Approval date: October 19, 2010
Modification date: 09/03/2015
Modification date: 09/06/2017
Date of modification.
Tegeo capsules instructions
Please read this instruction manual carefully and use under the guidance of a physician
【Drug name】.
Generic name: Tegeo capsules
English name: Tegafur, Gimeracil and Oteracil Potassium Capsules
Hanyu Pinyin: Tiji’ ao Jiaonang
Ingredients
This product is a compound preparation, each capsule contains.
20mg: Tegafur 20mg, Gimeracil 5.8mg, Oteracil Potassium 19.6mg.
Specification of 25mg: Tegafur 25mg, Gimeprazine 7.25mg, Otilacid Potassium 24.5mg.
Properties
This product is a capsule, the content of white or off-white granules or powder.
Indications
Unresectable locally advanced or metastatic gastric cancer.
Specification
(1) 20mg (based on tegafur) (2) 25mg (based on tegafur)
Dosage and Administration
Dosage.
Tegeo capsules are used in combination with cisplatin for the treatment of unresectable locally advanced or metastatic gastric cancer.
In general, the first dose for adults is determined according to the body surface area according to the table below. The dose is administered orally twice daily, after breakfast and dinner, for 28 consecutive days with a 14-day break for one treatment cycle. The dose is administered until the patient’s condition deteriorates or becomes intolerable.
Body surface area (m2) Initial dose (based on tegafur) <1.25 40mg per dose ≥1.25 to <1.5 50mg per dose ≥1.5 60mg per dose Dosing may be increased or decreased according to the patient’s condition. Each dose is administered in increasing or decreasing order in four dose classes of 40mg, 50mg, 60mg, and 75mg. If there are no safety concerns such as abnormal laboratory tests (blood tests, liver and kidney function) or gastrointestinal symptoms caused by the drug, and if the physician determines that an increase is necessary, the dose may be increased by one dose level in the above order, up to 75mg/dose. If a dose reduction is required, the dose will be reduced in accordance with the dose class, with a lower limit of 40mg/dose. Cisplatin is administered orally for 21 consecutive days, with a 14-day break and an intravenous drip of 60 mg/m2 on day 8 of dosing for one treatment cycle. Administer until the patient’s condition deteriorates or becomes intolerable.
Precautions for dosing.
Dosing may be increased or decreased according to the patient’s condition by referring to the following criteria
Decrease first dose increment stop each 40mg each 50mg stop ← each 40mg each 50mg each 60mg stop ← each 40mg each 50mg each 60mg each 75mg increment should not exceed one dose level per cycle. 2.
2. If the chemotherapy interval needs to be shortened, safety issues such as abnormal laboratory tests (blood count, liver and kidney function) and gastrointestinal symptoms caused by this drug must be confirmed, but the chemotherapy interval should not be less than 7 days. The safety of shortening the chemotherapy interval in patients with inoperable or recurrent breast cancer has not been confirmed (no clinical experience with the drug). To avoid serious adverse effects such as myelosuppression and fulminant hepatitis, laboratory tests (routine blood and liver and kidney functions) and comprehensive observation of the patient’s condition must be performed before the start of each chemotherapy treatment, and at least once every 2 weeks during chemotherapy. If any abnormalities are found, appropriate measures must be taken, such as prolonging the chemotherapy interval, reducing the dose or stopping the drug as specified above. The first treatment cycle or increase in dose must be more closely observed and examined. 4. Basic studies (rats) have found that fasting changes the bioavailability of octreotide potassium, resulting in a weakened inhibition of fluorouracil phosphorylation, thus reducing the antitumor effect of the drug.
Precautions for patient use.
Patients should be aware of the following when administering the drug.
This drug is packaged in an aluminum-plastic blister (PTP) and patients should be informed that they need to press the drug out of the blister before taking the drug. There have been reports of patients accidentally taking aluminum foil plates, resulting in esophageal perforation and serious complications such as mediastinitis.
[Adverse reactions].
Foreign clinical trials
1. Combination therapy
A multicenter phase III randomized controlled trial comparing Tegeo capsules alone (Tegeo capsules 40-60 mg/dose orally twice daily for 28 consecutive days with a 14-day break) and Tegeo capsules combined with cisplatin (Tegeo capsules 40-60 mg/dose orally twice daily for 21 consecutive days with 60 mg/m2 cisplatin on day 8) in patients with advanced gastric cancer was conducted in Japan. The major adverse reactions of 298 patients who could be evaluated for adverse reactions in a multicenter phase III randomized controlled trial of treatment are shown in the table below.
Incidence of adverse reactions Monotherapy group (n=150) Combination therapy group (n=148) Leukopenia (CTC≥3 degree #1) 38% (2%) 70% (11%) Neutropenia (CTC≥3 degree) 42% (11%) 74% (40%) Anemia (CTC≥3 degree) 33% (4%) 68% (26%) Thrombocytopenia (CTC≥3 degree) 18% (0%) 49% (5%) Loss of appetite (CTC ≥ 3 degrees) 37% (6%) 72% (30%) Nausea (CTC ≥ 3 degrees) 26% (1%) 67% (11%) Vomiting (CTC ≥ 3 degrees) 14% (2%) 36% (4%) Stomatitis (CTC ≥ 3 degrees) 21% (0%) 29% (0.7%) Diarrhea (CTC ≥ 3 degrees) 23% (3%)34% (4%)Weakness (CTC≥3 degrees)33% (1%)57% (4%)Hyperpigmentation (CTC≥3 degrees)40% (0%)36% (0%)Rash (CTC≥3 degrees)19% (1%)22% (2%)Overflowing tears (CTC≥3 degrees)16% (0.7%)18% (0%)#1 Common Toxicity Determination by National Cancer Institute Criteria (NCI CTCAE) grading.
The late phase II clinical trial of combination chemotherapy for non-small cell lung cancer (21 consecutive days of oral tegeo capsules with 60 mg/m2 cisplatin given at day 8) found that all 55 patients evaluable for adverse reactions experienced adverse reactions, and the major adverse reactions are shown in the table below.
Incidence of adverse reactions combination therapy non-small cell lung cancer patients (55 patients)#2100.0% (61.8%)Leukopenia (<2000/mm3) 52.7% (5.5%)Neutropenia (<1000/mm3) 65.5% (29.1%)Hemoglobin reduction (<8g/dL) 90.9% (21.8%)Thrombocytopenia (<5×104/mm3)60.0% (1.8%)Aspartate aminotransferase (AST) elevation 14.5%Alanine aminotransferase (ALT) elevation 14.5%Loss of appetite (CTC ≥3 degrees)78.2% (12.7%)Nausea (CTC ≥3 degrees)65.5% (10.9% ) Vomiting (CTC ≥ 3 degrees) 38.2% (7.3%) Diarrhea (CTC ≥ 3 degrees) 34.5% (7.3%) Stomatitis 25.5% Hyperpigmentation 23.6% Skin rash 9.1%
#2: Graded according to the National Cancer Institute Common Toxicity Criteria for Adjudication (NCI CTCAE).
2. Monotherapy
Of the 578 patients who could be evaluated for adverse reactions (excluding previously treated breast, pancreatic, and bile duct cancer patients described below), the incidence of adverse reactions was 87.2% (504 patients). The incidence of adverse reactions was higher in patients with inoperable or recurrent breast, pancreatic, and bile duct cancers treated with paclitaxel previously compared with other types of tumors, 96.4%, 98.3%, and 94.9%, respectively. The incidence of adverse reactions was higher in patients with pancreatic cancer, and gastrointestinal reactions such as loss of appetite, nausea, vomiting and diarrhea were particularly pronounced. The following adverse reactions are common when used as monotherapy.
Adverse reactions monotherapy all patients
(578 cases) #3 previously treated breast cancer patients
(55 patients) with pancreatic cancer
(59) Patients with bile duct cancer
(59 cases)#3 patients with gastric cancer
(134 cases) Incidence
(CTC ≥3 degrees)#487.2%
(22.5%) 77.6%
(20.9%)96.4%
(30.9%)98.3%
(42.4%)94.9%
(30.5%)Leukopenia (<2000/mm3)45.8%
(2.8%)48.5%
(3.7%)69.1%
(9.1%)32.2%
(0%)49.2%
(3.4%) Neutropenia
(<1000/mm3) 43.9%
(8.5%)47.8%
(7.5%)72.7%
(10.9%)27.1%
(6.8%)42.4%
(5.1%) Hemoglobin reduction (<8g/dL) 38.1%
(5.7%)38.8%
(7.5%)45.5%
(3.6%)50.8%
(5.1%)50.8%
(6.8%)Thrombocytopenia
(<5×104/mm3)10.9%
(1.6%)9.0%
(1.5%)38.2%
(1.8%)33.9%
(1.7%)23.7%
(0%) Elevated AST (GOT) 11.1% 4.5% 34.5% 18.6% 37.3% Elevated ALT (GPT) 11.1% 3.7% 29.1% 16.9% 27.1% Loss of appetite
(CTC ≥3 degrees) 33.9%
(3.5%)22.4%
(2.2%)54.5%
(5.5%)61.0%
(13.6%)33.9%
(6.8%) Nausea
(CTC ≥3 degrees) 22.3%
(0%) 9.7%
(0%)47.3%
(0%)55.9%
(10.2%)32.2%
(3.4%) Vomiting
(CTC ≥3 degrees) 7.8%
(0.5%) 2.2%
(0%) 30.9%
(0%) 35.6%
(5.1%) 20.3%
(1.7%) Diarrhea
(CTC ≥3 degrees) 18.7%
(2.9%) 12.7%
(3.0%) 38.2%
(5.5%) 37.3%
(6.8%) 22.0%
(1.7%) General discomfort #522.3%11.9%47.3%47.5%35.6% Stomatitis 17.1%11.2%41.8%25.4%27.1% Hyperpigmentation 21.3%18.7%47.3%39.0%42.4% Rash 11.8%9.7%16.4%22.0%22.0%
#3: Includes phase II multicenter registration clinical trials conducted in Japan in gastric, colorectal, non-small cell lung, head and neck, and breast cancers; excludes patients with previously treated breast, pancreatic, and bile duct cancers.
#4: Use the National Cancer Institute Common Toxicity Criteria for Adjudication (NCI CTCAE) or the Japanese Society of Clinical Oncology classification.
#5: Includes malaise.
3. Time to onset of adverse reactions and recovery time
The time to onset of adverse reactions in 453 patients enrolled in phase II clinical trials of tegeo capsules for the treatment of gastric, colorectal, head and neck, non-small cell lung cancer (monotherapy), inoperable or recurrent breast cancer, pancreatic cancer, and bile duct cancer were analyzed as follows.
The median time required from the start of drug administration to the lowest values of white blood cell count <3000/mm3, hemoglobin <8g/dL, and platelet count <7.5×104/mm3 throughout the cycle was 27, 25, and 24 days, respectively; the median time required to confirm recovery above these standards was 7, 5.5, and 6 days, respectively.
Time required for the occurrence of abnormal laboratory test values to the lowest value: median value (range) Time required for the recovery of cases to recovery: median value (range) Leukopenia 92 cases 27 days (4-43 days) 85 cases 7 days (1-93 days) Hemoglobin reduction 29 cases 25 days (5-43 days) 24 cases 5.5 days (1-21 days) Thrombocytopenia 28 cases 24 days (9-51 days) 25 cases 6 days (1-46 days)
The median time required for adverse reactions such as diarrhea, rash and stomatitis associated with this drug to occur from the first administration was 24.5 days, 21 days and 28 days, respectively; the median time required for the above adverse reactions to return to normal from the most severe grade was 9 days, 14 days and 13.5 days, respectively.
Number of cases of symptom occurrence Time required for occurrence: median value (range) Number of cases of recovery Time required for recovery: median value (range) Diarrhea 100 cases 24.5 days (2-189 days) 95 cases 9 days (1-62 days) Rash 67 cases 21 days (2-248 days) 63 cases 14 days (2-254 days) Stomatitis 100 cases 28 days (3-262 days) 94 cases 13.5 days (2-99 days)
4. adverse reactions in patients with abnormal renal function
The incidence of adverse reactions in the post-marketing drug application (gastric cancer) analysis, grouped by creatinine clearance (Ccr estimation) calculated using the Cockcroft-Gault formula according to gender, age, weight, and serum creatinine value, is shown in the table below. The incidence of adverse reactions increased with decreasing creatinine clearance, while the severity of adverse reactions increased. The incidence of adverse reactions was lower in those with lower dosages (one grade lower than the standard dose) compared to those with the standard dose for the first administration.
Ccr Estimated value
(mL/min) Patients whose first dose was the standard dose Patients whose first dose was lower Incidence of adverse reactions Incidence of serious adverse reactions (grade 3 or higher) Incidence of adverse reactions Incidence of serious adverse reactions (grade 3 or higher) ≥8079.2%
(835/1054)26.8%
(282/1054)70.7%
(224/317)24.3%
(77/317)≥50 ~ <8080.8%
(1087/1345)32.3%
(434/1345)71.7%
(309/431)26.0%
(112/431)≥30 ~ <5087.4%
(319/365)42.5%
(155/365)79.9%
(123/154)33.8%
(52/154) <3090.0%
(18/20)75.0%
(15/20)82.4%
(14/17)47.1%
(8/17) Cockcroft-Gault formula.
Males.
(140 – age) × weight (kg)
Ccr=
72 × serum creatinine (mg/dL)
Females.
(140 – age) × body weight (kg) × 0.85
Ccr=
72 × serum creatinine (mg/dL)
5. Important adverse effects
1) Myelosuppression, hemolytic anemia: Severe myelosuppression such as complete blood cytopenia, granulocytopenia (symptoms: fever, sore throat and general malaise), leukopenia, anemia and thrombocytopenia (incidence as above) and hemolytic anemia (incidence unknown) may occur and should be closely observed. If abnormalities are detected, necessary measures such as discontinuation of the drug must be taken.
2) Disseminated intravascular coagulation (DIC): Because of the possibility of DIC (0.4%), close attention should be paid to the patient’s condition. If abnormal hematological tests such as platelet count, serum fibrin degradation products (FDP) and plasma fibrinogen are found, the drug should be discontinued and necessary measures should be taken.
3) Serious liver function abnormalities such as fulminant hepatitis: Serious liver function abnormalities such as fulminant hepatitis (including those caused by resurrection of hepatitis B virus) may occur (incidence unknown), and liver function checks, etc. should be performed regularly and the patient’s status should be closely monitored, and appropriate measures such as drug discontinuation should be taken if abnormalities occur. (See [Warning] for details).
4) Dehydration: Severe diarrhea may lead to dehydration (incidence unknown) and must be closely monitored. If abnormalities are found, the drug must be stopped and appropriate measures such as rehydration must be taken.
5) Severe enteritis (0.5%): Hemorrhagic enteritis, ischemic enteritis, necrotizing enteritis may occur and should be closely observed. If severe abdominal pain, diarrhea and other symptoms occur, the drug must be discontinued and appropriate measures must be taken.
*6) Interstitial pneumonia: Interstitial pneumonia (0.3%) may occur (early symptoms: cough, shortness of breath, dyspnea and fever) and must be closely observed. If abnormalities are found, the drug must be discontinued and appropriate measures such as chest X-ray and administration of adrenal corticosteroids must be taken.
(7) Myocardial infarction, angina pectoris, arrhythmia, heart failure: Myocardial infarction, angina pectoris, arrhythmia (including ventricular tachycardia) and heart failure (incidence is unknown) may occur and must be closely observed. If chest pain, fainting, palpitations, abnormal ECG, dyspnea and other symptoms are found, the drug must be stopped and appropriate measures taken.
(8) Severe stomatitis, peptic ulcer, gastrointestinal bleeding and gastrointestinal perforation: Severe stomatitis (incidence unknown), peptic ulcer (0.5%), gastrointestinal bleeding (0.3%) and gastrointestinal perforation (incidence unknown) may occur and must be closely observed. If abnormalities are found, the drug must be discontinued and abdominal X-ray and other examinations must be performed as needed; and appropriate measures must be taken.
(9) Acute kidney injury and nephrotic syndrome: Serious kidney diseases such as acute kidney injury and nephrotic syndrome (incidence unknown) may occur and must be closely observed. If abnormalities are found, the drug shall be discontinued and appropriate measures shall be taken.
(10) Toxic epidermal necrolysis (TEN) and Steven-Johnson syndrome: TEN and Steven-Johnson syndrome (incidence unknown) may occur and should be closely monitored. If abnormalities are found, the drug must be discontinued and appropriate measures must be taken.
(11) Cerebral leukomalacia and other neuropsychiatric abnormalities: cerebral leukomalacia (the main symptoms are disorders of consciousness, cerebellar ataxia and dementia-like symptoms), disorders of consciousness, disorientation, drowsiness, memory loss, extrapyramidal symptoms, speech disorders, tetraplegia, gait disorders, urinary incontinence or sensory disorders (the incidence of which is unknown) may occur and should be closely observed. If the above symptoms appear, the drug must be discontinued.
(12) Acute pancreatitis: Acute pancreatitis may occur (incidence unknown) and should be closely observed. If abdominal pain or elevated serum amylase occurs, the drug shall be discontinued and appropriate measures shall be taken.
(13) Rhabdomyolysis: rhabdomyolysis may occur (incidence unknown), symptoms include muscle pain, weakness, elevated phosphocreatine kinase (CK) and elevated blood/urine myoglobin, discontinue and take appropriate measures, and pay attention to prevent acute kidney injury caused by rhabdomyolysis.
(14) Loss of smell: Olfactory impairment (0.1%) and loss of smell (incidence unknown) may occur and should be closely monitored. If abnormalities are found, the drug must be discontinued and appropriate measures must be taken.
(15) Lacrimal duct obstruction: Lacrimal duct obstruction may occur (incidence unknown), and some of these patients have been reported to have undergone surgical treatment. If symptoms such as tearing are detected, appropriate measures such as eye examination are required.
* The incidence of interstitial pneumonia and other lung diseases has been studied in patients with non-small cell lung cancer.
Post-marketing studies of drug use in non-small cell lung cancer showed an incidence of interstitial pneumonia of 0.7% (11/1669) and other lung diseases including radiation pneumonia, dyspnea and respiratory failure of 0.7% (12/1669).
6. Other adverse reactions
The following adverse reactions may occur, and if abnormalities are found, appropriate measures such as dose reduction or discontinuation should be taken. If drug allergy is detected, the drug should be stopped and appropriate measures should be taken.
The incidence of hand-foot syndrome is higher in previously treated breast cancer patients (21.8%).
A post-marketing clinical study of this drug found a higher incidence of tear spillage in patients with unresectable or recurrent gastric cancer (16.0%).
Incidence
Classification Incidence ≥ 5% 0.1% ≤ Incidence < 5% Incidence Unknown Hematology Leukopenia, neutropenia, thrombocytopenia, erythrocytopenia, decreased hemoglobin, decreased erythrocyte pressure product, low lymphocyte bleeding tendency (subcutaneous bleeding spots, epistaxis, abnormal coagulation factors), eosinophilia, leukocytosis Elevated hepatic AST (GOT), ALT (GPT) Elevated, elevated bilirubin, elevated alkaline phosphatase (ALP) jaundice, positive urobilinogen Kidney Elevated BUN, elevated creatinine, proteinuria, hematuria Gastrointestinal tract Loss of appetite, nausea and vomiting, diarrhea, stomatitis, abnormal taste Intestinal obstruction, abdominal pain, bloating, epigastric pain, gastritis, abdominal rumbling, clay-like stools, constipation, xerostomia, labyrinthitis, tongue inflammation, dry mouth Skin hyperpigmentation erythema, desquamation, flushing, blistering hand-foot syndrome, skin ulcers, dermatitis, hair loss, nail abnormalities, nail fungus, herpes simplex, dry/rough skin photosensitivity dermatitis, DLE (discoid lupus erythematosus)-like rash allergy rash pruritus psychoneurological general discomfort numbness, headache, dull headache, vertigo dizziness cardiovascular hypotension, hypertension, electrocardiogram (ECG) abnormalities, Raynaud's syndrome palpitations eyes tearing, conjunctivitis, keratitis corneal erosion, eye pain, decreased vision, dry eye corneal ulcer, corneal clouding, corneal limbal stem cell deficiency other elevated lactate dehydrogenase (LDH), decreased total protein, decreased albumin fever, generalized heat sensation, rhinitis, pharyngitis, sputum, urine sugar, increased blood sugar, edema, myalgia, elevated CK (CPK), arthralgia, electrolyte abnormalities (elevated blood sodium, decreased blood sodium, elevated blood potassium, decreased blood potassium The incidence of these effects is based on the results of single-agent clinical trials conducted prior to the approval of this product.
7. Precautions for adverse reactions
(1) Acute leukemia (in some cases accompanied by pre-leukemia) or myelodysplastic syndrome (MDS) has been reported in patients treated with Tegeo capsules.
(2) A very small number of patients lack the fluorouracil metabolizing enzyme, dihydropyrimidine dehydrogenase (DPD), and may experience serious adverse reactions (e.g., stomatitis, diarrhea, hematopoietic abnormalities, and neurological disorders) during the initial period of administration if fluorouracil-based drugs are used.
(3) Cerebral infarction has been found, but the causal relationship with Tegeo capsules is uncertain.
(4) Otilacid potassium is readily decomposed in a strongly acidic environment (dogs), and a decrease in the concentration of otilacid potassium diminishes its effect in inhibiting adverse GI reactions (rats), so it is possible that a significant decrease in gastric pH could lead to diarrhea.
(5) Scleral hyperpigmentation of the bulbar conjunctiva and corneal clouding have been observed in dogs after repeated dosing.
II. Domestic clinical trials
In the clinical trial of gastric cancer conducted in China by Nippon Da Peng Pharmaceutical Industry Co., Ltd, the adverse reactions that could be evaluated in 230 patients were all known adverse reactions reported in Japan, and the safety results in the tegeo combined with cisplatin group and the tegeo alone group in the clinical trial conducted in Japan were basically not different, and no new serious adverse reactions were found. the incidence of adverse reactions with CTC ≥ 3 degrees is as follows : The
Hematologic adverse reactions in the tegeo combined with cisplatin group included: anemia 5.3%, granulocytopenia 5.3%, decreased erythrocyte pressure volume 2.6%, decreased hemoglobin 10.5%, decreased lymphocytes 5.3%, decreased neutrophils 17.1%, decreased platelets 6.6%, decreased red blood cells 2.6%, decreased white blood cells 13.2%, increased AST 1.3%, increased LDH elevation 1.3%, BUN elevation 1.3%; non-hematological adverse reactions included: diarrhea 6.6%, nausea 2.6%, vomiting 6.6%, enteritis 1.3%, liver function abnormalities 2.6%, allergy 1.3%, lung infection 1.3%.
Hematologic adverse reactions in the tegeo monotherapy group included: anemia 2.5%, decreased hemoglobin 6.3%, lymphopenia 8.8%, neutropenia 3.8%, leukopenia 1.3%, neutrophilia 1.3%, leukocytosis 1.3%, elevated ALP 1.3%, hypokalemia 1.3%, and elevated creatine kinase 1.3%; non-hematologic adverse reactions Including: diarrhea 3.8%, enteritis 1.3%, vomiting 1.3%, decreased appetite 2.5%, edema of the extremities 1.3%.
Contraindications]
Contraindicated in patients with a history of severe hypersensitivity to the constituents of Tegeo capsules.
Contraindicated in patients with severe myelosuppression (may aggravate myelosuppression).
Contraindicated in patients with severe renal abnormalities (see [Pharmacokinetics] for details).
Contraindicated in patients with severe hepatic abnormalities (may aggravate hepatic abnormalities).
Contraindicated in patients being treated with other fluorouracil-based antineoplastic agents (including combination therapy) (see [Drug Interactions] for details).
Contraindicated in patients receiving fluorocytosine therapy (see [Drug Interactions] for details).
Contraindicated in patients being treated with solifudine and its structural analogue (brovudine) (see [Drug Interactions] for details).
Contraindicated in women who are pregnant or at risk of pregnancy (see [Pregnancy and Lactation] for details).
Precautions]
1. Use with caution [Tegeo capsules should be used with caution in the following patients].
(1) Patients with bone marrow suppression [may aggravate bone marrow suppression].
(2) Patients with abnormal renal function [may aggravate adverse reactions such as myelosuppression due to increased blood concentrations of 5-FU when urinary excretion of gimeprazine, a 5-FU catabolic enzyme inhibitor, is significantly reduced (see [Pharmacokinetics] for details)].
(3) Patients with abnormal liver function [may aggravate abnormal liver function].
(4) Patients with infectious diseases [infectious diseases may be exacerbated by myelosuppression].
(5) Patients with abnormal glucose tolerance [may exacerbate abnormal glucose tolerance].
(6) Patients with a history of interstitial pneumonia or interstitial pneumonia [may lead to exacerbation or progression of symptoms].
(7) Patients with a history of heart disease or cardiac disease [may exacerbate symptoms].
(8) Patients with peptic ulcers or bleeding [may aggravate symptoms].
(9) Elderly patients (see [Geriatric Use] for details).
2. Important Precautions.
(1) If other fluorouracil-based antineoplastic agents or fluorocytosine antifungal agents are required after discontinuation of Tegeo capsules, there must be a minimum 7-day washout period (see [Drug Interactions] for details).
(2) After discontinuation of other fluorouracil-based antineoplastic agents or fluorocytosine antifungal agents, there must be an appropriate elution period if tegeo capsules are used, taking into account the effects of the previous drug (see [Drug Interactions] for details).
(3) There are reports of severe hematopoietic dysfunction when fluorouracil analogs are combined with the antiviral drugs solifudine or brovudine, which may endanger the patient’s life. Therefore, do not use in combination with solifudine and its structural analogues. After discontinuation of solifudine and its structural analogues, a minimum elution period of 56 days must be allowed before using tegeo capsules, taking into account the effects of the previous drug (see [Drug Interactions] for details).
(4) Cases of severe infectious disease (sepsis) produced by myelosuppression resulting in patient death due to infectious shock and disseminated intravascular coagulation have been reported; therefore, special care should be taken to avoid the development or exacerbation of infection or bleeding tendencies.
(5) Use in pregnant women requires consideration of potential gonadal effects.
(6) This product may initiate or aggravate interstitial pneumonia, which can be fatal in severe cases. Therefore, before administration of Tegeo capsules, the patient should be examined to determine if he/she has interstitial pneumonia. Patients should be closely observed for breathing, cough and presence of fever during administration, and a chest X-ray should be performed. If abnormalities are found, the drug should be discontinued immediately and appropriate measures should be taken. Patients with non-small cell lung cancer are more likely to develop lung diseases such as interstitial pneumonia than patients with other cancers (see [Adverse Reactions] for details).
(7) Use of this product in patients who are hepatitis B virus carriers, or HBs antigen negative HBc antibody positive, or HBs antigen negative HBs antibody positive, may induce hepatitis caused by resurrection of hepatitis B virus. Confirmation of hepatitis virus infection should be made prior to administration of this product and appropriate measures should be taken prior to administration. Continue to monitor liver function or hepatitis virus markers after starting this product and watch for signs and symptoms of hepatitis B virus reanimation.
[For pregnant and lactating women].
Pregnancy.
Tegeo capsules are contraindicated in pregnant women. [There have been reports of neonatal malformations in pregnant women following administration of uracil tegafur tablets (UFT). In addition, teratogenic effects have been found in animal studies (fetal visceral abnormalities, skeletal abnormalities and delayed ossification were found in pregnant rats and rabbits following continuous oral administration of Tegeo capsules (equivalent to 7 mg/kg and 1.5 mg/kg of tegafur))]. If pregnancy occurs while taking the drug, use of the product should be discontinued and the potential risk to the fetus must be explained to the patient. Genetic counseling may be considered.
Lactation.
Lactating women should discontinue breastfeeding while taking Tegeo capsules. It is not known whether tegeo and its metabolites are secreted in human milk; animal pharmacodynamic/toxicological data suggest that tegeo and its metabolites can be secreted into breast milk. The risk of this product to the newborn/infant cannot be excluded. Breastfeeding should be discontinued during treatment with this product.
Fertility.
There are no data on the effect of this product in combination with cisplatin on human fertility. Non-clinical studies have shown no effect of this product on fertility in male and female rats.
Contraception.
Pregnancy should be avoided in women of childbearing age during treatment with this product.
Contraception should be used in both male and female patients during and for 6 months after discontinuation of the drug.
[Pediatric Use].
The safety of tegeo capsules in low birth weight infants, newborns, infants, young children and children has not been demonstrated [No clinical information is available. If Tegeo Capsules must be used in children, the effects on the gonads should be considered, with special attention to the occurrence of adverse reactions].
Geriatric use]
Due to the reduced physiological function of the elderly, this drug should be used with caution.
Drug Interactions
(1) Contraindications to drug combination (this product should not be used in combination with the following drugs)
Drug signs, symptoms and management mechanisms and risk factors Fluorouracil-based antineoplastic agents: 5-FU, UFT, tegafur, deoxyfluridine, capecitabine, carmofur; folinic acid + UFT combination therapy, levulinic acid + fluorouracil combination therapy Combination of these drugs (therapy) can lead to severe hematopoietic abnormalities and gastrointestinal reactions such as diarrhea and stomatitis in the early stage. These drugs should not be taken for at least 7 days after discontinuation of Tegeo capsules. If such drugs have been used before, an appropriate washout period is required before Tegeo capsules are started to be administered in order to avoid their effects. Gimepyrimidine contained in Tegeo capsules inhibits the catabolism of combined fluorouracil or fluorouracil produced by this class of drugs, resulting in a significant increase in fluorouracil blood levels (see [Pharmacokinetics] for details). Fluorouracil-based antifungal drugs: Fluorouracil solifudine and its structural analogs such as bromovudine have been found to cause severe hematopoietic dysfunction when combined with fluorouracil-based drugs and the antiviral drug solifudine or its structural analogs such as bromovudine, which may be life-threatening in some patients. Tegeo should not be used concurrently with solifudine or brovudine and should not be used within 4 weeks of the last use of solifudine or brovudine. The metabolite of solifudine and bromovudine, bromovinyluracil (BVU), irreversibly inhibits dihydropyrimidine dehydrogenase, resulting in increased blood levels of 5-FU, a metabolite of tegeo capsules, in the body. (2) Precautions for co-administration (Caution is required when this product is combined with the following drugs)
Drug signs, symptoms and management mechanisms and risk factors Phenytoin toxicity (nausea, vomiting, nystagmus and abnormal movements) may occur with phenytoin, and the general condition of the patient should be closely observed. If abnormalities are detected, appropriate measures such as discontinuation of the drug must be taken. Tegafur may inhibit the metabolism of phenytoin, which may lead to an increase in phenytoin blood levels. Potassium warfarin may enhance the effect of potassium warfarin, and changes in coagulation should be noted. The mechanism of action is unknown. Tipiracil may cause severe myelosuppression and other side effects when used in combination with this product, which may enhance the reverse transcription of DNA by Tipiracil.
Tipiracil hydrochloride affects the metabolism of this product by blocking thymidine phosphorylase. Other antineoplastic agents or radiation therapy may aggravate adverse reactions such as abnormal hematopoietic function and gastrointestinal reactions, and the patient’s condition must be closely monitored and appropriate measures such as dose reduction or discontinuation must be taken if abnormalities are detected. The adverse reactions are aggravated by each other.
Drug overdose]
The highest single dose ever observed was 1400 mg; the patient developed leukopenia (grade 3). Acute adverse reactions to overdose have been reported including: nausea, vomiting, diarrhea, oral mucositis, gastrointestinal irritation, hemorrhage, bone marrow depression, and respiratory failure. The proper medical treatment following an overdose should include conventional and supportive therapy aimed at correcting the clinical adverse reactions that have occurred and preventing possible complications.
There is no antidote for overdose.
Pharmacology and Toxicology
Pharmacological effects
Tegeo inhibits tumor growth in subcutaneous transplantation nude mouse models of human gastric, colorectal, breast, lung, pancreatic and kidney cancer cell lines, inhibits tumor growth in in situ transplantation nude mouse models of human gastric and colorectal cancer cell lines, and prolongs survival time in Lewis lung cancer and L5178Y metastasis models in mice.
Tegeo is composed of tegafur (FT), gimeprazine (CDHP) and otelacil potassium (Oxo). The mechanism of action is as follows: FT is gradually converted to 5-fluorouracil (5-FU) in vivo after oral administration. CDHP selectively and reversibly inhibits DPD, a 5-FU catabolic enzyme present in the liver, thereby increasing the concentration of 5-FU from FT. Oxo is distributed in the gastrointestinal tract after oral administration and selectively and reversibly inhibits orotate phosphoribosyltransferase, thereby selectively inhibiting the conversion of 5-FU to 5-fluoronucleotide, thereby reducing the anti-tumor activity of 5-FU without affecting the gastrointestinal tract. It can selectively inhibit the conversion of 5-FU to 5-fluoronucleotide, thus reducing the toxic side effects in the gastrointestinal tract without affecting the anti-tumor activity of 5-FU.
The main mechanism of action of 5-FU is the competitive binding of its active metabolites, FdUMP and dUMP, to thymine nucleotide synthase, along with the formation of trimers with reduced folic acid, thereby inhibiting DNA synthesis. In addition, 5-FU is converted to FUTP and integrated into RNA molecules, thereby disrupting RNA function.
Toxicological studies
General toxicity: Toxic reactions in rats, dogs and monkeys following repeated administration of anticancer drugs have been associated with toxic effects on rapidly dividing cells, such as anemia, decreased immune and digestive function, impaired spermatogenesis, and atrophy of male and female reproductive organs.
Tegeo has produced multiple dermal adverse reactions in rats (footpad and tail keratosis) and dogs (skin crusting and erosion). In addition, hyperpigmentation of the skin and eyes and corneal clouding were seen in dogs following repeated dosing; cataracts were seen in rats following repeated dosing. These changes are reversible.
Reproductive toxicity: No adverse effects of tegeo on fertility were seen in male and female rats. Fetal visceral abnormalities, skeletal abnormalities and delayed ossification were seen in pregnant rats and rabbits given tegeo orally (equivalent to tegafur 7 mg/kg and 1.5 mg/kg). The high risk of developmental toxicity at clinical doses was mainly due to the toxicity of tegafur (5-FU), while Oxo had a lesser effect.
Genotoxicity: Tegeo was negative in the revertant mutation test. Tegeo induced chromosomal mutations in Chinese hamster lung cells treated for 48 h. Its component Oxo induced mutations on CHL chromosomes, while CDHP did not. Tegeo caused slight chromosome breakage in mouse bone marrow cells in vivo.
Pharmacokinetics
1.Pharmacokinetics
(1) Blood concentration.
The pharmacokinetic parameters of 12 tumor patients after a single oral dose of tegeo capsules 32-40mg/m2 after meals are shown in the table below. 52.8% of gimepyrimidine (CDHP), 7.8% of tegafur (FT), 2.2% of potassium octreotide (Oxo), 11.4% of the metabolite cyanuric acid (CA) and 7.4% of fluorouracil (5-FU) were excreted from the urine within 72 hours of dosing.
Table 1 Pharmacokinetic parameters of oral tegeo capsules in 12 tumor patients (n = 12, mean ± SD)
Cmax (ng/ml)Tmax (hr)AUC (0-48h) (ng – hr/ml)T1/2 (hr)Tegafur 1971.0±269.02.4±1.228216.9±7771.413.1±3.15-FU128.5±41.53.5±1.7723.9±272.71.9±0.4 Gimeprazine 284.6±116.62.1±1.21372.2±573.73.0±0.5 Otiracetam potassium 78.0±58.22.3±1.1365.7±248.63.0±1.4 CA117.9±184.43.4±1.0892.0±1711.73.8±1.6 Tegeo capsules 25 to A dose-dependent increase in AUC and Cmax of FT, CDHP, Oxo and 5-FU was seen after oral administration of 200 mg/person. Oral administration of Tegeo capsules 32-40 mg/m2 twice daily for 28 consecutive days and blood concentrations were measured on days 1, 7, 14 and 28 of administration, respectively, and showed that blood concentrations rapidly reached steady-state levels. Even after the end of continuous administration, endogenous uracil decreased rapidly, suggesting that the DPD inhibitory effect of CDHP was reversible and no potentiation was observed.
(2) In the clinical pharmacology, pancreatic cancer and bile duct cancer trials, the pharmacokinetic indexes of the patients were examined in detail, and their creatinine clearance (Ccr estimation) was calculated using the Cockcroft-Gault formula according to their serum creatinine values, gender, age and body weight, according to which they were divided into groups with normal renal function and groups with mildly abnormal renal function, and their AUCs were calculated as shown in Table 2 below.
Table 2 AUC values (mean ± SD) for each group after oral administration of Tegeo capsules in patients with different renal functions
Ccr estimate AUC (0-8hr)>80mL/min
(n=17) 50-80 mL/min
(n=11)FT10060±184211320±27175-FU541.2±174.8812.4±244.9CDHP977.8±327.91278.0±306.6Oxo155.7±97.5458.2±239.7
2.Protein binding rate
In vitro tests showed that the human serum protein binding rates of FT, CDHP, Oxo and 5-FU were 49% to 56%, 32% to 33%, 7% to 10% and 17% to 20%, respectively.
3.Metabolic enzymes
In vitro tests show that the enzyme involved in the conversion of FT to 5-FU is mainly CYP2A6 in human liver microsomal cytochrome P450 isoenzymes.
Storage】Sealed and stored at room temperature.
Package】Polyvinyl chloride solid pharmaceutical hard tablets and pharmaceutical aluminum foil.
(1) 20mg specification (according to tegafur): 6 capsules/plate, 7 capsules/plate, 14 capsules/plate; 12 capsules/box, 14 capsules/box, 28 capsules/box, 30 capsules/box, 42 capsules/box, 56 capsules/box, 84 capsules/box.
(2) 25mg specification (according to tegafur): 6 capsules/plate, 7 capsules/plate, 14 capsules/plate; 12 capsules/box, 14 capsules/box, 28 capsules/box, 30 capsules/box, 42 capsules/box.
【Validity】18 months
【Execution standard
【Approval number】.
(1) 20mg specification (according to tegafur): State Drug Administration H20100150
(2) 25mg specification (according to Tegafur): State medicine quanzhi H20100151
Manufacturer
Company name: Qilu Pharmaceutical Co.
Production Address: No. 8888, Tourism Road, High-tech Zone, Jinan City
Zip code: 250100
Telephone number: (0531) 83126000/83126111/83126333/83126548
Fax number: (0531) 83126288/83126545
Web address: http://www.qilu-pharma.com