ティッジオカプセル
適応症
切除できない局所進行または転移性胃がん。
臨床薬理学
1.抗腫瘍効果Tiggioは、ヌードマウス（ラットおよびマウス）に移植されたヒト胃癌、結腸直腸癌、乳癌、肺癌、膵臓癌、腎癌の成長を阻害し、マウスのルイス肺癌およびL5178Y転移を延長します。モデルの生存時間。 2.作用機序Tiggioカプセルは、テガフール（FT）、ゲムシタビン（CDHP）、およびオキシラチンカリウム（オキソ）で構成されています。その作用機序は次のとおりです。経口投与後、体内でFTは徐々に5-フルオロウラシル（5-FU）に変換されます。 CDHPは、肝臓に存在する5-FU異化酵素DPDを選択的に可逆的に阻害し、それによってFTからの5-FUの濃度が増加します。体内の5-FU濃度の増加に伴い、腫瘍組織の5-FUリン酸化産物5-フルオロヌクレオチドは高濃度を維持することができ、それにより抗腫瘍効果が強化されます。オキソは経口投与後に胃腸管に分布し、オロチン酸ホスホリボシルトランスフェラーゼを選択的に可逆的に阻害し、それによって5-FUの5-フルオロヌクレオチドへの変換を選択的に阻害し、それにより5-FUの抗腫瘍活性に影響を与えません。胃腸の副作用を減らします。 5-FUの作用の主なメカニズムは、その活性代謝産物FdUMPおよびdUMPによりチミジンシンターゼに競合的に結合し、葉酸が減少した三量体を形成し、それによってDNA合成を阻害することです。さらに、5-FUはFUTPに変換され、RNA分子に組み込まれるため、RNA機能が破壊されます。
使用法と投与量
局所進行または転移性胃癌の切除不能患者の治療のためのシスプラチンと組み合わせたTiggioカプセル...（説明書を参照）
処方
カプセル
仕様書
（1）20 mgの仕様：テガフール20 mg、ゲムシタビン5.8 mg、オルチプラズカリウム19.6 mg。
（2）25 mgの仕様：テガフール25 mg、ゲムシタビン7.25 mg、オルチプラズカリウム24.5 mg。
取扱説明書
承認日2008年12月19日
変更日1）2010年1月12日
2）2010年2月1日
3）2011年7月18日
ティッジオカプセルの指示
指示を注意深く読み、医師の指導の下で使用してください。
[警告]
1.この薬は、Tiggioカプセルを使用する必要があるがん患者にのみ使用できます。患者は応急処置施設のある病院で、がん化学療法の豊富な経験を持つ医師の指導の下で診察を受ける必要があります。 Teggioカプセルを含む化学療法レジメンの使用を決定する前に、すべての併用薬の指示をお読みください。化学療法を開始する前に、患者の有効性とリスクについて詳細に説明し、患者または保護者のインフォームドコンセントを得る必要があります。
2.従来の経口フルオロウラシルとは異なり、Tiggioカプセルの用量制限毒性（DLT）は骨髄抑制です（詳細については[有害反応]を参照）臨床検査を頻繁に実施し、結果を注意深く観察する必要があります。
3.この薬は劇症肝炎などの重度の肝機能障害を引き起こす可能性があります。食欲不振などの症状とともに早期の肝機能障害または疲労が見つかった場合は、注意深く観察する必要があります。黄und（強膜黄色の染色）が見つかった場合は、すぐに薬物を停止し、適切な措置を講じてください。
4.この薬は、他のフルオロウラシル抗腫瘍薬、フルオロウラシルベースの化学療法レジメン[ロイコボリン/テガフール-ウラシル（UFT）併用化学療法など]、抗真菌薬フルオロシトシンなどと併用しないでください。重度の造血機能障害などの有害反応を引き起こす（[薬物相互作用]を参照）。
5.この薬は、重度の造血機能不全などの副作用を引き起こす可能性のあるセリフジンやブロブジンなどの抗ウイルス薬と併用しないでください。一部の患者は生命を脅かす可能性があります（詳細については[薬物相互作用]を参照）。
6.この薬を使用する前にこのマニュアルを注意深く読み、[使用法および用法]の規則を厳守してください。
[薬の名前]
一般名：Tiggio Capsules
製品名：ウェイカンダ
英語名：Tegafur, Gimeracil and Oteracil Potassium Capsules
中国語ピンイン：Tiji'ao Jiaonang
[成分]この製品は化合物製剤であり、主成分はテガフール、ゲムシタビン、およびエチラシルカリウムです。
【特性】本製品は硬いカプセルで、その内容は白色またはオフホワイトの粒子または粉末です。
[効能]除去できない局所進行または転移胃癌。
[仕様]（1）20 mgの仕様：テガフール20 mg、ゲムシタビン5.8 mg、オルチプラズカリウム19.6 mg。
（2）25 mgの仕様：テガフール25 mg、ゲムシタビン7.25 mg、オルチプラズカリウム24.5 mg。
[用法・用量]
シスプラチンと組み合わせたTiggioカプセルは、局所進行または転移性胃癌の切除不能患者の治療に使用されます。
一般に、成人の最初の投与量は、次の表に従って体表面積に応じて決定されます。 使用法は1日2回、朝食と夕食後に経口、28日間の連続投与、14日間の休息、治療サイクルです。 患者の状態が悪化するか耐えられなくなるまで投与する。
体表面積（㎡） | 最初の用量（テガフールに基づく） |
＜1.25 | 毎回40mg |
≥1.25~＜1.5 | 毎回50mg |
≥1.5 | 毎回60mg |
投与量は、患者の状態に応じて増減できます。 各用量は、40 mg、50 mg、60 mg、75 mgの4つの用量レベルで順次増減されます。 臨床検査（血液ルーチン、肝機能、腎機能）の安全性とこの薬によって引き起こされる胃腸症状が見られず、医師が増分を増やす必要があると判断した場合、上記の順序、上限に従って用量レベルを追加できます 75 mg /時間です。 量を減らす必要がある場合は、用量レベルに応じて減らされ、下限は40mg /時間です。 21日間の連続経口投与、14日間の休息、および1治療サイクルの投与8日目にシスプラチン60mg / m 2の静脈内注入。 患者の状態が悪化するか耐えられなくなるまで投与する。
使用法と使用上の注意：
患者の状態に応じて、投与量は次の基準に従って増減できます。また、増加量は各サイクルで1つの投与量レベルを超えてはなりません。
削減 | 初回投与 | インクリメント |
薬を止める | 毎回40mg | 毎回50mg |
薬を止める ← 毎回40mg | 毎回50mg | 毎回60mg |
薬を止める ← 毎回40mg←毎回50mg | 毎回60mg | 毎回75mg |
2.化学療法の間隔を短くする必要がある場合は、この薬によって引き起こされる臨床検査（血液ルーチン、肝機能、腎機能）および胃腸症状の安全性を確認する必要がありますが、化学療法の間隔は7日以上でなければなりません。手術不能または再発した乳がん患者の化学療法間隔を短くすることの安全性は確認されていません（臨床経験なし）。
3.骨髄抑制や劇症肝炎などの重篤な副作用を避けるために、化学療法を開始する前に臨床検査（血液ルーチンおよび肝臓と腎臓の機能）を実行し、患者の状態を徹底的に観察する必要があります。化学療法中に少なくとも2週間に1回、検査を1回行う必要があります。 。異常が見つかった場合は、化学療法の間隔を延ばす、上記の規制に従って薬剤を減らす、または停止するなど、適切な対策を講じる必要があります。綿密な観察と検査は、最初の治療サイクルまたは増分で実施する必要があります（詳細については、[臨床試験]を参照）。
4.基礎研究（ラット）により、空腹時薬物はオルチプラズカリウムの生物学的利用能を変化させ、フルオロウラシルリン酸化の阻害につながり、それによって薬物の抗腫瘍効果が低下するため、食後に服用する必要があることがわかりました。
患者の使用上の注意：
患者は薬に注意を払う必要があります。
この薬は、アルミニウムプラスチックブリスターパック（PTP）です。薬を服用する前に、薬をブリスターから押し出すように患者に知らせる必要があります。患者が誤ってアルミホイルパネルを取り、食道の穿孔を引き起こし、縦隔炎などの深刻な合併症を引き起こすことが報告されています。
【副作用】
まず、外国の臨床試験：
併用療法
日本で進行した胃癌患者の場合、Teggioカプセルの単剤（40-60 mg /回の経口Teggioカプセルの連続28日間、1日2回、14日間の休息）とTiglioカプセルとシスプラチンの併用を比較する（40から60 mg /回、1日2回、8日目に60 mg / m2シスプラチンの経口Teggioカプセルの複数の第III相ランダム化比較試験）、および副作用のある298人の患者を評価しました。副作用を下の表に示します。
副作用 | 発生率 | |
単剤グループ (n=150) | 併用治療グループ (n=148) | |
白血球減少症 (CTC ≥ 3 学位) | 38%（2%） | 70%（11%） |
好中球の減少 (CTC ≥ 3 学位) | 42%（11%） | 74%（40%） |
貧血 (CTC ≥ 3 学位) | 33%（4%） | 68%（26%） |
血小板減少症 (CTC ≥ 3 学位) | 18%（0%） | 49%（5%） |
食欲不振 (CTC ≥ 3 学位) | 37%（6%） | 72%（30%） |
嫌な (CTC ≥ 3 学位) | 26%（1%） | 67%（11%） |
嘔吐 (CTC ≥ 3 学位) | 14%（2%） | 36%（4%） |
口内炎 (CTC ≥ 3 学位) | 21%（0%） | 29%（0.7%） |
下痢 (CTC ≥ 3 学位) | 23%（3%） | 34%（4%） |
弱い (CTC ≥ 3 学位) | 33%（1%） | 57%（4%） |
色素沈着 (CTC ≥ 3 学位) | 40%（0%） | 36%（0%） |
発疹 (CTC ≥ 3 学位) | 19%（1%） | 22%（2%） |
涙 (CTC ≥ 3 学位) | 16%（0.7%） | 18%（0%） |
In the late phase II clinical trial of non-small cell lung cancer combined with chemotherapy (21 days of oral Teggio capsules, 60 mg/m2 cisplatin on day 8), 55 patients with adverse reactions were found to have adverse reactions, the main adverse The reaction is shown in the table below.
副作用 | Combination therapy |
Non-small cell lung cancer patients (55 cases) | |
Incidence rate (CTC ≥ 3 degrees)＃4 | 100.0%（61.8%） |
Leukopenia（〈2000/mm³） | 52.7%（5.5%） |
Neutrophil reduction（〈1000/mm³） | 65.5%（29.1%） |
Hemoglobin reduction（〈8g/dl） | 90.9%（21.8%） |
Thrombocytopenia（〈5×104/mm³） | 60.0%（1.8%） |
AST increase (GOT) | 14.5% |
ALT increase (GPT) | 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% |
Pigmentation | 23.6% |
Rash | 9.1% |
#4: Graded according to the American Cancer Institute's Common Toxicity Judging Criteria.
2. Monotherapy
Among the 578 patients who were able to assess adverse events (excluding the following previously treated breast, pancreatic, and cholangiocarcinoma patients), the incidence of adverse events was 87.2% (504 patients). Compared with other types of tumors, the incidence of adverse reactions in patients with inoperable or recurrent breast cancer, pancreatic cancer, and cholangiocarcinoma who had been treated with paclitaxel was higher, 96.4%, 98.3%, and 94.9%, respectively. Pancreatic cancer patients have a higher incidence of adverse reactions, especially gastrointestinal reactions such as loss of appetite, nausea, vomiting and diarrhea. When using a single drug, the following adverse reactions are common:
Adverse reactions | Monotherapy | ||||
All patients (578 cases)＃1 | Previously treated breast cancer patients (55 cases) | Pancreatic cancer patients (59 cases) | Patients with cholangiocarcinoma (59 cases) | ||
＃1 | Gastric cancer patients (134 cases) | ||||
Incidence rate （CTC≥3 degree）＃2 | 87.2%（22.5%） | 77.6%（20.9%） | 96.4%（30.9%） | 98.3%（42.4%） | 90.4%（30.5%） |
Leukopenia（〈2000/mm³） | 45.8%（2.8%） | 48.5%（3.7%） | 69.1%（9.1%） | 32.2%（0%） | 49.2%（3.4%） |
Neutrophil reduction（〈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%） | 45.9%（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%） |
AST increase (GPT) | 11.1% | 4.5% | 34.5% | 18.6% | 37.3% |
ALT increase (GPT) | 11.1% | 3.7% | 29.1% | 16.9% | 27.1% |
#1: Includes phase II multicenter registration clinical trials for gastric cancer, colorectal cancer, non-small cell lung cancer, head and neck cancer, and breast cancer in Japan; excluding patients with previously treated breast, pancreatic, and cholangiocarcinoma;
#2: Use the American Toxicological Institute's Common Toxicity Judging Criteria or the Japanese Society of Clinical Oncology's classification;
#3: Includes fatigue.
3. The occurrence time and recovery time of adverse reactions
Analysis of 453 patients with gastric cancer, colorectal cancer, head and neck cancer, non-small cell lung cancer (monotherapy), inoperable or recurrent breast cancer, pancreatic cancer, and cholangiocarcinoma in the late phase II clinical trial The reaction occurs, and the results are as follows:
The median time required from the start of administration to the white blood cell count <3000/mm3, the lowest value of hemoglobin <8g/dL, platelet count <7.5×104/mm3 was 27 days, 25 days and 24 days, respectively. The median time required to confirm recovery to the above criteria was 7 days, 5.5 days, and 6 days, respectively.
Abnormal laboratory test value | Number of occurrences | Time to the lowest value: median (range) | Number of recovery cases | Time 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 values of the adverse reactions such as diarrhea, rash and stomatitis associated with this drug from the first administration to the time of adverse reactions were 24.5 days, 21 days and 28 days, respectively; the above adverse reactions were from the most serious level to recovery. The median time required for normal is 9 days, 14 days, and 13.5 days, respectively.
Symptom | Number of occurrences | Time required to occur: median (range) | Number of recovery cases | Recovery time: 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 application of drugs (gastric cancer) within 1 year after the listing of foreign products is grouped according to the creatinine clearance rate (Ccr estimate) calculated by Cockcroft-Gault formula according to gender, age, body weight, serum creatinine value, etc. The incidence of adverse reactions is as follows: Shown. The incidence of adverse reactions increased with the decrease of creatinine clearance rate, and the severity of adverse reactions increased. Patients with lower doses (one grade lower than the standard dose) had a lower incidence of adverse events than patients who received the standard dose for the first dose.
Ccr estimate | The first dose is a standard dose of the patient | Patients with lower initial dose | ||
Adverse reaction rate | The incidence of serious adverse reactions (3 degrees or more) | Adverse reaction rate | The incidence of serious adverse reactions (3 degrees or more) | |
＜30 | 85.0% （17/20） | 65.0% （13/20） | 82.4% （14/17） | 35.3% （6/17） |
≥30~＜50 | 84.1% （307/365） | 36.4% （133/365） | 76.0% （117/154） | 29.9% （46/154） |
≥50~＜80 | 77.1% （1037/1345） | 25.9% （349/1345） | 66.1% （285/431） | 20.9% （90/431） |
≥80 | 72.5% （764/1054） | 20.4% （215/1054） | 64.7% （205/317） | 19.9% （63/317） |
Cockcroft-Gault：
male：
(140-age)×body weight（kg）
Ccr=——————————————
72×Serum creatinine（mg/dL）
female：
（140-age）×body weight（kg）×0.85
Ccr=————————————————
72×Serum creatinine（mg/dL）
5. Important adverse reactions
1) Myelosuppression, hemolytic anemia: may cause severe myelosuppression such as whole blood cell reduction, neutropenia (symptoms: fever, sore throat and general malaise), leukopenia, anemia and thrombocytopenia (incidence rate as above) and hemolytic anemia (The incidence is unknown) and must be closely observed. If an abnormality is found, necessary measures such as stopping the drug must be taken.
2) Disseminated intravascular coagulation (DIC): Due to the possibility of DIC (0.4%), patients should be closely monitored. If hematological examinations such as platelet count, serum FDP, and plasma fibrinogen are found to be abnormal, the drug must be discontinued and necessary measures taken.
3) Severe liver dysfunction such as fulminant hepatitis (incidence rate is unknown) (see [Warning] for details).
4) Dehydration: Dehydration may occur due to severe diarrhea (incidence is unknown) and should be closely observed. If abnormalities are found, the drug should be stopped and appropriate measures such as rehydration should be taken.
5) Severe enteritis: severe enteritis (0.5%) may occur and should be closely observed. If you have severe abdominal pain, diarrhea and other symptoms, you should stop taking the drug and take appropriate measures.
6) Interstitial pneumonia*: Interstitial pneumonia may occur (0.3%) (early symptoms: cough, shortness of breath, difficulty breathing, and fever) and should be closely observed. If an abnormality is found, the drug should be discontinued and chest X-ray and adrenocortical hormone administered.
7) Severe stomatitis, digestive tract ulcers, gastrointestinal bleeding and digestive tract perforation: severe stomatitis (unknown incidence), digestive ulcer (0.5%), gastrointestinal bleeding (0.3%) and digestive tract perforation may occur ( The incidence is unknown) and must be closely observed. If abnormalities are found, the drug should be stopped, and abdominal X-ray examination should be performed as needed, and appropriate measures should be taken.
8) Acute renal failure: Serious kidney disease such as acute renal failure (incidental rate) may occur and should be closely observed. If abnormalities are found, stop the drug and take appropriate measures.
9) Steven-Johnson syndrome and toxic epidermal necrosis (Lyell syndrome): Steven-Johnson syndrome and toxic epidermal necrosis may occur (incidence is unknown) and should be closely observed. If abnormalities are found, stop the drug and take appropriate measures.
10) abnormalities of the neuropsychiatric system such as leukoencephalopathy: leukoencephalopathy may occur (main symptoms are disturbance of consciousness, cerebellar ataxia and dementia-like symptoms), disturbance of consciousness, disorientation, lethargy, memory loss, extrapyramidal symptoms , language barriers, quadriplegia, gait disturbances, urinary incontinence or sensory disturbances (incidental rates are unknown) should be closely observed. If the above symptoms occur, you should stop taking the medicine.
11) Acute pancreatitis: Acute pancreatitis may occur (incidence rate is unknown) and should be closely observed. If abdominal pain or elevated serum amylase is present, discontinue the drug and take appropriate action.
12) Rhabdomyolysis: Rhabdomyolysis may occur (unexpected incidence), symptoms include muscle pain, weakness, elevated CK, and elevated blood/urinary myoglobin. Stop the drug and take appropriate measures, and take care to prevent rhabdomyolysis. Caused by acute renal failure.
13) Loss of olfactory: olfactory disturbance (0.1%), olfactory loss (unexplained rate) may occur, and close observation is required. If abnormalities are found, stop the drug and take appropriate measures.
* Studies of the incidence of interstitial pneumonia and other lung diseases in patients with non-small cell lung cancer.
Drug use in non-small cell lung cancer after drug marketing showed an incidence of interstitial pneumonia of 0.7% (11/1669), and the incidence of other lung diseases including radiation pneumonitis, dyspnea, and respiratory failure was 0.7% (12/). 1669).
6. Other adverse reactions
The following adverse reactions may occur. If abnormalities are found, appropriate measures such as reduction or withdrawal should be taken. If the drug is allergic, stop the drug and take appropriate measures. The incidence of hand-foot syndrome was higher in previously treated breast cancer patients (21.8%). The clinical study of the drug after the market found that the incidence of tears in patients with gastric cancer who could not be resected or relapsed was higher (16.0%).
Classification Incidence rate | Incidence rate≥5% | 0.1%≤Incidence rate＜5% | Incidence is unknown |
Hematology | Leukopenia, neutropenia, thrombocytopenia, red blood cell reduction, hemoglobin reduction, decreased hematocrit, lymphopenia | Hemorrhagic tendency (subcutaneous hemorrhage, nasal discharge, abnormal blood coagulation factors, eosinophilia, leukocytosis) | |
Liver | Increased AST (GOT), elevated ALT (GPT), elevated bilirubin, elevated ALP | Astragalus, urinary biliary positive |
The above incidence rate is calculated based on the results of the single drug clinical trial before the product is approved.
7, adverse reactions precautions
(1) Patients with treatment with Tiggio capsules have been reported to have acute leukemia (individual cases with pre-leukemia) or myelodysplastic syndrome (MDS).
(2) A very small number of patients lack the fluorouracil-metabolizing enzyme dihydropyrimidine dehydrogenase (DPD). If fluorouracil is used, serious adverse reactions (such as stomatitis, diarrhea, hematopoietic dysfunction, and nerves may occur at the initial stage of administration). Systemic disease).
(3) A cerebral infarction has been found, but the causal relationship with the Tiggio capsule is not certain.
(4) Potassium oltipraz is easily decomposed in a strong acid environment (canine), while the decrease in the concentration of oltipraz potassium can reduce its inhibitory effect on the digestive tract (rat), so the pH of the stomach is significantly reduced. May cause diarrhea.
(5) After the repeated administration of the dog, the conjunctival sclera pigmentation and corneal cloud were found.
Second, domestic clinical trials:
The results showed that the incidence of adverse reactions related to this product was 83.78%, mainly 68.47% of the blood system (the incidence of leukopenia was 45.05%, the incidence of thrombocytopenia was 20.72%, mostly decreased by I and II degrees) The digestive system was 46.85% (nausea, vomiting 39.64%, diarrhea 7.21%), and the other 14.41%. The adverse reactions of the blood system of this product are equivalent to tegafur, but its digestive tract reaction is significantly better than tegafur.
The incidence of adverse events related to this product was 2.70%, mainly due to mild gastrointestinal bleeding, red blood cell reduction, and the incidence was lower than tegafur (3.48%).
【taboo】
1. Disabled for patients with a history of severe allergies to the composition of the Tiglio capsule.
2. Patients with severe myelosuppression are banned (may increase myelosuppression).
3. Patients with severe renal dysfunction are banned [As a result of 5-FU catabolic enzyme inhibitor-giramin, a significant decrease in urinary excretion may lead to an increase in the blood concentration of 5-FU, thereby aggravating adverse reactions such as myelosuppression (see 【Pharmacokinetics】).
4. Patients with severe liver dysfunction are banned (may exacerbate liver dysfunction).
5. Patients who are receiving other fluorouracil antineoplastic agents (including combination therapy) are banned (see [Drug Interactions] for details).
6. Patients who are receiving flucytosine therapy are banned (see [Drug Interactions] for details).
7. Patients who are receiving treatment with solfivudine and its structural analogues (bromofudine) are banned (see [Drug Interactions] for details).
8. Prohibition of pregnancy or possible pregnancy (see [Pregnant women and lactating women]].
【Precautions】
1. Use with caution [The following patients should use Tegio capsules with caution]
(1) Patients with myelosuppression [may increase myelosuppression];
(2) Patients with abnormal renal function [Because of the 5-FU catabolic enzyme inhibitor - the decrease of urinary excretion of cytosine may cause an increase in the blood concentration of 5-FU, thereby aggravating adverse reactions such as myelosuppression (see [ Pharmacokinetics】);
(3) Patients with abnormal liver function [may increase liver function abnormalities];
(4) Patients with infectious diseases [Infectious diseases may be aggravated by myelosuppression];
(5) Patients with abnormal glucose tolerance [may increase the abnormal glucose tolerance];
(6) Patients with a history of interstitial pneumonia or interstitial pneumonia [may cause worsening of symptoms or progression of the disease];
(7) Patients with a history of heart disease or heart disease [may aggravate symptoms];
(8) Patients with peptic ulcer or bleeding [may aggravate symptoms];
(9) elderly patients (see [Geriatric Use] for details).
2. Important considerations
(1) After stopping the drug, if you need to take other fluorouracil antitumor drugs or flucytosine antifungal drugs, you must have a washout period of at least 7 days (see [Drug Interactions] for details).
(2) After the other fluorouracil antineoplastic agents or fluorocytosine antifungal drugs are deactivated, taking into account the effects of previous drugs, such as the use of Tiggio capsules, there must be an appropriate elution period (see [Drug Interactions] for details] ).
(3) It has been reported that fluorouracils combined with the antiviral drug solifedine or brovudine can cause severe hematopoietic dysfunction and may endanger the lives of patients. So don't use it in combination with Solifudine and its structural analogues. After discontinuation of solifedine and its structural analogs, there must be at least a 56-day washout period prior to the use of the Tiggio capsules (see [Drug Interactions]), taking into account the effects of previous drugs.
(4) Cases of severe infectious diseases caused by myelosuppression (septicemia) have been reported to cause death due to septic shock and disseminated intravascular coagulation. Therefore, special attention should be paid to avoiding the occurrence or aggravation of infection or bleeding tendency. .
(5) The use of pregnant women needs to take into account the potential gonad effects.
(6) This product may cause or aggravate interstitial pneumonia, and severe cases may kill. Therefore, before giving the Tiggio capsule, the patient is examined to determine if there is interstitial pneumonia. During the administration, the patient should be closely observed for symptoms such as breathing, coughing, and fever, and a chest X-ray should be performed at the same time. If an abnormality is found, stop the drug immediately and take appropriate measures. Patients with non-small cell lung cancer are more likely to develop lung disease such as interstitial pneumonia than other cancer patients (see [Adverse Reactions] for details).
【Pregnant women and lactating women】
(1) Women who are pregnant or may have a pregnancy are banned from the Tiggio capsule. [Pregnant women have developed neonatal malformations after taking UFT. In addition, teratogenic effects have been found in animal studies (continuous oral tigeol capsules (equivalent to tegafur 7 mg/kg and 1.5 mg/kg) in pregnant rats and rabbits have found fetal visceral abnormalities, skeletal abnormalities and delayed ossification) ].
(2) Lactating women should stop breastfeeding when taking Tiggio capsules [There is no clinical data, but animals (rats) have found that Tiggio capsules can be excreted through milk].
【Children's medication】
The safety of tiggio capsules in low birth weight infants, newborns, infants, young children and children has not been validated [no clinical data available. If a child must use a Tiggio capsule, the effect on the gonad must be considered, with special attention to the occurrence of adverse reactions].
【Geriatric Use】 Due to the decline in the physiological function of the elderly, this drug should be used with caution.
【medicine interactions】
(1) Contraindications for the use of drugs (this product may not be combined with the following drugs)
Drug | Symptoms, signs and treatment | Mechanism and risk factors |
Fluorouracil antineoplastic agents: 5-FU, UFT, tegafur, deoxyfluorouridine, capecitabine, carmofur; leucovorin + UFT combination therapy, levo-folinate + fluorouracil combination therapy | The combination of this type of drug (therapy) can lead to severe hematopoietic dysfunction and gastrointestinal reactions such as diarrhea and stomatitis. Do not take these drugs for at least 7 days after stopping the Tiggio capsule. If such a drug has been used, in order to avoid its effects, an appropriate elution period must be available before the start of dosing of the Tiggio capsule. | The gemcitabine contained in the Tiggio capsule can inhibit the fluorouracil of the combined use or the catabolism of the fluorouracil produced by the drug, resulting in a significant increase in the concentration of fluorouracil (see [Pharmacokinetics] for details). |
Fluorouracil antifungal: flucytosine | ||
Solivudine and its structural analogues such as brovudine | Fluorouracils have been found to cause severe hematopoietic dysfunction when combined with the antiviral drug solifedine or its structural analogs such as brovudine, and some patients may be life threatening. | The bromo-vinyl uracil (BVU), a metabolite of solifedine and bromivudine, irreversibly inhibits dihydropyrimidine dehydrogenase, resulting in an increase in the plasma concentration of 5-FU, a metabolite of the Tiggio capsule in vivo. |
（2）Precautions for combined use (note that this product should be used together with the following drugs)
Drug | Symptoms, signs and treatment | Mechanism and risk factors |
Phenytoin | Phenytoin poisoning (nausea, vomiting, nystagmus, and motor abnormalities) may occur, and the general condition of the patient must be closely observed. If abnormalities are found, appropriate measures such as stopping the drug should be taken. | Tegafur inhibits the metabolism of phenytoin, which leads to an increase in the plasma concentration of phenytoin. |
Warfarin potassium | May enhance the role of warfarin potassium, pay attention to changes in coagulation function | The mechanism of action is unknown |
Other antineoplastic drugs or radiation therapy | It may aggravate adverse reactions such as hematopoietic dysfunction and gastrointestinal reactions. The patient's condition should be closely observed. If abnormalities are found, appropriate measures such as reduction or withdrawal should be taken. | Aggravate adverse reactions between each other. |
（2）Precautions for combined use (note that this product should be used together with the following drugs)
Drug | Symptoms, signs and treatment | Mechanism and risk factors |
Phenytoin | Phenytoin poisoning (nausea, vomiting, nystagmus, and motor abnormalities) may occur, and the general condition of the patient must be closely observed. If abnormalities are found, appropriate measures such as stopping the drug should be taken. | Tegafur inhibits the metabolism of phenytoin, which leads to an increase in the plasma concentration of phenytoin. |
Warfarin potassium | May enhance the role of warfarin potassium, pay attention to changes in coagulation function | The mechanism of action is unknown |
Other antineoplastic drugs or radiation therapy | It may aggravate adverse reactions such as hematopoietic dysfunction and gastrointestinal reactions. The patient's condition should be closely observed. If abnormalities are found, appropriate measures such as reduction or withdrawal should be taken. | Aggravate adverse reactions between each other. |
【Drug overdose】Once a drug overdose occurs, it should be closely monitored and supported and symptomatic. [Clinical trial] First, the results of foreign clinical trials
(1) combination therapy
SPIRITS test: In a case of 305 patients with advanced gastric cancer in Japan, compare the single drug of Teggio capsule (hereinafter referred to as the single drug group, oral Teggio capsule 40-60 mg/time for 28 consecutive days, 2 times a day, each 6 weeks of repeated) and Tiggio capsule combined with cisplatin treatment (hereinafter referred to as the combination treatment group, oral Teggio capsule 40 ~ 60mg / time for 21 consecutive days, 2 times a day, the eighth day of cisplatin 60mg / m2, each In a multicenter phase III randomized controlled trial of 5-week repeats, the primary endpoint was overall survival (OS) and the secondary outcome was progression-free survival (PFS) and tumor remission. The baseline characteristics of the patients in both groups were balanced and comparable. Among the 298 patients analyzed, the median survival time was 13 months and 11 months in the combination group (148 cases) and the single drug group (150 cases), respectively, and the Hazard ratio was 0.77 (95% confidence). Interval 0.61-0.98, Log-rank test p=0.04), combined treatment reduced the risk of death by approximately 23% compared with the single-agent group; the median PFS was 6 months and 4 months, respectively, and the Hazard ratio was 0.57. (95% confidence interval 0.44-0.73, Log-rank test p < 0.0001), compared with the control group, this product / cisplatin combined chemotherapy can reduce the risk of recurrence by about 43%. In addition, in 193 evaluable target lesions, the objective response rates were 54% (95% confidence interval 43-65%) and 31% (95% confidence interval 23-41%; Fisher) Test, p=0.002).
SC-101 trial: a randomized controlled multicenter clinical study involving 15 Chinese research centers. 230 patients with advanced gastric cancer were randomly assigned to the Teggio monotherapy group (hereinafter referred to as the monotherapy group, 80 patients, orally for 28 consecutive days). Tiggio capsule 40 ~ 60mg / time, 2 times a day, repeated every 6 weeks), Tiggio capsule combined with cisplatin group (hereinafter referred to as the combined treatment group, 76 cases, oral Tiogel capsule 40 ~ 60mg for 21 consecutive days) / time, 2 times a day, on the 8th day, cisplatin 60mg / m2, repeated every 5 weeks) and fluorouracil combined with cisplatin group (hereinafter referred to as the control group, 74 cases, fluorouracil 600mg / m2 / day intravenous infusion, cisplatin 20 mg/m 2 /day, intravenous infusion for 30 minutes, administration on days 1 to 5, repeated every 4 weeks). All patients need to be administered until the tumor progresses or is intolerable. Patients in the control group who failed treatment could continue to use the Teggio monotherapy for second-line treatment. The primary outcome measure was tumor remission rate, and the secondary indicators were overall survival (OS) and treatment failure time (TTF). The baseline demographic characteristics of the three groups of patients were comparable. The Independent Efficacy Evaluation Committee evaluated the imaging data according to the RECIST criteria. The results showed that among the 224 patients, the combined treatment group (74 cases), the single drug group (77 cases), and the control group (73 cases) had tumor remission rates of 37.8%, 24.7%, and 19.2%, the combination treatment group was significantly better than the control group (CMH test, P=0.021); 41 patients in the control group received the second-line treatment with tiggio single drug, the tumor remission rate was 14.6. %. The median OS of the combination therapy group, the single drug group, and the control group were 433 days, 267 days, and 309 days, respectively (the survival time of the control group included 41 cases of treatment failure and transferred to the second-line treatment of Teggio single-agent). The combination treatment group Significantly better than the control group (Log-rank test, P = 0.038) and single drug group (Log-rank test, P < 0.001); median TTF were 159 days, 126 days and 85 days, respectively, the combination treatment group was significantly better than Control group (Log-rank, P < 0.001) and single drug group (Log-rank, P = 0.008).
(2) monotherapy
Summarize the results of clinical trials of oral tiggio capsules (80-150 mg per day, calculated as tegafur) twice a day, and the effective rate of gastric cancer was 46.5% (60/129). The results included an early phase II trial of single drug chemotherapy for digestive tract tumors in Japan and two late phase II clinical trials for gastric cancer. The details of each test are as follows:
Early phase II trial: For patients with advanced gastric cancer, oral administration of 50-75 mg/times of Tiogel capsules for 2 consecutive days, repeated every 6 weeks for more than 2 cycles. A total of 31 patients were enrolled, and 28 patients with curative effect (including 9 patients with retreatment) were evaluated. The objective response rate was 53.6% (15/28, 90% confidence interval 38.4-68.1%).
Late phase II clinical trial (gastric cancer T test): For patients with advanced gastric cancer, oral administration of 40-60 mg/time of Teggio capsules for 28 consecutive days, twice a day, repeated every 6 weeks. A total of 51 cases were selected, all of which were evaluable (including primary lesion evaluation cases), including 1 case of complete remission and 24 cases of partial remission. The objective response rate was 49% (25/51, 95% confidence interval 35.9-62.3%). .
Late phase II clinical trial (K-stomach cancer test): For patients with advanced gastric cancer, oral administration of 40-60 mg/time of Teggio capsules for 28 consecutive days, twice a day, repeated every 6 weeks. A total of 51 patients were enrolled, of which 50 patients (including primary lesion evaluation cases) were evaluated, including 20 patients with partial response, and the objective response rate was 40.0% (20/50, 95% confidence interval 30.4-58.9%).
Second, the results of domestic clinical trials
1. Test method
A total of 226 patients with advanced gastric cancer were randomly divided into two groups, 111 in the experimental group and 115 in the control group, using a multicenter, randomized, positive drug parallel controlled trial.
Test group: Oral Tiggio capsules 80mg/m2/d (administered according to body surface area), taken once after breakfast and after dinner (maximum daily dose should not exceed 150mg), continuous medication for 14 days, stop taking medicine One week was a cycle; cisplatin: 75 mg/m2, intravenous infusion (D1, 2, 3) in three days, repeated for three weeks.
Control group: oral tegaflu 800 mg/m2/d (administered according to body surface area), taken in 3 times, continuous medication for 14 days, and one week rest for one week. Cisplatin: 75 mg/m2, intravenous infusion (D1, 2, 3) in three days, repeated for three weeks. Each group of patients was treated with at least 2 cycles for efficacy evaluation. Such as CR, PR or SD can continue treatment until the disease progresses, PD is switched to other chemotherapy regimens or radiotherapy. CR and PR must be confirmed after four weeks.
2, observation indicators
(1) Effectiveness indicator: response rate
(2) Safety indicators: laboratory tests, vital signs, and adverse events.
3. Test results
The effective rate (CR+PR) of the test group was 27.93%, and that of the control group was 7.83%. Among them, the effective rate of the initial treatment group was 30.77%, and that of the control group was 10.91%; the effective rate of the retreated patients was 25.42%, and the control group was 5.00%.
【Pharmacology and Toxicology】
Pharmacological effects:
1, anti-tumor effect
Tiggio inhibits the growth of human gastric cancer, colorectal cancer, breast cancer, lung cancer, pancreatic cancer and renal cancer in nude mice (rats and mice), and prolongs the survival time of mouse Lewis lung cancer and L5178Y metastasis model.
2, the mechanism of action
The Tiggio capsule consists of tegafur (FT), gemcitabine (CDHP) and oxylatyne potassium (Oxo). Its mechanism of action is: FT is gradually converted into 5-fluorouracil (5-FU) in the body after oral administration. CDHP selectively reversibly inhibits the 5-FU catabolic enzyme, DPD, present in the liver, thereby increasing the concentration of 5-FU from FT. Along with the increase of 5-FU concentration in the body, the 5-FU phosphorylation product 5-fluoronucleotide in tumor tissues can maintain a high concentration, thereby enhancing the anti-tumor effect. Oxo is distributed in the gastrointestinal tract after oral administration, and can selectively reversibly inhibit orotate phosphoribosyltransferase, thereby selectively inhibiting the conversion of 5-FU into 5-fluoronucleotide, thereby not affecting the antitumor activity of 5-FU. Reduce gastrointestinal side effects. The main mechanism of action of 5-FU is to competitively bind to thymidine synthase by its active metabolites FdUMP and dUMP, and to form a trimer with reduced folate, thereby inhibiting DNA synthesis. In addition, 5-FU is converted to FUTP and integrated into RNA molecules, thereby disrupting RNA function.
Toxicological research:
The acute toxicity test showed that the LD50 of mice was 441-551 mg/kg, and the LD50 of Beagle dogs was 53 mg/kg. Long-term toxicity test results show that this product is administered orally to SD rats and Beagle dogs for 13-52 weeks. The main toxic target organ is bone marrow hematopoietic stem cells.
【Pharmacokinetics】
1. Pharmacokinetics
(1) blood concentration
Twelve cancer patients were given a single oral dose of 32-40 mg/m2 after the meal. The pharmacokinetic parameters calculated according to the blood concentration are shown in the following table:
Table 1 Pharmacokinetic parameters (n=12, mean±S.D.)
Cmax（ng/ml） | Tmax（hr） | AUC（0-48h） （ng•hr/ml） | T½（hr） | |
Tegafur | 1791.0±269.0 | 2.4±1.2 | 28216.9±7771.4 | 13.1±3.1 |
5-FU | 128.5±41.5 | 3.5±1.7 | 723.9±272.7 | 1.9±0.4 |
Gempyrimidine | 284.6±116.6 | 2.1±1.2 | 1372.2±573.7 | 3.0±0.5 |
Oturacil potassium | 78.0±58.2 | 2.3±1.1 | 365.7±248.6 | 3.0±1.4 |
The cumulative excretion rates of the components in the urine within 72 hours after administration were: gemcitab 52.8%, tegafur 7.8%, oxytila potassium 2.2%, metabolite cyanuric acid 11.4%, 5-FU 7.4%.
After oral administration of this product at 25-200 mg/person, the AUC values and Cmax of tegafur, gemcitabine, oltipraz potassium and 5-FU increased in a dose-dependent manner. Two times a day, oral administration of this product 32 ~ 40 mg / m2 for 28 consecutive days, blood concentration was measured on the 1, 7, 14, 28 days, respectively, the results showed that the plasma concentration reached a steady state. In addition, endogenous uracil decreased rapidly after continuous administration, indicating that the reversible inhibitory effect of gemcitabine on DPD was enhanced.
(2) The rats were used alone or in combination with other fluoropyrimidines for 7 consecutive days, and the plasma concentration of 5-FU in plasma was measured 2 hours after the last administration. The results showed that the concentration of 5-FU after combination with 5-FU, tegafur, tegafur-uracil, carmofur, deoxyfluorouridine and flucytosine was 4.1 times that of the product group. 8.1 times, 2.8 times, 5.7 times, 6.9 times, 2.3 times, which may increase the side effects of the combined group.
(3) The AUC values of patients with normal renal function and mild renal impairment are as follows:
Table 2 AUC values of each component after oral administration of this product in patients with different renal functions (mean±S.D.)
Ccr estimate | AUC（0-8hr） | |
＞80ml/min（n=17） | 50ml~80ml/min（n=11） | |
Tegafur | 10060±1842 | 11320±2717 |
5-FU | 541.2±174.8 | 812.4±244.9 |
Gempyrimidine | 977.8327.9 | 1278.0±306.6 |
Oturacil potassium | 155.7±97.5 | 458.2±239.7 |
Note: Cockcroft-Gault formula:
Creatinine clearance = (140-age) × body weight (kg) / (72 × serum creatinine value (mg / dL)
(For women, the above value should be ×0.85)
2, protein binding
In vitro tests showed that the serum albumin binding rates of the components and 5-FU in the prescription were: 49-50% for tegafur, 32-33% for gemcitabine, 7-10% for oltipraz potassium, and 5-FU 17 -20%.
3. Metabolizing enzymes
In vitro tests have shown that the enzyme involved in the conversion of tegafur to 5-FU is mainly CYP2A6 in human liver microsomal cytochrome P450.
【Storage】sealed, stored at room temperature (10 ~ 30 ° C).
【Packing】aluminum plastic packaging.
20mg specification (based on tegafur): 12 capsules/box, 14 capsules/box, 28 capsules/box, 42 capsules/box.
25mg specification (in tegafur): 12 tablets / box, 24 / box, 36 / box.
【Validity Period】24 months
【Executive Standards】 State Food and Drug Administration Standard YBH14202008
【Approval Number】
1, 20mg specification (based on tegafur): Chinese medicine standard word H20080802
2, 25mg specification (based on tegafur): Chinese medicine standard word H20080803
【manufacturer】
Company Name: Shandong New Times Pharmaceutical Co., Ltd.
Production address: No. 1 North Outer Ring Road, Feixian County, Shandong Province Post code: 273400
Phone number: 0539-8336336 (Sales) 5030608 (Quality Management Department)
Fax number: 0539-5030900
Website: www.LUNAN.com.cn
24-hour customer service hotline: 400-0539-310
