Remdesivir and Hydroxychloroquine: A Compassionate Use in Covid-19

2020 ◽  
Vol 21 ◽  
Author(s):  
Amritpal Kaur ◽  
Gaurav Chaudhary ◽  
Pargat Singh ◽  
Sandeep Arora ◽  
Rajwinder Kaur
Keyword(s):  
Literature Search ◽  
Review Paper ◽  
Off Label Use ◽  
Compassionate Use ◽  
Off Label ◽  
Parenteral Route ◽  
Randomized Controlled ◽  
Novel Coronavirus ◽  
Microsoft Office ◽  
Antiparasitic Agents

Objective:: Early in December 2019, a mass of sufferers with Novel Coronavirus Pneumonia (SAS-CoV-19) in Wuhan (China) roused worldwide concern. Hardly any drugs showed the light of hope concerning the depletion in the period of treatment and virological suppression is troubled. Furthermore, numerous sufferers have undergone off-label use or compassionate use treatments as well as antiretroviral, antiparasitic agents, anti-inflammatory compounds, and convales-cent plasma in either oral/parenteral route. This study aims to compile and analyze the efficient value of Remdesivir and Hydroxychloroquine and give an insight to their drug profile in the treatment and management of COVID-19 patients. Method:: The literature search from PubMed, Crossref, Springer, Bentham Sciences, Google Scholar, DOAJ, ScienceDirect, and MEDLINE by using keywords like COVID-19, SAS-COV-2, Remdesivir, and hydroxychloroquine was done and ap-propriate peer-reviewed review articles, as well as research articles, were included and compiled in this review paper. The figures were prepared by using ChemOffice 2016 (ChemDraw Professional 2016) and Microsoft Office. Results:: The results of this study indicate that remdesivir in 5/10 studies from collected literature show a reduction in time of recovery and 5/10 shows no variance and having limitations. However, 6/12 shows an increase in the survival/reduction in time of recovery and 6/12 shows no effect or has limitations in the case of hydroxychloroquine. Conclusion:: There is a need to assess more pharmacokinetics and randomized controlled trials (RCT) for both remdesivir and hydroxychloroquine. Furthermore, studies should be conducted in different combinations along with hydroxychloro-quine and remdesivir to get efficient results.

Comparison of Thromboembolic Event Rates in Randomized Controlled Trials and Observational Studies of Recombinant Factor VIIa for Off-Label Indications.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1403-1403 ◽  
Author(s):  
Veronica Yank ◽  
Aaron C. Logan ◽  
C. Vaughan Tuohy ◽  
Dena M. Bravata ◽  
Kristan Staudenmayer ◽  
...  
Keyword(s):  
Cardiac Surgery ◽  
Observational Studies ◽  
Thromboembolic Event ◽  
Meta Analysis ◽  
Thromboembolic Events ◽  
Off Label Use ◽  
Off Label ◽  
Randomized Controlled ◽  
Event Rates ◽  
Label Use

Abstract Abstract 1403 Poster Board I-425 Background: Recombinant factor VIIa (rFVIIa) is a potent hemostatic agent licensed for treatment of bleeding in hemophiliac patients with inhibitors but has been increasingly used off-label to treat or prevent bleeding, despite sparse data to support its efficacy and a possible increase in thromboembolic events. While randomized controlled trials (RCTs) provide the best evidence regarding efficacy, they may not identify rare but important adverse events. Observational studies may capture the rate of such events in clinical practice more accurately. Objectives: To compare rates of thromboembolic events associated with off-label use of rFVIIa in RCTs and observational studies. Methods: Studies of off-label application of rFVIIa were identified by review of 10 literature and clinical trial databases through February, 2009. The off-label indications examined were trauma, non-traumatic intracranial hemorrhage (ICH), and adult cardiac surgery. When an appropriate number and quality of studies were available, data from RCTs and higher quality comparative observational studies were combined via meta-analysis using the arc sine statistical method, a method that characterizes uncommon events more accurately than more conventional methods. To describe the absolute rate of thromboembolism for patients treated with rFVIIa in RCTs versus observational studies, we analyzed data from the interventional arms of RCTs and comparative observational studies, as well as data from non-comparative observational studies with 15 or more patients. Results: Included Studies Our search identified 4 RCTs and 4 observational studies of rFVIIa use in ICH. Two RCTs and 5 observational studies were identified for trauma. For cardiac surgery, 2 RCTs, 2 higher quality comparative observational studies (included in the meta-analysis), and 8 additional observational studies were identified. Meta-analyses The meta-analysis of the RCTs investigating use of rFVIIa in ICH showed a trend toward increased thromboembolic risk with rFVIIa (arcsine summary effect size 0.100, 95% CI -0.072-0.272). For trauma, the two RCTs did not provide sufficient data to perform meta-analysis. Individually, they did not demonstrate significantly different incidences of thromboembolic events with rFVIIa compared to placebo but may have been underpowered to detect such differences. For cardiac surgery, the meta-analysis of the 4 studies showed a significant increase in thromboembolic events in the rFVIIa group (arcsine summary effect 0.14; 95% CI 0.038- 0.242). Absolute rates of thromboembolic events in RCTs versus observational studies In ICH, thromboembolic event rates in the treatment arms of the RCTs ranged from 0.07-0.11, while those in the observational studies ranged from 0-0.20. In trauma, thromboembolic event rates in the RCT treatment arms ranged from 0.03-0.06, whereas those in the observational studies ranged from 0.02-0.11. In cardiac surgery, thromboembolic event rates in the RCTs ranged from 0.07-0.22 compared to a range of 0-0.25 in the observational studies. For all three indications, Figure 1 shows that the weighted mean thromboembolic event rates associated with rFVIIa use are higher in the observational studies than in the RCTs. Patients in the observational studies tended to be older and have a worse prognosis than those enrolled in the RCTs. Conclusions: We identified a trend toward significantly higher rates of thromboembolic adverse events with off-label use of rFVIIa compared to placebo in our meta-analyses of ICH and cardiac surgery, but no similar pattern in trauma trials. For each of these indications, we identified a higher rate of thromboembolic adverse events associated with the use of rFVIIa in observational trials compared to RCTs. This finding suggests that patients receiving off-label rFVIIa for these off-label indications in real-world practice may be at higher risk of thromboembolic events than patients enrolled in clinical trials and may caution against widespread use, especially in the absence of convincing data on efficacy. Disclosures: Off Label Use: This study examines the off-label use of rFVIIa in randomized controlled trials and observational studies of intracranial hemorrhage, trauma, and cardiac surgery.

scholarly journals The RING study: A Randomized Controlled Trial of GCSF-stimulated Granulocytes in Granulocytopenic Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. SCI-16-SCI-16 ◽  
Author(s):  
Thomas H. Price
Keyword(s):  
Median Number ◽  
High Dose ◽  
Success Rates ◽  
Off Label Use ◽  
Control Groups ◽  
Off Label ◽  
Intention To Treat ◽  
Randomized Controlled ◽  
Microbial Response ◽  
And Control

Bacterial and fungal infections continue to be a major clinical problem in patients with prolonged severe neutropenia due to hematopoietic stem cell transplantation or aggressive chemotherapy. Although early controlled trials suggested that granulocyte transfusions were modestly effective in this setting, the doses of granulocytes provided in these studies were considered to be inadequate. Renewed interest in this therapy came with the possibility of greatly increasing the dose transfused by administering granulocyte colony-stimulating factor (G-CSF) ± dexamethasone to normal granulocyte donors. Subsequent studies showed that three to four times as many granulocytes could be collected from such donors, that these cells circulated in neutropenic recipients, and that the cells appeared to function normally both in vitro and in vivo. The evidence for clinical efficacy of this high-dose therapy has been inconclusive. The RING study is a recently completed randomized controlled study examining the efficacy of high-dose granulocyte transfusion therapy, carried out as part of the NHLBI Transfusion Medicine/Hemostasis Clinical Trials Network. Fourteen clinical sites participated. Subjects eligible for the study were those with neutropenia (ANC<500) and proven/probable/presumed bacterial or fungal infection. Subjects were randomized to receive either: 1) standard antimicrobial therapy; or 2) standard antimicrobial therapy plus daily granulocyte transfusions from normal donors stimulated with G-CSF (450µg) and dexamethasone (8mg). The primary endpoint was a composite one: survival plus a microbial response, both evaluated 42 days after randomization. Microbial response was determined by a blinded adjudication panel. Desired sample size was 236 subjects, designed to have 80% power to detect a 20% difference in success rates between the treatment and control groups. One hundred and fourteen subjects were enrolled. Subjects in both arms were well matched in terms of demographics, underlying disease, types and sites of infection, and severity of illness. Of the 56 subjects randomized to the granulocyte arm, 51 received at least one transfusion. Among these 51 subjects, the median number of transfusions was five (quartiles 3 and 9) given over a median of six days (quartiles 4 and 11). The median number of granulocytes administered per transfusion was 54.9x109 (quartiles 26.1x109, 72.5x109). Among subjects with sufficient data to determine the primary outcome, success rates were 42% (20/48) and 43% (21/49) for the granulocyte and control groups, respectively (p> 0.99) on Intention to Treat analysis, and 49% (17/35) and 41% (16/39), respectively, for subjects who adhered to their assigned treatments (Per Protocol analysis; p=0.64). Overall, patient infections were 36% invasive fungal, 27% invasive bacterial, 11% fungemia, and 26% bacteremia. Differences in primary endpoint success rates for granulocyte and control arms were not statistically significantly different for any infection type whether analyzed by Intention to Treat or Per Protocol. Because of the low accrual, the power of this study to detect a 20% difference in the overall success rates was reduced to approximately 40%; it is thus possible that a true effect was missed, particularly if the effect is limited to certain subject subsets. Disclosures Off Label Use: In the study being discussed, G-CSF is administered to normal blood donors. This is an off-label use of G-CSF. .

scholarly journals A brief note on randomized controlled trials and compassionate/off-label use of drugs in the early phases of the COVID-19 pandemic

2020 ◽  
Vol 9 ◽  
pp. 1-2 ◽  
Author(s):  
Matteo Bassetti ◽  
Paolo Pelosi ◽  
Chiara Robba ◽  
Antonio Vena ◽  
Daniele Roberto Giacobbe
Keyword(s):  
Randomized Controlled Trials ◽  
Controlled Trials ◽  
Off Label Use ◽  
Off Label ◽  
Randomized Controlled ◽  
Early Phases ◽  
Label Use

FLUOROQUINOLONES IN PEDIATRIC PATIENTS: NO MORE “OFF-LABEL USE”

2015 ◽  
Vol 101 (1) ◽  
pp. e1.54-e1
Author(s):  
Natalie Dinavitser ◽  
Maya Berlin ◽  
Reuven Miller ◽  
Victoriya Finkel-Pekarsky ◽  
Matitiahu Berkovitch
Keyword(s):  
Literature Search ◽  
Adverse Reactions ◽  
Pediatric Patients ◽  
Reporting System ◽  
Cartilage Damage ◽  
Tendon Injury ◽  
Off Label Use ◽  
Off Label ◽  
Spontaneous Reports ◽  
Pediatric Use

Fluoroquinolones (FQs) are used in pediatric patients worldwide. However, due to cartilage damage in young animals they are not approved for children under 18 years of age for most indications. Major regulatory authorities such as EMA, FDA, UK, Ireland, NZ and Australia indicate that FQs are contraindicated in children. Ciprofloxacin and levofloxacin can be prescribed to children, but only for a few indications. As a result, FQs are used “off-label” in this population. From our experience, we believe that FQs should not be contraindicated in children. However, evidence-based data is needed.ObjectiveTo investigate whether FQ use in children may cause musculoskeletal adverse reactions (ADRs).MethodsWe reviewed the Israel Ministry of Health ADR reporting system and VigiLyze (WHO reporting system) for musculoskeletal ADRs due to FQs in children. A literature search– Medline, Pubmed, Cochraine database and pharmacologic textbooks, for musculoskeletal ADRs among FQ treated pediatric patients was conducted. Terms used: Fluoroquinolones, ciprofloxacin, levofloxacin, ofloxacin, arthropathy, tendinophaty, arthralgia, children, pediatric use.ResultsDuring the period 1968 to Feb 2015, the Israeli MOH did not receive spontaneous reports regarding FQs in children. The VigiLyze program identified 192 ADR reports in children related to FQs: arthralgia, arthropathy, myalgia, and tendon injury. Most ADRs were transient and reversible. The literature search indicated that although musculoskeletal ADRs are not uncommon, they are mild, transient, and not necessarily due to FQs. Joint MRI, performed in some of the studies, did not reveal cartilage damage.ConclusionsFQs should be registered for pediatric patients as for adults.

Promoting the Off–label Use of Medicines: Where to Draw the Line?

2016 ◽  
Vol 7 (2) ◽  
pp. 426-433
Author(s):  
Genevra Forwood ◽  
James Killick
Keyword(s):  
Public Health ◽  
Clinical Trials ◽  
Patient Safety ◽  
Marketing Authorisation ◽  
Regulatory System ◽  
Eu Law ◽  
Off Label Use ◽  
Compassionate Use ◽  
Off Label ◽  
Label Use

In Europe, medicines can only be marketed once they have passed through a strict regulatory process, designed primarily to protect patient safety. It is only after in–depth testing on the targeted disease population, including three phases of clinical assessment and clinical trials, that a medicine will obtain a ‘marketing authorisation’. Given its primary goal of ensuring patient safety, EU law only allows a few narrow exceptions to the requirement of amarketing authorisation. Adrug can only be used “off–label”, meaning outside the limits of its marketing authorization, in authorised clinical trials or under one of the strictly defined exceptions, such as severe public health risk, compassionate use for groups of patients or for individual patients on a named patient basis.However, in recent years, a trend has emerged Among Member States to push the boundaries of the existing regulatory system, and actively promote the off–label use of medicines on the ground that they are cheaper than the alternative, authorised medicine. It is questionable whether this trend is in line with EU law.

scholarly journals Zugelassene Systemtherapien in der Dermatologie

Der Hautarzt ◽  
2021 ◽  
Author(s):  
Monika Kleinhans ◽  
Carolin Funke-Lorenz ◽  
Joachim Dissemond
Keyword(s):  
Off Label Use ◽  
Compassionate Use ◽  
Off Label ◽  
Early Access ◽  
Access Programme ◽  
Label Use

Zusammenfassung Hintergrund Für den Fachbereich Dermatologie steht gerade in den letzten Jahren ein zunehmendes Spektrum an Systemtherapien zur Verfügung. Bei einigen dieser Medikamente handelt es sich um einen Off-label-Use, was beispielsweise zu Problemen bei der Kostenerstattung führen kann. Dieser Beitrag soll daher einen Überblick über die derzeit zugelassenen Systemtherapien in der Dermatologie bieten und weitere Alternativen wie Compassionate Use und Early-Access-Programme aufzeigen. Material und Methoden Die Recherche der zugelassenen Medikamente in Deutschland wurde online in der Datenbank für Arzneimittel des Bundesinstituts für Arzneimittel und Medizinprodukte durchgeführt. Zudem erfolgte ein Abgleich mit den Angaben in der Roten Liste. Ergebnisse Für insgesamt 50 dermatologisch relevante Krankheitsbilder werden tabellarisch die jeweils zugelassenen Systemtherapien dargestellt. Diskussion Es kann festgestellt werden, dass die enormen Weiterentwicklungen der letzten Jahre und die zunehmend gute Evidenz in vielen Fällen trotz oftmals fehlender klinischer Studien im Fachbereich der Dermatologie sehr Erfolg versprechende systemische Behandlungskonzepte bieten. Jedoch kann der oft notwendige Off-label-Use Schwierigkeiten im klinischen Alltag verursachen. Der behandelnde Arzt sollte ebenso wie der Patient daher immer informiert sein, wenn es sich bei einer geplanten Therapie um einen Off-label-Use handelt. Es sollten zuvor zugelassene Alternativen in Erwägung gezogen werden, und eine adäquate Aufklärung der Patienten sollte erfolgen.

scholarly journals Less invasive treatments for pure aortic insufficiency: Are we there yet?

2022 ◽  
Author(s):  
Jessica Forcillo
Keyword(s):  
Gold Standard ◽  
Transcatheter Aortic Valve Replacement ◽  
Heart Valves ◽  
Aortic Insufficiency ◽  
Off Label Use ◽  
Compassionate Use ◽  
Valve Repair ◽  
Off Label ◽  
Transcatheter Aortic Valve ◽  
Transcatheter Heart Valve

The gold standard for the treatment of pure aortic insufficiency (PAI) is surgical valve repair or replacement.1 With the newest transcatheter heart valve technologies and the accumulating years of experience of heart teams with the current transcatheter aortic valve replacement (TAVR) prostheses, implanters have push the envelope with off-label use of those valves designed and approved for aortic stenosis, in patients with pure aortic insufficiency especially those at higher risks or for compassionate use.3 However, new prostheses are currently under investigation in clinical use and evidences are provided on the safety and efficacy of those latter. It will be discussed in this commentary, the actual clinical evidences and the use of transcatheter heart valves, in and off label, for the treatment of pure aortic insufficiency.

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