COVID -19 Treatment- Remdesivir, tocilizumab, favipiravir

COVID -19 Treatment- Remdesivir, tocilizumab, favipiravir, what we need to know :

Remdesivir

Remdesivir, sold under the brand name Veklury,[8][9] is a broad-spectrum antiviral medication developed by the biopharmaceutical company Gilead Sciences.[10] It is administered via injection into a vein.[11][12] During the COVID-19 pandemic, remdesivir was approved or authorized for emergency use to treat COVID‑19 in around 50 countries.[13] Updated guidelines from the World Health Organization in November 2020 include a conditional recommendation against the use of remdesivir for the treatment of COVID-19.[14]

Remdesivir was originally developed to treat hepatitis C,[15] and was subsequently investigated for Ebola virus disease and Marburg virus infections[16] before being studied as a post-infection treatment for COVID-19.[17]

The most common side effect in healthy volunteers is raised blood levels of liver enzymes (a sign of liver problems).[8] The most common side effect in people with COVID‑19 is nausea.[8] Side effects may include liver inflammation and an infusion-related reaction with nausea, low blood pressure, and sweating.[18]

The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.[20]

In the European Union, remdesivir is indicated for the treatment of coronavirus disease 2019 (COVID‑19) in adults and adolescents (aged twelve years and older with body weight at least 40 kilograms (88 lb)) with pneumonia requiring supplemental oxygen.[4][8]

In the United States, remdesivir is indicated for use in adults and adolescents (aged twelve years and older with body weight at least 40 kilograms (88 lb)) for the treatment of COVID‑19 requiring hospitalization.[7] In November 2020, the FDA issued an emergency use authorization (EUA) for the combination of baricitinib with remdesivir, for the treatment of suspected or laboratory confirmed COVID-19 in hospitalized people two years of age or older requiring supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).[25]



Controversy

According to international experts from the British Medical Journal, remdesivir "probably has no important effect on the need for mechanical ventilation and may have little or no effect on the length of hospital stay". Because of the high price, the authors point out that remdesivir may divert funds and efforts away from other treatments against COVID‑19.[26][27]

In November 2020, the World Health Organization updated its guideline on therapeutics for COVID-19 to include a conditional recommendation against the use of remdesivir, triggered by results from the WHO Solidarity trial.[14][23] Gilead issued a statement in response to the updated World Health Organization treatment guidelines.[28]

Side effects

The most common adverse effects in people treated with remdesivir were respiratory failure and blood biomarkers of organ impairment, including low albumin, low potassium, low count of red blood cells, low count of thrombocytes, and elevated bilirubin (jaundice).[29] Other reported adverse effects include gastrointestinal distress, elevated transaminase levels in the blood (liver enzymes), infusion site reactions, and electrocardiogram abnormalities.[12] Remdesivir may cause infusion‐related reactions, including low blood pressure, nausea, vomiting, sweating or shivering.[30]

Monitoring and Adverse Effects

Remdesivir can cause gastrointestinal symptoms (e.g., nausea), elevated transaminase levels, an increase in prothrombin time (without a change in the international normalized ratio), and hypersensitivity reactions.

Liver function tests and prothrombin time should be obtained in all patients before remdesivir is administered and during treatment as clinically indicated. Remdesivir may need to be discontinued if alanine transaminase (ALT) levels increase to >10 times the upper limit of normal and should be discontinued if an increase in ALT level and signs or symptoms of liver inflammation are observed.

patients with an estimated glomerular filtration rate (eGFR) of <50 mL/min were excluded from some clinical trials of remdesivir; other trials had an eGFR cutoff of <30 mL/min. Remdesivir is not recommended for patients with an eGFR <30 mL/min due to lack of data.5 Renal function should be monitored before and during remdesivir treatment as clinically indicated.3

Drug-Drug Interactions

Minimal to no reduction in remdesivir exposure is expected when remdesivir is coadministered with dexamethasone, according to information provided by Gilead Sciences (written communication, July 2020). Chloroquine or hydroxychloroquine may decrease the antiviral activity of remdesivir; coadministration of these drugs is not recommended.3 Remdesivir is not expected to have any significant interactions with oseltamivir or baloxavir

Considerations in Pregnancy

  • Pregnant patients were excluded from the clinical trials that evaluated the safety and efficacy of remdesivir for the treatment of COVID-19, but preliminary reports of remdesivir use in pregnant patients from the remdesivir compassionate use program are reassuring.
  • Among 86 pregnant and postpartum hospitalized patients with severe COVID-19 who received compassionate use remdesivir, the therapy was well tolerated, with a low rate of serious adverse events.8
  • Remdesivir should not be withheld from pregnant patients if it is otherwise indicated.

Considerations in Children

  • The safety and effectiveness of using remdesivir to treat COVID-19 have not been evaluated in pediatric patients aged <12 years or weighing <40 kg.
  • Remdesivir is available through an FDA EUA for the treatment of COVID-19 in hospitalized pediatric patients weighing 3.5 kg to <40 kg or aged <12 years and weighing ≥3.5 kg.

  • Clinical Trials

    Several clinical trials that are evaluating the use of remdesivir for the treatment of COVID-19 are currently underway or in development. Please see ClinicalTrials.gov for the latest information.

  • tocilizumab


  • Tocilizumab (INN, trade name Actemra), also known as atlizumab, is an immunosuppressive drug, mainly for the treatment of rheumatoid arthritis (RA) and systemic juvenile idiopathic arthritis, a severe form of arthritis in children. It is a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R). Interleukin 6 (IL-6) is a cytokine that plays an important role in immune response and is implicated in the pathogenesis of many diseases, such as autoimmune diseases, multiple myeloma and prostate cancer. 

  • COVID-19[edit]

    The pathogenesis of the acute pulmonary treatment injury related to COVID-19 is related to a severe hyperinflammatory state with high amounts of pro-inflammatory cytokines such as IL-6, IL-1, IL-2, and TNF-Ī±.[16][17] Preliminary trial data has suggested that tocilizumab may be effective in improving outcomes for patients severely affected by the SARS-CoV-2 virus; REMAP-CAP trial has provided sufficient evidence for it to be added to the approved list.[18][19]

    Adverse effects[edit]

    The most common adverse effects observed in clinical trials were upper respiratory tract infections (more than 10% of patients), nasopharyngitis (common cold), headache, and high blood pressure (at least 5%). The enzyme alanine transaminase was also elevated in at least 5% of patients, but in most cases without symptoms. Elevated total cholesterol levels were common.[20] Among the less common side effects were dizziness, various infections, as well as reactions of the skin and mucosae like mild rashes, gastritis and mouth ulcer. Rare but severe reactions were gastrointestinal perforations (0.26% in six months) and anaphylaxis (0.2%).[21]

    Interactions[edit]

    There are no certain interactions with other drugs. The blood plasma levels of simvastatin were reduced by 57% after a single dose of tocilizumab, but it is not known whether this is clinically relevant. A possible mechanism is that the elevated IL-6 levels of patients with RA suppress the biosynthesis of various cytochrome P450 enzymes, notably CYP1A2, CYP2C9, CYP2C19 and CYP3A4. Tocilizumab lowers IL-6 and thus normalises cytochrome levels, increasing the metabolization of simvastatin (and possibly other cytochrome metabolised drugs).[21]

    Mechanism of action[edit]

    Besides other functions, interleukin 6 (IL-6) is involved in the development of immunological and inflammatory reactions. Some autoimmune diseases like RA are associated with abnormally high IL-6 levels. Tocilizumab binds soluble as well as membrane bound interleukin-6 receptors, hindering IL-6 from exerting its pro-inflammatory effects.[21][22] It has been noted that the membrane bound form and soluble form of the IL-6 receptor may have different effects in the pathogenesis of rheumatoid arthritis with the soluble form being more implicated in disease progression.[23]

  • In January 2021, the REMAP-CAP trial released preliminary evidence that tocilizumab and sarilumab could reduce fatalities among severely ill Covid-19 patients. The drugs were added to the UK recommended list for COVID-19 treatment.[50] The following month, the RECOVERY Trial revealed a similar result: 29% of the patients in the tocilizumab group died within 28 days compared with 33% in the usual care group, a statistically significant reduction of the risk of death on top of the reduction already given by dexamethasone. It also reduced the chance of a patient needing to go on a ventilator or dying from 38% to 33%. Researchers reported that tocilizumab and dexamethasone combined should cut death risk by about a third for patients on oxygen and halve it for those on a ventilator.[51][52]

  • favipiravir

  • Favipiravir, sold under the brand name Avigan among others,[3] is an antiviral medication used to treat influenza in Japan.[4] It is also being studied to treat a number of other viral infections,[4] including Covid-19.

    Side effects[edit]

    There is evidence that use during pregnancy may result in harm to the baby.[6] Teratogenic and embryotoxic effects were shown on four animal species.[6][8]

    Mechanism of action[edit]

    The mechanism of its actions is thought to be related to the selective inhibition of viral RNA-dependent RNA polymerase.[

  •  

  • Highlights

    •

    Favipiravir is approved by some countries, including India, for COVID-19 treatment.

    •

    Favipiravir has shown rapid viral clearance and faster clinical improvement.

    •

    Various treatment recommendations include favipiravir for COVID-19 treatment.

    •

    Several ongoing clinical trials will further substantiate favipiravir role.

  • The Russian guidelines recommend a dosage regimen for patients weighing less than 75 kg as 1600 mg BID on day 1 and 600 mg BID from days 2–10. For patients weighing from 75 kg to 90 kg (inclusive): 2000 mg BID on day 1 and 800 mg BID on days 2–10. For patients weighing over 90 kg: 2400 mg BID on day 1 and further 1000 mg BID on days 2–10. The Saudi Ministry of Health protocol included favipiravir in mild to moderate cases in adults (1600 mg/dose BID on the first day; followed by 600 mg/dose BID for 7–10 days) as well as in pediatric patients (10–15 kg; loading dose: One tablet PO BID for one day; maintenance dose from day 2; half tablet (100 mg) PO BID); 16–21 kg: loading dose of two tablets PO BID one day (maximum 800 mg/day) and maintenance dose (from day 2) of one tablet PO BID (maximum 400 mg/day). It is also recommended in severe cases

  • Contraindications, precautions, and warning

    It is contraindicated in pregnant and lactating women. Because of the observation of its teratogenic potential in animal studies, it is contraindicated in pregnant and suspected pregnant women. It is found distributed in sperms; hence, it is advised to use effective contraceptive methods by both women and men of reproductive age during the course and 7 days post-therapy (Nagata et al., 2015, Delang et al., 2018). Additionally, it is contraindicated in patients with hypersensitivity, severe hepatic impairment, and severe renal impairment. Favipiravir should be administered with care in patients with gout or a history of gout, with hyperuricemia (Fabiflu Prescribing Information).

    Drug–drug interactions

    Precautions are advised while administrating pyrazinamide, repaglinide, theophylline, famciclovir, and sulindac (Obach et al., 2004). The partial data are available regarding its interaction with other drugs. Previous studies report an increased AUC of acetaminophen and acetaminophen glucuronide with coadministration of favipiravir (Obach et al., 2004). A potential risk of drug interaction occurs between the drugs that inhibit aldehyde oxidase, and favipiravir needs to be monitored cautiously. It needs to be carefully administered and monitored in the elderly; however, clinical studies are yet to be conducted in children.

    COVID-19


    There is limited evidence suggesting that, compared to other antiviral drugs, favipiravir might improve outcomes for people with COVID-19, but more rigorous studies are needed before any conclusions can be drawn.[21]

    As of April 2021 several clinical trials of favipiravir as a treatment for COVID-19 had been carried out or were underway, including one as part of a large UK scheme named "PRINCIPLE"

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