COVID-19: Medication therapy

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Background

  • As of December 2020, there is currently only a single FDA-approved therapeutic for the treatment
    • However, there are many therapeutics that have been considered for therapy and available for off-label use and through FDA Emergency-Use-Authorization.

Evidence Supported Acute Therapies

Dexamethasone

  • Dosage: 6mg Qday
    • Dexamethasone improves 28d mortality compared to placebo in patients requiring IMV (NNT = 8.5) and those patients requiring oxygen therapy (NNT = 29).
    • There was no benefit to patients not requiring oxygenation support and potentially harm

Remdesivir

  • For 5 days or until the time of hospital discharge, whichever comes first.
  • Indication[1]
    • SpO2≤94% on ambient air (at sea level) or requiring supplemental oxygen via low flow device
    • There is insufficient data to recommend for or against use in patients using high flow oxygen, mechanical ventilation or ECMO (NIH COVID-19 Guidelines).
  • Contraindications[2]
    • Alanine transaminase or aspartate transaminase >5 times the upper limit of normal
    • Creatinine clearance of <30 mL/minute
      • Can be considered in patients with calculated creatinine clearance of <30 mL/minute and in patients receiving hemodialysis if the benefits outweigh the risk (limited data).
      • At this time, there are no recommended dose adjustments for this patient population.
    • Pediatric patients 3.5kg to 12 years of age; should not be given if ALT is >10 times normal.[3]

Investigational Therapies

NIH panel does not recommend initiation of any investigational therapies outside of a clinical trial[4]

Antivirals

Chloroquine or Hydroxychloroquine With or Without Azithromycin

  • FDA cautions against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems[5]
  • NIH panel recommends against the use of chloroquine or hydroxychloroquine with or without azithromycin for the treatment of COVID-19 in hospitalized patients.[6]
  • In nonhospitalized patients, the Panel recommends against the use of chloroquine or hydroxychloroquine with or without azithromycin for the treatment of COVID-19, except in a clinical trial.[7]
  • NIH panel recommends against the use of high-dose chloroquine (600 mg twice daily for 10 days) for the treatment of COVID-19.[8]

Lopinavir/Ritonavir and Other HIV Protease Inhibitors

  • NIH Panel recommends against using lopinavir/ritonavir (AI) or other HIV protease inhibitors to treat COVID-19, except in a clinical trial.[9]
  • Known in the U.S as Kaletra, this HIV medication has been widely used in China to treat COVID patients.[10].
  • An RCT with 199 confirmed COVID-19 positive patients concluded that there was no benefit to treating hospitalized patients with Lopinavir/Ritonavir versus supportive care.[11]
  • Dose: 400/100mg BID x 10 days. [12]

Ivermectin

  • NIH Panel recommends against the use of ivermectin for the treatment of COVID-19, except in a clinical trial.[13]

Oseltamivir

  • Coronaviruses do not utilize neuraminidase for the budding stage of reproduction and therefore no activity is expected.
  • Several small trials have not shown any benefit in patients with COVID-19. [14]

Baloxavir marboxil

  • Several clinical trials are underway however there is no evidence at this time for the efficacy of Baloxavir marboxil in treating COVID-19

Favipiravir

  • A small, open label, non-randomized trial in China has shown promising results and has not been peer reviewed.[15]
  • A small prospective, open label study conducted in China has shown promise in symptom reduction for moderately ill patients with COVID-19 and has not yet been peer reviewed [16]

Ribavirin

  • Has been used in patients with MERS with inconclusive results.[17]
  • Small trials in China and North America have failed to establish a therapeutic benefit of Ribavirin. [18]

Azithromycin

  • Macrolide antibiotic with purported anti-inflammatory effects in certain respiratory conditions such as COPD.
  • A small French study with 20 patients showed benefit in reducing symptoms and viral carriage when combined with Hydroxychloroquine. [19]
  • Recommended if there is concern for bacterial superinfection[20]
  • Dosage: 500mg x 1 day. Then 250mg x 4 days.

Immunomodulators

Interferon

  • Typically used in combination with ribavirin, interferons have been studied for patients with other coronaviruses, with mixed results. Their adverse effect profiles are also generally unfavorable.

Tocilizumab

  • FDA approved Interleukin-6 (IL-6) monoclonal antibody receptor antagonist used to treat rheumatoid arthritis and cytokine release storm syndrome.
  • Multiple anecdotal reports and cases showing marked improvement in oxygenation and clinical outcome after drug administration.[21] [22]
  • FDA approved randomized double-blinded clinical trial under way to evaluate its safety and efficacy. [23]
  • Dosage: Typically 8 mg/kg single dose, though some reports suggest giving repeated dosages in critically ill patients. [24]

Convalescent Plasma

  • Prior studies with convalescent plasma involving SARS, H1N1, and Ebola have had proven benefit in critically ill patients. [25]
  • Involves obtaining plasma/antibodies from patients who have recovered from COVID-19 and injecting them into critically ill patients.
  • Shown to have possible clinical improvement in patients with severe ARDS and COVID-19. [26]

Anticoagulation

  • Anticoagulation may be associated with lower mortality due to COVID-19 associated vascular thromboemboli resulting in increased dead space ventilation. [27]
  • Do not give anticoagulation to patients who have a high risk of bleeding as judged by the treating physician.
  • Before starting anticoagulation, check cbc, pt/ptt, d-dimer. Hold anticoagulation if platelet count <50,000 or INR >1.5.
  • In admitted patients with moderate or severe COVID-19:
  • High risk: No definitive criteria, but clinician should use a combination of respiratory distress, o2 requirement, elevated d-dimer, creatinine, and crp in making determination.

Dosing

  • ICU: Heparin drip per PE protocol (goal PTT 70 - 110) or Enoxaparin SC 1mg/kg BID.
  • High risk admitted patients:
    • CrCl > 50: Enoxaparin SC 1m/kg BID
    • CrCl <50:
      • On renal replacement Therapy: Apixaban 5mg PO BID or heparin drip PE protocol.
      • Not on renal replacement Therapy: Apixaban 5mg PO BID or Adjusted Dose Enoxaparin.
  • Not high risk:
    • Apixaban 2.5-5.0mg PO BID or Enoxaparin SC 40mg QD.

Other experimental agents

Contraindicated Therapies

  • NSAIDS
    • There is anecdotal evidence to suggest that NSAIDs could potentially harm patients infected with COVID-19.[28]
    • Some experts suggest avoiding NSAIDs altogether while recommending the use of paracetamol/acetaminophen instead. [29]
    • It is important to note that there is no strong evidence to suggest NSAIDs should be avoided in general in COVID-19 patients[30]
  • ACEi/ARBs
    • There is an increase in mortality in patients with both hypertension and COVID-19 infection. [31]
    • ACEi and ARBs, used in the treatment of hypertension, has been postulated to contribute to the increased mortality by upregulating membrane-bound angiotensin-converting enzyme 2 (ACE2) which allows COVID-19 entry into human cells. [32]
    • Currently, however, there is insufficient evidence to recommend against using ACEi and ARBs in patients with COVID-19. [33]
  • Nebulizers
    • Avoid nebulizers as they are generally ineffective and may aerosolize virus
    • Albuterol with spacer is safer, though probably ineffective unless co-occuring reactive airway disease
      • MDI equivalents: Albuterol or ipratropium
        • <20 kg or 5yrs old: 4-5 puffs with a spacer every 20 minutes. 4 breaths between puffs.
        • >20 kg or 5yrs old: 8-10 puffs with a spacer every 20 minutes. 4 breaths between puffs.

COVID-19 vaccines

See:

See Also

External Links

References

  1. https://www.covid19treatmentguidelines.nih.gov/antiviral-therapy/remdesivir/
  2. https://www.covid19treatmentguidelines.nih.gov/antiviral-therapy/remdesivir/
  3. https://www.fda.gov/media/137566/download
  4. https://www.covid19treatmentguidelines.nih.gov/antiviral-therapy/
  5. https://www.fda.gov/drugs/drug-safety-and-availability/fda-cautions-against-use-hydroxychloroquine-or-chloroquine-covid-19-outside-hospital-setting-or
  6. https://www.covid19treatmentguidelines.nih.gov/antiviral-therapy/
  7. https://www.covid19treatmentguidelines.nih.gov/antiviral-therapy/
  8. https://www.covid19treatmentguidelines.nih.gov/antiviral-therapy/
  9. https://www.covid19treatmentguidelines.nih.gov/antiviral-therapy/
  10. https://www.reuters.com/article/us-health-coronavirus-china-wuhan-hospit/key-china-coronavirus-hospital-says-hiv-drug-beneficial-to-patients-idUSKCN21R1LX
  11. Cao, B., Wang, Y., Wen, D., Liu, W., Wang, J., Fan, G., ... & Li, X. (2020). A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19. New England Journal of Medicine.
  12. https://www.massgeneral.org/assets/MGH/pdf/news/coronavirus/mass-general-COVID-19-treatment-guidance.pdf
  13. https://www.covid19treatmentguidelines.nih.gov/antiviral-therapy/
  14. Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. E-pub Date: aheadofprint February 2020. DOI # 10.1001/jama.2020.1585 . https://www.ncbi.nlm.nih.gov/pubmed/32031570
  15. https://www.jwatch.org/na51293/2020/04/09/favipiravir-potential-antiviral-covid-19
  16. https://www.medrxiv.org/content/10.1101/2020.03.17.20037432v3
  17. Arabi YM, et al. Ribavirin and Interferon Therapy for Critically Ill Patients With Middle East Respiratory Syndrome: A Multicenter Observational Study. Clin Infect Dis. 2019 Jun 25. https://www.ncbi.nlm.nih.gov/pubmed/31925415.
  18. Devaux CA1, Rolain JM2, Colson P2, Raoult D2. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19?. Int J Antimicrob Agents. 2020 Mar 12:105938. doi: 10.1016/j.ijantimicag.2020.105938.
  19. Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020:105949. [PMID: 32205204] doi:10.1016/j.ijantimicag.2020.105949
  20. https://www.massgeneral.org/assets/MGH/pdf/news/coronavirus/mass-general-COVID-19-treatment-guidance.pdf
  21. Xu X et al. Effective Treatment of Severe COVID-19 Patients with Tocilizumab. Unpublished study. 2020) https://www.ser.es/wp-content/uploads/2020/03/TCZ-and-COVID-19.pdf
  22. Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review. JAMA. Published online April 13, 2020. doi:10.1001/jama.2020.6019
  23. “Roche Initiates Phase III Clinical Trial of Actemra/RoActemra in Hospitalised Patients with Severe COVID-19 Pneumonia.” Roche, www.roche.com/media/releases/med-cor-2020-03-19.htm.
  24. Luo, Pan. “Tocilizumab Treatment in COVID-19: A Single Center Experience.” Journal of Medical Virology, 2020, doi:10.1002/jmv.25801.
  25. Chen, Long et al. “Convalescent plasma as a potential therapy for COVID-19.” The Lancet. Infectious diseases vol. 20,4 (2020): 398-400. doi:10.1016/S1473-3099(20)30141-9
  26. “Shen C, Wang Z, Zhao F, et al. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA. Published online March 27, 2020. doi:10.1001/jama.2020.4783”
  27. Tang et al. J Thromb Haemost 2020 Mar 27. PMID: 32220112
  28. Willsher, Kim. “Anti-Inflammatories May Aggravate Covid-19, France Advises.” The Guardian, Guardian News and Media, 14 Mar. 2020, www.theguardian.com/world/2020/mar/14/anti-inflammatory-drugs-may-aggravate-coronavirus-infection.
  29. Day, Michael. “Covid-19: Ibuprofen Should Not Be Used for Managing Symptoms, Say Doctors and Scientists.” Bmj, 2020, p. m1086., doi:10.1136/bmj.m1086.
  30. Pergolizzi JV Jr, Varrassi G, Magnusson P, et al. COVID-19 and NSAIDS: A Narrative Review of Knowns and Unknowns. Pain Ther. 2020;9(2):353-358. doi:10.1007/s40122-020-00173-5
  31. Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. Published online March 13, 2020. doi:10.1001/jamainternmed.2020.0994
  32. Fang, Lei, et al. “Are Patients with Hypertension and Diabetes Mellitus at Increased Risk for COVID-19 Infection?” The Lancet Respiratory Medicine, vol. 8, no. 4, 2020, doi:10.1016/s2213-2600(20)30116-8.
  33. Patel AB, Verma A. COVID-19 and Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers: What Is the Evidence? JAMA. Published online March 24, 2020. doi:10.1001/jama.2020.4812