202205212335COVID-19 注射型抗病毒藥物韋如意(瑞德西韋) VEKLURY®(remdesivir瑞德西韋)-用藥須知及醫療人員指引 202201.pdf

疾管署COVID-19 注射型藥物-VEKLURY® (Remdesivir)-病人用藥須知及醫療人員指引 202201.pdf
最後更新日期 2022/1/1COVID-19 治療用藥領用方案
Remdesivir (RDV) 屬於注射型藥物. 因此僅住院患者可使用. 基層診所或衛生所無法開立
注意: 插管或使用ECMO的患者, 使用"韋如意VEKLURY" 無法縮短住院天數

Remdesivir: Drug informatio uptodate
住院病患
美國建議同時使用 remdesivir + dexamethasone. 無法使用類固醇也可以用 remdesivir + baricitinib 
但 WHO 不建議住院患者使用 remdesivir. 不管疾病嚴重度如何. 
Note: US guideline recommendations on the role of remdesivir for hospitalized patients vary. In general, guidelines recommend use in conjunction with dexamethasone (IDSA [Bhimraj 2021]; NIH 2022; SCCM [Alhazzani 2021]); if a corticosteroid cannot be used, may use remdesivir in combination with baricitinib (NIH 2022). However, the World Health Organization recommends against the use of remdesivir in hospitalized patients, regardless of disease severity (WHO 2020).

非住院病患
Nonhospitalized patients:(但台灣不太可能在診所注射這種藥物. 也不太可能讓病人帶回家自己打)
可用於輕度至中度高風險的 COVID-19 非住院病患 (後面的住院或死亡是對於severe COVID-19的註記)
Note: Reserve use for the treatment of mild to moderate COVID-19 in nonhospitalized patients at high risk for progression to severe COVID-19, including hospitalization or death.

baricitinib 成分藥品安全資訊風險 109-10
Baricitinib (Olumiant®) 中文商品名 愛滅炎膜衣錠(中文仿單連結)
Baricitinib 用於治療 rheumatoid arthritis 的藥物. 作用是抑制 JAK (janus kinase). 
baricitinib 可能會增加憩室炎風險, 對容易發生憩室炎的病患要小心使用. 
發生憩室炎的高風險族群-- 先前曾有憩室相關疾病的病人及長期使用可能增加發生憩室炎風險的藥品(NSAIDs、皮質類固醇、鴉片類藥品)的病人。
照片來自FB醫藥安全資訊網, 有兩種劑型. 2mg 和 4mg

4
韋如意(瑞德西韋)警訊 Remdesivir Special Alerts -Health Canada Remdesivir Safety Alert August 2021
2021年加拿大提出關於瑞德西韋的警訊, 使用之後可能導致竇性緩脈 sinus bradycardia
加拿大核准韋如意用於治療 COVID-19 肺炎且須使用氧氣的患者. 
Health Canada's review of available information has found a possible link between the risk of sinus bradycardia and the use of Veklury (remdesivir). Veklury is authorized in Canada to treat COVID-19 in adults and adolescents with pneumonia and requiring oxygen. Health Canada will work with the manufacturer to update the Canadian product safety information to inform health care providers and patients about the potential risk of sinus bradycardia and will continue to monitor safety information.

注意事項:
某些情況使用"韋如意VEKLURY"可能會有害, 或降低療效. 不建議使用
1. eGFR < 30 
2. 12歲以下或 體重 < 40 kg
3. 需監測肝功能. 

"韋如意VEKLURY"在臨床研究中顯示的療效資訊
一項包含了 1062 例住院的 COVID-19 病人(159 位輕至中症以及 903 位重症)的臨床研究(NIAID-ACTT-1) ,顯示 "韋如意VEKLURY"可加快某些病人的康復時間 (time to recovery),使這些病人在醫院住院及治療的時間縮短。該研究證明,在整體研究族群中接受 "韋如意VEKLURY"治療的病人,中位康復時間為 10 天。而接受安慰劑治療的病人則為 15 天。對於重症病人,接受"韋如意VEKLURY"治療的病患,中位康復時間為 11 天,安慰劑組則為 18 天。然而,重症病人在已裝上葉克膜或機械呼吸器
才開始接受 "韋如意VEKLURY"治療,康復時間兩組沒有差異。

2022-05-21 23:40疾管署-VEKLURY®-病人用藥須知及醫療人員指引 202201.pdf

韋如意®凍晶乾燥注射劑100毫克/瓶 衛部藥輸字第027899號
韋如意目前核准使用的適應症為治療必須住院之成人與兒童病人(12 歲(含)以上且體重至少 40 公斤)的
2019 冠狀病毒疾病(COVID-19)。僅可於醫院或可提供類似住院照護之急性照護的醫療照護機構內投予。為
及早發現可能的副作用,在使用韋如意治療之前與治療期間,您的醫師或其他醫療人員會每天監測您的症
狀和檢驗結果。

如何使用韋如意
對成人及 12 歲(含)以上且體重至少 40 公斤的兒童病人,建議劑量為於第 1 天靜脈輸注單劑 VEKLURY 200 毫克(起始劑量),然後從第 2 天起每天一次靜脈輸注 VEKLURY 100 毫克(維持劑量)。
• 對不須使用侵入性機械呼吸器及/或體外膜氧合器(葉克膜/ECMO)的病人,建議的治療時間為 5 天。如果病人未呈現臨床改善的效果,治療可額外延長最多 5 天,總治療時間為最長 10 天。
• 對須使用侵入性機械呼吸器及/或葉克膜的病人,建議的治療時間為 10 天
• 韋如意必須先稀釋再靜脈輸注給藥。

售價: 在uptodate網站的資訊有列出售價
Pricing: US
Solution (Veklury Intravenous) 100 mg/20 mL (per mL): $31.20 (每CC 31.2 美元, 一瓶  20cc= 624 美元)
Solution (reconstituted) (Remdesivir Intravenous) 100 mg (per each): $624.00
Solution (reconstituted) (Veklury Intravenous) 100 mg (per each): $624.00


相關研究報告
瑞德西韋的效果, 下面這篇是在2022年1月發表在 BMC(生物醫學核心感染症期刊)
關於BMC Infectious disease 我之前也不太熟, 不過疾管署網站有一篇文章(連結在這), 提到疾管局楊季融等人研究曲狀桿菌之檢驗技術開發、抗藥性與感染症之流行狀況監測, 登上生物醫學核心感染症期刊(BMC Infectious Diseases)。
BMC infectious disease 至少是疾管署可認可的期刊吧. Impact Factor 3.1
Safety and clinical outcomes of remdesivir in hospitalised COVID-19 patients: a retrospective analysis of active surveillance database
這篇研究當時的背景, 文章中有提到, 在 2020年12月28日, 全球共八千萬確診病例, 印度是世界第二最受影響的國家, 有一千多萬確診個案. 
As of 28 December 2020, the global incidence of COVID-19 had reached 80, 838, 931 confirmed cases; India was the second most-affected country in the world, with a case burden of 10, 207, 871 confirmed cases
2329 個案例, 共有 65.38% 使用 remdesivir, 最常一起使用的藥物是抗生素(64.90%)或類固醇(47.90%)
不良反應共 119 例, 最常見的副作用是 噁心 嘔吐(45.40%), 另有 14.28% 肝指數上升
84% 改善或治癒
6.77% 死亡
9.16% 不好不壞
60歲以下的死亡率明顯低於 60歲以上的人
在使用氧氣的患者, 使用低流量氧氣的個案, 治癒率明顯高於其他(機械式呼吸器,非侵襲性呼吸器,高流量氧氣)的個案
與死亡風險相關因子包括
1. 60歲以上
2. 心臟疾病
3. DM
4. 需使用高流量氧氣, 或非侵襲式呼吸器, 或機械式呼吸器
Results
Of the 2329 patients included, 67.40% were men. Diabetes (29.69%) and hypertension (20.33%) were the most common comorbidities. At remdesivir initiation, 2272 (97.55%) patients were receiving oxygen therapy. Remdesivir was administered for 5 days in 65.38% of patients. Antibiotics (64.90%) and steroids (47.90%) were the most common concomitant medications. Remdesivir was overall well tolerated, and total 119 adverse events were reported; most common were nausea and vomiting in 45.40% and increased liver enzymes in 14.28% patients. 84% of patients were cured/improved, 6.77% died and 9.16% showed no improvement in their clinical status at data collection. Subgroup analyses showed that the mortality rate was significantly lower in patients < 60 years old than in those > 60 years old. Amongst patients on oxygen therapy, the cure/improvement rate was significantly higher in those receiving standard low-flow oxygen than in those receiving mechanical ventilation, non-invasive ventilation, or high-flow oxygen. Factors that were associated with higher mortality were age > 60 years, cardiac disease, diabetes high flow oxygen, non-invasive ventilation and mechanical ventilation.
Conclusion
Our analysis showed that remdesivir is well tolerated and has an acceptable safety profile. The clinical outcome of cure/improvement was 84%, with a higher improvement in patients < 60 years old and on standard low-flow oxygen.

下面第二篇研究是 2021年8月19日發表於 Clinical Infectious Disease
Remdesivir and Mortality in Patients with COVID-19
(另一個PubMed連結只有摘要)
這是一篇斷代回溯性研究, 分析使用最佳支持性療法(best supportive care, BSC) 與使用remdesivir (RDV)的差異
2020年二月到五月之間住院的患者. 總共 1138 人. 
收錄條件是罹患COVID-19, CXR有肺炎, 血氧濃度≤ 94%或缺氧需使用氧氣治療
RDV是實驗組, BSC是對照組
286 使用 RDV
852 使用 BSC. 其中 400 使用氯奎寧 hydroxychloroquine, 
所有患者有 20.4%使用類固醇, RDV組有 12.6%, BSC 組有23%

下圖是 fig 1 (圖片連結在此)


surviving curve 圖片連結在此




Abstract
Background: The impact of remdesivir (RDV) on COVID-19 mortality is controversial, and the mortality effect in sub-groups of baseline disease severity has been incompletely explored. The purpose of this study was to assess the association of RDV with mortality in patients with COVID-19.
Methods: In this retrospective cohort study we compared persons receiving RDV to persons receiving best supportive care (BSC). Patients hospitalized between 2/28/20 - 5/28/20 with laboratory confirmed SARS-CoV-2 infection were included when they developed COVID-19 pneumonia on chest radiography, and hypoxia requiring supplemental oxygen or SpO2 ≤ 94% on room air. The primary outcome was overall survival assessed with time-dependent Cox proportional-hazards regression and multivariable adjustment, including calendar time, baseline patient characteristics, corticosteroid use and effects for hospital.
Results: 1,138 patients were enrolled including 286 who received RDV, and 852 treated with BSC, 400 of whom received hydroxychloroquine. Corticosteroids were used in 20.4% of the cohort (12.6% in RDV and 23% in BSC). In persons receiving RDV compared to those receiving BSC the HR (95%CI) for death was 0.46 (0.31 - 0.69) in the univariate model, p<0.001 and 0.60 (0.40 - 0.90) in the risk-adjusted model, p=0.014. In the sub-group of persons with baseline use of low-flow oxygen, the HR (95%CI) for death in RDV compared to BSC was 0.63 (0.39 - 1.00), p=0.049.
Conclusion: Treatment with RDV was associated with lower mortality compared to BSC. These findings remain the same in the subgroup with baseline use of low-flow oxygen.

下面這篇研究是兩年前的. 使用呼吸器的COVID-19患者使用RDV治療, 無法顯著改善死亡率(有稍微改善). 但可縮短插管天數. 
Open Forum Infect Dis. 2020 Oct 13;7(11):ofaa481. doi: 10.1093/ofid/ofaa481. eCollection 2020 Nov.
Remdesivir Use in Patients Requiring Mechanical Ventilation due to COVID-19
Abstract
Background: Remdesivir has been associated with accelerated recovery of severe coronavirus disease 2019 (COVID-19). However, whether it is also beneficial in patients requiring mechanical ventilation is uncertain.
Methods: All consecutive intensive care unit (ICU) patients requiring mechanical ventilation due to COVID-19 were enrolled. Univariate and multivariable Cox models were used to explore the possible association between in-hospital death or hospital discharge, considered competing-risk events, and baseline or treatment-related factors, including the use of remdesivir. The rate of extubation and the number of ventilator-free days were also calculated and compared between treatment groups.
Results: One hundred thirteen patients requiring mechanical ventilation were observed for a median of 31 days of follow-up; 32% died, 69% were extubated, and 66% were discharged alive from the hospital. Among 33 treated with remdesivir (RDV), lower mortality (15.2% vs 38.8%) and higher rates of extubation (88% vs 60%), ventilator-free days (median [interquartile range], 11 [0-16] vs 5 [0-14.5]), and hospital discharge (85% vs 59%) were observed. Using multivariable analysis, RDV was significantly associated with hospital discharge (hazard ratio [HR], 2.25; 95% CI, 1.27-3.97; P = .005) and with a nonsignificantly lower mortality (HR, 0.73; 95% CI, 0.26-2.1; P = .560). RDV was also independently associated with extubation (HR, 2.10; 95% CI, 1.19-3.73; P = .011), which was considered a competing risk to death in the ICU in an additional survival model.
Conclusions: In our cohort of mechanically ventilated patients, RDV was not associated with a significant reduction of mortality, but it was consistently associated with shorter duration of mechanical ventilation and higher probability of hospital discharge, independent of other risk factors.

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