- 學位論文
某醫學中心 Voriconazole 使用現狀之回溯性研究
A Retrospective Analysis for the Safety and Effectiveness of Voriconazole in a Medical Center in Taiwan
摘要
背景： Voriconazole是新一代廣效性三唑類抗黴菌藥，在2002年通過美國食品藥物管理局的許可，2003年通過我國衛生署的藥品許可證，治療的適應症為侵入性麴菌感染、念珠菌黴菌血症、念珠菌食道感染、及其他的嚴重黴菌感染。一般來說voriconazole的耐受性良好，但仍有少數嚴重的藥物不良反應被報告，此外，voriconazole由肝臟酵素代謝，且會抑制CYP 2C19、CYP2C9和CYP3A4，會與多種藥品產生藥品交互作用。Voriconazole屬於相對新的抗黴菌藥品，臨床上使用的經驗較少，因此本研究藉由回溯性分析的方式，了解voriconazole的使用現狀。 研究目的： 分析voriconazole的處方型態，例如：使用劑量、劑型、途徑、適應症的適當性；並且評估voriconazole的臨床治療反應、藥物不良反應與病人特質、處方型態之關係。並且記錄可能與voriconazole相關的藥品交互作用。 研究設計、地點、對象： 此研究地點於國立臺灣大學醫學院附設醫院進行收案，為單中心，回溯性病例分析之研究。研究對象則從西元2008年1月1日至2008年12月31日期間在研究地點中有開方voriconazole的病人。 研究方法： 以個案報告表記錄紙本病歷及電子病歷之資料，包括病人基本資料、合併症、黴菌感染危險因子、實驗室檢驗值、適應症、給藥方式、潛在藥品交互作用、藥品不良反應等相關變項。在結束voriconazole治療時，由一名感染專科醫師評估臨床治療反應，並且探討治療效果與病人特質、處方型態之間的關係；若在治療期間發生疑似voriconazole引起的藥品不良反應，利用Naranjo Scale評估voriconazole引起藥品不良反應的可能性，也將探討是否有潛在的危險因子存在會增加藥物不良反應的發生率。檢定兩組之間是否有差異的統計方法包含Student’s t test、Mann-Whitney U Test、和χ2 test；利用羅吉斯迴歸分析尋找影響臨床反應以及增加藥品不良反應的危險因子。 研究結果： 本研究收入了94位病人在2008年於本院使用voriconazole治療黴菌感染，共有105次voriconazole治療療程。病人平均年齡44.3±21.12歲，男性比例佔56.4%。68.1%（64/94）的病人之潛在疾病為血液腫瘤，2位病人沒有任何潛在疾病。在105次治療療程中，有16.2%（17/105）是被證實的侵入性黴菌感染，30.4%（32/105）極有可能為侵入性黴菌感染，45.7%（48/105）的療程治療可能的侵入性黴菌感染，2.9%作為經驗性療法，4.8%則無法確定voriconazole的適應症。 105次的療程中共有54.3%（57/105）的比例，以voriconazole作為黴菌感染的初始治療，而救援治療則最常作為amphotericin B的替代療法。32.4%（34/105）在起始治療時選擇注射劑型，其中只有5.9%（2/34）的病人沒有依仿單建議給予速效劑量。病人平均的維持劑量為3.8 ± 1.18 mg/kg（口服），3.7 ± 0.76 mg/kg（注射）。Voriconazole的治療時間中位數為29天（1-701天）。 Voriconazole臨床治療反應的結果，其中29.5%（31/105）的療程評估為complete response，28.6%（30/105）為partial response，其餘39%（41/105）病人則評估為治療效果不佳，其中有10.5%（11/105）的病人死亡，1位病人失去追蹤。在105次療程中有41次（39%）療程中出現藥品不良反應，共發生55種品項之不良反應，由voriconazole引起之可能性評估結果為，3件（5.5%）為確定，24件（43.6%）為極有可能，28件（50.9%）為可能；其中最常發生的副作用為肝臟酵素異常，發生率高達26.6%（28/105）。藥物不良反應的發生與病人特質、處方型態、臨床反應均無相關。在voriconazole治療期間併用最多的潛在交互作用的藥品為prednisolone（16/105，15.2%），但仍可能併用到配伍禁忌的藥品（6/105，5.7%），例如:carbamazepine、ergonovine、rifampin。在併用潛在交互作用的療程中，20%（21/105）疑似發生藥物不良反應。 不同適應症對於臨床治療反應的結果並無統計上顯著差異（p-value = 0.35），但是羅吉斯回歸模式得到在進入試驗前病人有置入導尿管以及沒有使用白血球生成素的病人會增加voriconazole治療失敗的機率。 結論： 在以血液腫瘤為主的病人群中，voriconazole主要治療可能的侵入性黴菌感染（45.7%），且通常作為salvage therapy的角色，以口服治療為主。整體來說，本院voriconazole的處方型態符合文獻中建議的使用方式。有關voriconazole臨床治療反應，有58.1%的比例治療反應良好（complete response or partial response），最常見之副作用為肝臟酵素異常，發生率高達26.6%。
並列摘要
Background: Voriconazole is a new generation triazole antifungal agent. It was approved by FDA in 2002 and Department of Health in Taiwan in 2003. Its indications include invasive aspergillosis, candidemia, esophageal candidiasis, and other mold infections due to Scedosporium apiospermum and Fusarium spp. Voriconazole is generally considered well tolerated, however, some severe adverse events have been reported. It plays an important role in the drug-drug interactions due to being substrate and inhibitors of CYP2C19, CYP2C9 and CYP3A4. The interactions may interfere in the clinical response and safety of voriconazole. Objective: This retrospective study attempted to describe the prescribing pattern of voriconazole, eg., voriconazole dosage, administration route, and indications. The relationship between clinical response and prescribing pattern was evaluated. Adverse events (AEs) potential caused by voriconazole, and risk factors would be discussed. Methods The study was a retrospective chart review. Patients who were treated with voriconazole in the National Taiwan University Hospital (NTUH) during 01/01~12/31/2008 were included. Patients’ data were collected from medical records and the computerized databases in the hospital, including patients’ demographic data, risk factors of fungal infections, laboratory data, indication for voriconazole, dosing regimen, drug interactions, adverse events, etc. We evaluated the clinical response upon discontinuation of voriconazole and 8 weeks after. Furthermore, we discussed the association between clinical response and patients’ characteristics and prescribing pattern. We also reviewed voriconazole associated AEs and assessed the probability with Naranjo Scale. The statistical methods included Student’s t test, Mann-Whitney U Test, and χ2 test. The logistic regression model was used to identify the risk factors of poor response and adverse events. Result The study included 94 patients and there were 105 treatment courses. The average age was 44.3±21.12 years old. Male accounted for 56.4%. Almost 70% patients (64/94) had hematological malignancies, 2 patients didn’t have any underlying disease. Voriconazole was indicated for the treatment of proven, probable, possible invasive fungal infections in 16.2%, 30.4%, and 45.7% of patients, respectively. But 5 patients were treated with voriconazole without evidence of fungal infection. Voriconzole was used as primary therapy in 54.3% of patients. Among 34 patients (32.4%) treated with IV voriconazole as initial therapy, 5.9% of patients (2/34) didn’t receive the loading dose. Average maintenance doses were 3.8 ± 1.18 mg/kg (oral) and 3.7 ± 0.76 mg/kg (IV). The median course duration was 29 (1~701) days. In terms of response, 29.5%, 28.6%, 39% of patients had complete response, partial response, and no response to voriconazole respectively. One patient lost to follow up. One tenth of patients died during voriconazole therapy with fungal infections. AEs occurred in 41 treatment courses (39 %). Because some patients had ≧ 1 adverse events, there were a total of 55 adverse events. Three AEs were considered as definite, 24 AEs as probable and 28 AEs as possible. The most common side effect was liver function abnormality (28/105, 26.7%). However, adverse events had no association between patients’ characteristics and prescribing pattern. The most common potential drug-drug interaction was involved prednisolone (16/105, 15.2%). There were also 6 treatment courses combined the contraindicated drugs, such as carbamazepine, ergonovine and rifampin. Approximately 20% of AEs (21/105) might be associated with drug-drug medicines. There was no difference between indications and clinical response (p-value = 0.35). In the logistic regression, if patients were on foley catheter and without G-CSF therapy before voriconazole therapy, the risk of treatment failure would be increased. Conclusion In this retrospective study, majority patients had hematological malignancies. Voriconazole was usually indicated for possible invasive fungal infections (45.7%) and as a salvage therapy. Most of patients were treated with oral formulation. In general, the administration of voriconazole in this study was consistent with clinical recommendation. Approximately 58% of patients had good response to voriconazole and the most common adverse event was live enzymes abnormality (26%). There were also 6 treatment courses combined the contraindicated drugs. Approximately 20% of AEs might be associated with drug-drug interactions.