determined by the doctor. It is necessary to strictly adhere to the compliance of the dosage form of a specific drug with the indications for use and dosage regimen. |
Orally, with water, 1 hour before or 1 hour after a meal (as part of combination therapy with cisplatin).
Treatment with the drug Teysuno should be prescribed and monitored by an oncologist with experience in diagnosing and treating patients with gastric neoplasms.
As part of combination therapy with cisplatin, the recommended standard dose of the drug Teysuno is 25 mg/m2 (specified by the tegafur dose) 2 times/day, in the morning and evening, for 21 days followed by a break for 7 days. The total duration of one treatment course is 28 days. Treatment is repeated every 4 weeks.
Standard and reduced doses of the drugs Teysuno and cisplatin are calculated based on the patient’s body surface area (BSA) (see tables 1 and 2).
If the patient’s body weight changes by 10% or more, and if the change is not associated with severe edema, the body surface area is re-determined, and the dose of the drug Teysuno is increased or decreased.
Cisplatin is administered as an intravenous infusion at the recommended dose of 75 mg/m2 once every 4 weeks. The use of cisplatin is discontinued after 6 courses of therapy, and the administration of the drug Teysuno is continued. If the use of cisplatin is discontinued before the 6th course, the administration of the drug Teysuno is resumed if the criteria necessary for continuing treatment are met.
During treatment, the patient’s general condition should be carefully monitored, peripheral blood counts, activity of “hepatic” transaminases, CrCl, and electrolyte levels should be regularly monitored. Treatment is discontinued in case of disease progression and development of toxicity symptoms that cannot be eliminated.
The patient should consume a sufficient amount of fluid (see the instructions for use of cisplatin).
Therapy aimed at treating anemia and diarrhea may be necessary.
Doses of Teysuno Used
Table 1. Standard and reduced doses of Teysuno and cisplatin
| Drug Name | Standard Dose (mg/m2) | Reduced Dose 1 (mg/m2) | Reduced Dose 2 (mg/m2) | ||
| Teysuno | 25* | → | 20* | → | 15* |
| And/or | |||||
| Cisplatin | 75 | → | 60 | → | 45 |
| * Expressed as tegafur content | |||||
Selection of Teysuno Dose
Table 2. Calculation of standard and reduced doses of Teysuno depending on body surface area (m2)
| Teysuno Dose | Single Dose mg (single dosing) | Daily Dose in mg | Number of capsules of each strength (2 doses/day) | |
| Standard Dose*: 25 mg/m2 | Capsules* 15 mg (brown-white) | Capsules* 20 mg (white) | ||
| BSA≥2.30 m2 | 60 | 120 | 0 | 3 |
| BSA=2.10- 2.29 m2 | 55 | 110 | 1 | 2 |
| BSA=1.90-2.09 m2 | 50 | 100 | 2 | 1 |
| BSA=1.70-1.89 m2 | 45 | 90 | 3 | 0 |
| BSA=1.50-1.69 m2 | 40 | 80 | 0 | 2 |
| BSA=1.30-1.49 m2 | 35 | 70 | 1 | 1 |
| BSA<1.29 m2 | 30 | 60 | 2 | 0 |
| First dose reduction: to 20 mg/m2 | ||||
| BSA≥2.13 m2 | 45 | 90 | 3 | 0 |
| BSA=1.88-2.12 m2 | 40 | 80 | 0 | 2 |
| BSA=1.30-1.87 m2 | 35 | 70 | 1 | 1 |
| BSA= 1.30- 1.62 m2 | 30 | 60 | 2 | 0 |
| BSA≤1.29 m2 | 20 | 40 | 0 | 1 |
| Second dose reduction: to 15 mg/m2 | ||||
| BSA≥2.17 m2 | 35 | 70 | 1 | 1 |
| BSA=1.67-2.16 m2 | 30 | 60 | 2 | 0 |
| BSA=1.30-1.66 m2 | 20 | 40 | 0 | 1 |
| BSA≤1.29 m2 | 15 | 30 | 1 | 0 |
| BSA values are determined to hundredths * Indicated by tegafur dose |
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Dosage adjustments during treatment
General Information
The severity of toxic manifestations associated with the use of Teysuno can be reduced with symptomatic therapy, as well as by reducing the dose of the drug or its temporary discontinuation. If moderate or severe symptoms of drug toxicity occur, patients should immediately inform their physician.
If treatment is interrupted due to toxic reactions, the missed dose of Teysuno should not be taken. The drug should also not be re-administered after vomiting. If the dose of Teysuno has been reduced, it should not be subsequently increased.
Dose Reduction Criteria
The dose of Teysuno is reduced according to the information presented in Tables 1, 3, 4 and 5. In case of toxicity reactions, the doses of each drug in the combination therapy (Teysuno and cisplatin) are sequentially reduced, a maximum of 2 times (see Table 1). With each reduction, the drug dose is decreased by approximately 20-25%. Detailed information on the number of Teysuno capsules for each dose reduction is provided in Table 2. Criteria for resuming treatment are indicated in Table 6.
Adjustment of the Teysuno dose in combination therapy with cisplatin, necessary when toxic reactions occur, can be done in two ways.
- During the 4-week treatment course
Patients take Teysuno daily from Day 1 to Day 21 of each treatment course and do not take it from Day 22 to Day 28. The days of this course when the drug was missed due to toxicity reactions are not repeated.
During the treatment course, the dose of the drug causing the observed toxicity reaction is adjusted, if such determination is possible. If the toxicity reaction could be caused by both drugs or cannot be attributed to one of them, a reduction in the dose of both drugs is recommended.
- At the start of the next treatment course
If treatment with Teysuno or cisplatin must be delayed, the start of the next treatment course is postponed until treatment with each drug becomes possible or until one of the drugs is completely discontinued.
Adjustment of Teysuno dose due to the occurrence of general toxic reactions, excluding cases of hematological and nephrological toxicity
Table 3. Dose reduction scheme for the development of general toxic reactions not related to hematological and nephrological toxicity
| Severity of toxicity symptomsa | Changes in Teysuno dose during the 21-day treatment course | Adjustment of Teysuno dose when taking the next dose/in the next course |
| Grade 1 | ||
| Symptoms occur at any time | Continue treatment at the same dose | Not performed |
| Grade 2b,c | ||
| Symptoms occur at any time | Temporarily discontinue treatment until symptom severity decreases to Grade 0 or 1 | Not performed |
| Grade 3 or higher | ||
| Symptoms identified for the first time | Temporarily discontinue treatment until symptom severity decreases to Grade 0 or 1 | Dose is reduced by 1 level compared to the previous level |
| Symptoms identified repeatedly | Temporarily discontinue treatment until symptom severity decreases to Grade 0 or 1 | Dose is reduced by 1 level compared to the previous level |
| Symptoms identified for the third time | Discontinue treatment | Discontinue the drug |
| a – According to the severity criteria for adverse reactions per the CTCAE classification of the National Cancer Institute, USA (version 3). b– In case of Grade 2 nausea and vomiting, the optimal dose of antiemetic drugs should be selected before discontinuing Teysuno. c – At the discretion of the treating physician, treatment may be continued without interruption or dose reduction for toxic reactions (regardless of their severity), since the likelihood of them becoming serious or life-threatening is low (e.g., alopecia, decreased libido/erectile dysfunction, dry skin). |
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Dose reduction of drugs upon occurrence of nephrotoxic reactions
Before the start of each treatment course and before the first dose of Teysuno on Day 1, CrCl should be determined.
Table 4. Scheme for reducing the dose of Teysuno and cisplatin with decreased CrCl (development of nephrotoxic reactions) at the start of the treatment course
| Creatinine Clearance | Change in Teysuno dose at the start of the treatment course | Change in cisplatin dose at the start of the treatment course |
| ≥50 ml/min | Dose not reduced | Dose not reduced |
| 30-49 ml/min | Start treatment at a dose reduced by one level | Start cisplatin treatment at a dose reduced by 50% compared to the dose used in the previous treatment course |
| <30 ml/mina | Discontinue the drug until renal function recovers (≥30 ml/min), then start treatment at a dose reduced by one level from the previous one | Discontinue the drug until renal function recovers (≥30 ml/min), then start cisplatin treatment at a dose reduced by 50% compared to the dose used in the previous treatment course |
| a – Treatment is not recommended for CrCl <30 ml/min. See section "Dosage adjustment in special patient groups/Renal impairment" | ||
Reduction of Teysuno dose upon occurrence of hematopoietic toxicity
Table 5. Hematological toxicity parameters requiring discontinuation of Teysuno treatment
| Non-hematological | Hematological |
| Baseline observed values or Grade 1 | Platelets ≥100×109/L |
| CrCl>30 ml/mina | Neutrophils ≥1.5 ×109/L |
| Hemoglobin ≥6.2 mmol/L | |
| CrCl should be determined at the beginning of each cycle before starting Teysuno treatment on day 1. | |
| a Treatment is not recommended for CrCl <30 ml/min. See section "Dosage adjustment in special patient groups/Renal impairment" | |
Dosage adjustment in special patient groups
Renal impairment
- In patients with mild renal impairment (CrCl 51-80 ml/min), no adjustment of the standard dose is required.
- In patients with moderate renal impairment (CrCl 30-50 ml/min), the recommended reduced dose 1 of Teysuno is 20 mg/m2 twice daily (by tegafur dose).
- In patients with severe renal impairment (CrCl <30 ml/min), the use of the drug is not recommended.
Use in elderly patients
In patients aged 70 years and older, no adjustment of the standard dose is required.
In hepatic impairment
In patients with hepatic impairment, no adjustment of the standard dose is required (see section “Pharmacokinetics”).
Ethnic differences
In patients of Asian origin, no adjustment of the standard dose is required (see section “Pharmacokinetics”).
In children
The efficacy and safety of Teysuno in children under 18 years of age have not been studied.
Adverse Reactions
Safety profile characteristics
Among 593 patients who received Teysuno and combinations with cisplatin, the following severe adverse reactions (Grade 3 severity with a frequency of at least 10%) were most commonly observed: neutropenia, anemia, and increased fatigue.
List of adverse reactions
Frequency of adverse reactions: very common (>1/10); common (>1/100, < 1/10); uncommon (>1/1000, <1/100); rare (>1/10 000, <1/1000); very rare (<1/10 000); frequency not known (currently no data on the prevalence of adverse reactions).
| System Organ Class | Very Common | Common | Uncommon | Rare/Very Rare |
| Infections and infestations | Septic shock, sepsis, upper and lower respiratory tract infections, acute pyelonephritis, urinary tract infections, oral infections and candidiasis, herpes simplex stomatitis, paronychia, furunculosis | |||
| Benign, malignant and unspecified neoplasms (including cysts and polyps) | Tumor hemorrhage, severe pain syndrome | |||
| Blood and lymphatic system disorders | Neutropenia, leukopenia, anemia, thrombocytopenia | Febrile neutropenia, lymphopenia | Pancytopenia, increased prothrombin time, increased INR (International Normalized Ratio), hypoprothrombinemia, shortened prothrombin time, granulocytopenia, leukocytosis, lymphocytopenia, increased monocyte count, thrombocythemia | Disseminated intravascular coagulation (DIC) syndrome |
| Immune system disorders | Hypersensitivity reactions | |||
| Endocrine disorders | Adrenal hemorrhage | |||
| Metabolism and nutrition disorders | Anorexia | Dehydration, hypokalemia, hyponatremia, hypocalcemia, hypomagnesemia, hypoalbuminemia, hyperkalemia | Hyperglycemia, increased alkaline phosphatase, LDH, hypophosphatemia, hypermagnesemia, gout, hypoproteinemia, hyperglobulinemia, hyperlipidemia, decreased food intake | |
| Psychiatric disorders | Insomnia | Confusional state, psychomotor hyperactivity, personality disorder, hallucinations, depression, anxiety, decreased libido, impotence | ||
| Nervous system disorders | Peripheral neuropathy, paresthesia, hyperesthesia, polyneuropathy, neurotoxicity, dysesthesia | Dizziness, headache, dysgeusia | Cerebrovascular accidents, cerebral hemorrhage, cerebrovascular disorders, convulsions, ischemic stroke, syncope, hemiparesis, aphasia, ataxia, metabolic encephalopathy, loss of consciousness, acoustic neuritis, memory impairment, balance disorder, somnolence, tremor, ageusia, parosmia, burning sensation, formication | |
| Eye disorders | Visual disturbances, lacrimal disorders (increased lacrimation, dry eye syndrome, nasolacrimal duct stenosis), conjunctivitis, corneal changes (corneal epithelial defect, corneal erosion, corneal injury, corneal opacity, corneal perforation, keratitis, punctate keratitis, ulcerative keratitis), blurred vision, visual impairment, diplopia, photopsia, visual acuity reduced | Allergic conjunctivitis, eyelid ptosis, conjunctival hyperemia | ||
| Ear and labyrinth disorders | Hearing impaired, deafness | Vertigo, ear discomfort, ear congestion sensation | ||
| Cardiac disorders | Hypotension, deep vein thrombosis, hypertension | Cardiac failure, acute myocardial infarction, pericardial effusion, atrial fibrillation, angina pectoris, ventricular fibrillation, tachycardia, palpitations, iliac artery thrombosis, hypovolemic shock, peripheral artery thrombosis, feeling hot, pelvic venous thrombosis, thrombophlebitis, phlebitis, superficial phlebitis, orthostatic hypotension, hematoma, skin redness, flushing | ||
| Respiratory, thoracic and mediastinal disorders | Dyspnea, epistaxis, hiccups, cough | Pulmonary embolism, pulmonary hemorrhage, exertional dyspnea, oropharyngeal pain, rhinorrhea, pharyngeal hyperemia, allergic rhinitis, dysphonia, productive cough, nasal congestion | Interstitial lung disease | |
| Gastrointestinal disorders | Diarrhea, vomiting, nausea, constipation | Gastrointestinal hemorrhage, stomatitis, gastrointestinal inflammatory disorders, flatulence, abdominal pain, dysphagia, abdominal discomfort, dyspepsia, dry mouth | Gastrointestinal perforation, esophagitis, gastrointestinal infections, ileitis, intestinal obstruction, ascites, lip edema, esophageal spasm, gastric mucosal ulceration, reflux esophagitis, reflux gastritis, retroperitoneal fibrosis, functional gastrointestinal disorders, hemorrhoidal hemorrhage, salivary hypersecretion, retching, salivary gland hypofunction, cheilitis, aerophagia, eructation, glossodynia, oral pain, tooth fragility | Acute pancreatitis |
| Hepatobiliary disorders | Hyperbilirubinemia, increased ALT, increased AST | Abnormal liver function tests, increased gamma-glutamyltransferase (GGT) | Acute hepatic failure | |
| Skin and subcutaneous tissue disorders | Palmar-plantar erythrodysesthesia syndrome, skin rash, hyperpigmentation, dry skin, pruritus, alopecia | Exfoliative rash, skin exfoliation, necrolytic migratory erythema, subcutaneous hemorrhage, allergic dermatitis, skin reactions, acneiform dermatitis, erythema, increased tendency to bruise, purpura, hyperhidrosis, night sweats, nail atrophy, skin depigmentation, skin discoloration, hypertrichosis | Toxic epidermal necrolysis, Stevens-Johnson syndrome, photosensitivity, nail disorder | |
| Musculoskeletal and connective tissue disorders | Bone and muscle pain | Muscle spasms, arthralgia, pain in extremity, back pain, neck pain, bone pain, joint swelling, discomfort, pressure and muscle weakness in extremity | Rhabdomyolysis | |
| Renal and urinary disorders | Renal failure, increased blood creatinine, decreased glomerular filtration rate, increased blood urea | Toxic nephropathy, oliguria, hematuria, renal function decreased, pollakiuria, increased creatine, decreased creatinine | ||
| Reproductive system and breast disorders | Erectile dysfunction, breast heaviness, nipple pain | |||
| General disorders and administration site conditions | Fatigue, asthenia | Mucosal fungal infections, pyrexia, weight decreased, peripheral edema, influenza-like illness | Multiple organ failure, general physical health deterioration, pain, edema, chest pain, chest discomfort, generalized edema, face edema, localized edema, weight increased, early satiety, chills, injection site reactions, malaise | |
| Injury, poisoning and procedural complications | Contusion, medical errors | |||
| aAdverse effects were distributed according to the classification of System Organ Classes based on the target organ. Similar terms used in the listed reactions were grouped into one term. | ||||
Contraindications
- hypersensitivity to tegafur, gimeracil, oteracil, or other components of the drug;
- hypersensitivity to fluoropyrimidine derivatives;
- concomitant and prior (within 4 weeks before the current treatment) use of DPD inhibitors, including sorivudine and its structural analogues such as brivudine;
- established dihydropyrimidine dehydrogenase deficiency;
- bone marrow suppression (severe leukopenia, neutropenia, or thrombocytopenia);
- In patients with severe renal impairment (CrCl<30 ml/min);
- concomitant use with allopurinol;
- concomitant use with fluoropyrimidine derivatives;
- contraindications for the use of cisplatin;
- pregnancy and breastfeeding;
- age under 18 years (efficacy and safety have not been established).
With caution
Moderate renal failure, hepatic failure, age over 70 years, concomitant use with coumarin indirect anticoagulants, folic acid and its derivatives, 5-nitroimidazole derivatives including metronidazole and misonidazole, with methotrexate, clozapine, cimetidine, phenytoin; rare hereditary diseases such as glucose-galactose intolerance, hereditary lactase deficiency, lactose intolerance, or glucose-galactose malabsorption.
Use in Pregnancy and Lactation
The use of Teysuno is contraindicated during pregnancy and breastfeeding (there is no clinical experience in this patient group). According to preclinical data, Teysuno has embryotoxic and teratogenic effects.
If pregnancy occurs during Teysuno treatment, the drug should be discontinued and the patient should be referred for genetic counseling.
Breastfeeding should be discontinued during Teysuno treatment, as the drug may pass into breast milk.
Use in Hepatic Impairment
Use the drug with caution in patients with hepatic failure; no adjustment of the standard dose is required.
Use in Renal Impairment
Use the drug with caution in patients with moderate renal failure.
In patients with mild renal impairment (CrCl 51-80 ml/min), no adjustment of the standard drug dose is required; in patients with moderate renal impairment (CrCl 30-50 ml/min), the recommended reduced dose of Teysuno is 20 mg/m2 twice daily (based on the tegafur dose); the use of the drug is not recommended in patients with severe renal impairment (CrCl<30 ml/min).
Pediatric Use
The use of the drug in children and adolescents under 18 years of age is contraindicated.
Geriatric Use
The drug should be used with caution in patients aged 70 years and older; no adjustment of the standard dose is required.
Special Precautions
Clinical symptoms requiring dose adjustment of the drug include diarrhea and symptoms of dehydration.
Most adverse effects are reversible and can be managed with symptomatic therapy; dose adjustment or temporary discontinuation may also be necessary.
Bone marrow suppression
Patients receiving combination therapy with Teysuno and cisplatin may experience bone marrow suppression, including neutropenia, leukopenia, thrombocytopenia, anemia, and pancytopenia.
Due to the increased risk of infectious diseases and other complications, patients with leukopenia and neutropenia should be regularly monitored by the attending physician; appropriate therapy (antibacterial drugs and drugs belonging to granulocyte colony-stimulating factors [G-CSF]) should be administered in a timely manner if necessary.
Patients with low platelet counts have an increased risk of bleeding; their platelet count and complete blood count should be regularly monitored.
In some cases, a dose reduction of Teysuno may be required (see the “Dosage and Administration” section).
Diarrhea
Patients with diarrhea require careful clinical monitoring and replacement of fluid and electrolyte losses if symptoms of dehydration appear. Antidiarrheal drugs should be used if necessary.
Treatment with antidiarrheal drugs (e.g., loperamide) should be started as early as possible from the onset of diarrhea, while ensuring adequate fluid and/or electrolyte intake.
Dose adjustment of Teysuno is performed for grade 2 diarrhea or higher, as well as in cases where diarrhea persists despite treatment.
Dehydration
Dehydration and any associated electrolyte disturbances must be corrected before starting treatment or eliminated at the very beginning of their development.
Special attention should be paid to identifying symptoms of dehydration and monitoring the condition of those patients who experience anorexia, asthenia, nausea, vomiting, diarrhea, stomatitis, and intestinal obstruction.
In such patients, correction of dehydration and electrolyte disturbances should be more active.
For grade 2 dehydration or higher, treatment should be stopped immediately and dehydration should be eliminated.
Treatment should not be resumed until dehydration and its causes are eliminated.
If necessary, dose adjustment of Teysuno may be used to reduce adverse effects (see the “Dosage and Administration” section).
Nephrotoxicity
The use of Teysuno and its combination with cisplatin may be accompanied by a transient decrease in the glomerular filtration rate, which may be caused by primary prerenal factors (such as dehydration, electrolyte disturbances, etc.).
In patients receiving combination therapy with Teysuno and cisplatin, grade 3 and higher adverse effects were observed, including increased blood creatinine concentration, decreased CrCl, toxic nephropathy, and acute renal failure.
To detect early manifestations of nephrotoxic effects during Teysuno treatment, it is recommended to regularly monitor renal function (in particular, determine plasma creatinine concentration, CrCl).
If the glomerular filtration rate decreases, the dose(s) of Teysuno and/or cisplatin should be adjusted according to Table 4 and supportive therapy should be prescribed (see the “Dosage and Administration” section).
Dehydration and diarrhea may increase the risk of the nephrotoxic effect of cisplatin.
Hyperhydration (forced diuresis) is necessary to reduce the risk of nephrotoxic effect associated with the use of cisplatin, as indicated in the cisplatin prescribing information.
Gimeracil increases the concentration of FU in the blood by inhibiting DPD, the main enzyme involved in the metabolism of FU.
Gimeracil is mainly excreted by the kidneys, so in patients with renal failure, the excretion rate of gimeracil decreases, and the concentration of FU in the blood increases.
During treatment, an increase in toxic effects due to increased FU can be expected (see the “Pharmacokinetics” section).
Severe renal failure
The use of Teysuno is not recommended in patients with severe renal failure due to increased adverse effects on the hematopoietic and lymphatic systems and an unpredictable increase in FU concentration due to impaired renal function in such patients (see the “Pharmacokinetics”, “Dosage and Administration”, and “Adverse Reactions” sections).
Ocular disorders
In patients with combination therapy with Teysuno and cisplatin, the most frequent ocular reactions were lacrimal duct disorders (8.8%), including increased lacrimation, dry eye syndrome, and nasolacrimal duct stenosis (see the “Adverse Reactions” section).
The severity of most ocular symptoms is corrected or reduced upon discontinuation of the drug and with appropriate treatment (artificial tear preparations, antibacterial drugs, implantation of glass or silicone tubes into the lacrimal puncta or canaliculi; patients are also advised to use glasses more often rather than contact lenses).
These disorders must be diagnosed in a timely manner; an ophthalmologist should be consulted at the first persistent symptoms of ocular disorders, in particular, increased lacrimation or symptoms of corneal dysfunction.
Refer to the cisplatin prescribing information to consider possible visual disturbances that may be caused by the use of cisplatin.
Coumarin indirect anticoagulants
Patients taking oral coumarin indirect anticoagulants are recommended to regularly monitor treatment efficacy parameters (INR and prothrombin time) and adjust the anticoagulant dose (see the “Drug Interactions” section).
Clinical studies have shown that concomitant use of Teysuno and indirect anticoagulants resulted in increased INR and the development of gastrointestinal bleeding, hemorrhagic disorders, hematuria, and anemia.
DPD inducers
When Teysuno and DPD inducers are used concomitantly, the concentration of FU may not reach an effective level. However, since DPD inducers are currently unknown, it is difficult to assess the interaction between these drugs.
Microsatellite instability
Teysuno has not been studied in patients with gastric cancer who have been tested for microsatellite instability (MSI). The relationship between sensitivity to FU and the presence of MSI in patients with gastric cancer has not been determined, and the relationship between Teysuno and MSI in patients with gastric cancer has not been studied.
Glucose-galactose intolerance/malabsorption syndrome
Teysuno contains lactose. Patients with rare hereditary diseases such as glucose-galactose intolerance, hereditary lactase deficiency, lactose intolerance, or glucose-galactose malabsorption should take the drug with caution.
Other fluoropyrimidine drugs
No comparative clinical studies of Teysuno and other oral FU derivatives have been conducted. In this regard, Teysuno should not be used instead of other drugs containing FU.
Use in women of reproductive age
Before starting treatment with Teysuno, an examination confirming the absence of pregnancy should be performed.
Women of reproductive age and their husbands should use reliable methods of contraception during Teysuno therapy and for at least 6 months after completion of therapy.
Possible effect on spermatogenesis in adults
There are no data on impaired spermatogenesis with the use of Teysuno; however, cases of decreased total sperm count and azoospermia have been reported in men using cisplatin (a drug used in combination therapy with Teysuno).
Effect on ability to drive and operate machinery
During treatment with Teysuno, a number of symptoms associated with the use of the drug (including those related to vision and the central nervous system) may occur, which may adversely affect the ability to drive a car and operate complex machinery. Therefore, patients should refrain from activities requiring concentration and high speed of psychomotor reactions.
Overdose
There is information that when Teysuno was used at a dose of 1400 mg, a patient experienced leukopenia (grade 3).
Symptoms of acute overdose include nausea, vomiting, diarrhea, mucositis, gastrointestinal irritation, bleeding, bone marrow suppression, and respiratory failure.
Treatment of overdose symptoms includes symptomatic therapy – performing generally accepted therapeutic and supportive measures aimed at correcting the occurring disorders, as well as preventing possible complications.
There is no specific antidote.
Drug Interactions
Studies on drug interactions in adults and children have not been conducted.
Other fluoropyrimidines
Concomitant use of other fluoropyrimidines, in particular, capecitabine, fluorouracil, tegafur, or flucytosine is contraindicated due to the combined enhancement of toxic effects. The period before the possible start of Teysuno after discontinuation of a fluoropyrimidine drug should be at least 7 days. The elimination period specified in the prescribing information of the fluoropyrimidine drug must be taken into account if Teysuno is prescribed after the use of another fluoropyrimidine drug.
Sorivudine and brivudine
Sorivudine and its chemical analogue brivudine irreversibly inhibit DPD, thereby enhancing the effect of FU. This can lead to an increase in clinically significant toxic effects of fluoropyrimidines, including the risk of fatal outcomes. Teysuno should not be used concomitantly with sorivudine or brivudine, or within 4 weeks after discontinuation of these drugs.
Inhibitors of the CYP2A6 isoenzyme
Since CYP2A6 is the main cytochrome P450 isoenzyme responsible for the conversion of tegafur to FU, concomitant use of Teysuno and CYP2A6 inhibitors should be avoided, as a decrease in the expected efficacy of Teysuno is possible (see the “Pharmacological Properties” section).
Folic acid and its derivatives
Concomitant use of folic acid and Teysuno in combination with cisplatin has not been studied. However, it is known that folic acid metabolites form a triple structure with thymidylate synthase and fluorodeoxyuridine monophosphate (FdUMP), potentially increasing the cytotoxicity of FU. Caution should be exercised as concomitant use may increase the toxicity of Teysuno.
5-Nitroimidazole derivatives, including metronidazole and misonidazole
Concomitant use of 5-nitroimidazole derivatives with Teysuno in combination with cisplatin has not been studied. Nevertheless, it is known that 5-nitroimidazole drugs may reduce the clearance of FU and, consequently, increase the plasma concentration of FU. Therefore, Teysuno with cisplatin and 5-nitroimidazole derivatives should be used concomitantly with caution.
Methotrexate
Concomitant use of methotrexate and combination therapy with Teysuno and cisplatin has not been studied. Nevertheless, it is known that methotrexate polyglutamate inhibits thymidylate synthase and dihydrofolate reductase, potentially increasing the cytotoxicity of FU. Therefore, the combination of Teysuno with cisplatin and methotrexate should be used concomitantly with caution.
Clozapine
Concomitant use of clozapine and combination therapy with Teysuno and cisplatin has not been studied. Nevertheless, due to possible pharmacodynamic interaction (myelotoxicity), caution should be exercised when used concomitantly with clozapine, as there may be an increased risk and severity of the hematological toxicity of Teysuno.
Concomitant use of cimetidine with Teysuno in combination with cisplatin has not been studied. Caution should be exercised when used concomitantly, as a decrease in renal clearance and an increase in the plasma concentration of FU are possible.
Indirect anticoagulants – coumarin derivatives
Teysuno increases the activity of coumarin indirect anticoagulants. Caution should be exercised when used concomitantly with Teysuno, as combined use may increase the risk of bleeding (see the “Special Precautions” section).
Fluoropyrimidine derivatives may increase the plasma concentration of phenytoin in case of concomitant use with phenytoin, thereby increasing the toxic effect of phenytoin. When phenytoin is used concomitantly with Teysuno, regular and frequent monitoring of the plasma concentration of phenytoin is recommended. The dose of phenytoin should be adjusted based on the information provided in the phenytoin prescribing information. If toxic reactions of phenytoin develop, appropriate measures should be taken.
Other drugs
Based on preclinical data, due to inhibition of FU phosphorylation, allopurinol may reduce the antitumor activity of the drug. Therefore, concomitant use of allopurinol and Teysuno is not recommended.
Other forms of interaction
Food intake
When taken concomitantly with food, a decrease in the plasma concentration of oteracil and gimeracil is possible, with a more pronounced decrease in the concentration of oteracil (see the “Pharmacokinetics” section). The drug should be taken 1 hour before or 1 hour after a meal, with water (see the “Dosage and Administration” section).
Storage Conditions
The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).
Shelf Life
The shelf life is 3 years. Do not use after the expiration date printed on the package.
Dispensing Status
The drug is dispensed by prescription.
Important Safety Information
This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.
Medical Disclaimer![Teysuno [Capsules] 1](https://www.medixlife.com/wp-content/uploads/Medixlife_favi_512.png "Teysuno [Capsules] 2")