Author: Alyssa Lear, PharmD

Introduction

1. Recently, oral coronavirus agents showed treatment efficacy in clinical studies for outpatients with COVID-19
2. Goals of therapy for outpatients with COVID-19:
   1. Prevent serious disease, reduce visits to an urgent care/hospital, reduce duration of illness, and reduce death
3. Fluvoxamine is FDA approved for the treatment of obsessive-compulsive disorder, but has recently been studied in COVID-19 infections
4. Paxlovid™ & molnupiravir are COVID-19 treatments available under Emergency Use Authorization (EUA) by the FDA
   1. Counsel patients on the risks and benefits of therapy and provide a corresponding Fact Sheet for Patients and Caregivers before prescribing EUA therapies
5. Demand for these drugs > supply
   1. Prioritization of these medications based on: age, vaccination status, immune status, and clinical risk factors
   1. For risk groups and patient prioritization for treatment, please review: https://www.covid19treatmentguidelines.nih.gov/therapies/statement-on-patient-prioritization-for-outpatient-therapies/
6. Patient specific factors and product availability should drive decision-making regarding choice of agent
7. For drug allocation/distribution information, please utilize: https://covid-19-therapeutics-locator-dhhs.hub.arcgis.com/

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Pharmacology
	Paxlovid™ (nirmatrelvir/ritonavir)	Molnupiravir	Fluvoxamine
Dose	Estimated glomerular filtration rate (eGFR) >60 mL/min: 300 mg nirmatrelvir with 100 mg ritonavir by mouth twice daily for 5 days eGFR <60 to ≥30 mL/min: 150 mg nirmatrelvir with 100 mg ritonavir twice daily for 5 days eGFR <30 ml/min: Not recommended  Severe hepatic impairment (Child-Pugh Class C): Not recommended	Molnupiravir 800 mg (four 200 mg capsules) twice daily for 5 days   No renal/hepatic dose adjustments recommended	Fluvoxamine 100 mg by mouth twice daily for 10 days   No renal/hepatic dose adjustments recommended
EUA Date	12/2021	12/23/2021 & Revised on 02/2022	N/A
Initiate within # days of symptom onset	< 5 days	< 5 days	< 7 days
Age for use	≥ 12 years	≥ 18 years	Study included patients ≥ 18 years
Administration	Oral	Oral	Oral
PK/PD	MOA: Nirmatrelvir – inhibitor of the SARS-CoV-2 main protease Prevents viral replicationRitonavir is a CYP3A inhibitor included to increase nirmatrelvir plasma levelsRitonavir alone has NO activity against SARS-CoV-2 Time to peak: Nirmatrelvir: 3 hrs & Ritonavir: 3.98 hrs Half-life elimination: Nirmatrelvir: 6.05 ± 1.79 hrs & Ritonavir: 6.15 hrs Metabolism: Ritonavir: hepatic via CYP3A4 (major) & CYP2D6 (minor) Excretion: Nirmatrelvir: urine & feces Ritonavir: urine & feces	MOA: A nucleoside analogue that inhibits SARS-CoV-2 replication by viral mutagenesis Time to peak: 1.5 hrs Half-life elimination: 3.3 hrs Excretion: Urine	MOA: A selective serotonin reuptake inhibitor with minimal or no effect on reuptake of norepinephrine or dopamine Time to peak, plasma: 3 to 8 hrs Half-life elimination: ~14 to 16 hrs; ~17 to 26 hrs for elderly Metabolism: Hepatic via oxidative demethylation and deamination Bioavailability: Immediate release: 53%; Extended release: 84% Excretion: Urine
Adverse Effects	Hepatotoxicity – transaminase elevations, clinical hepatitis, jaundice Risk of HIV-1 Resistance Development Dysgeusia Diarrhea High blood pressure	Hypersensitivity including anaphylaxis Bone & cartilage toxicity DiarrheaNausea Dizziness	HeadacheDrowsinessAnxietyNauseaIndigestionDizziness
Drug Interactions and warnings	Drug-drug interaction searches are REQUIRED prior to treatmentPaxlovid™ may increase plasma concentrations of medications metabolized by CYP3AMedications that inhibit or induce CYP3A may increase or decrease Paxlovid™ concentrations Can lead to clinically significant adverse effects & fatal events from greater exposures of concomitant medicationsCan lead to viral resistance from decreased Paxlovid™ exposures	N/A	Monitor for drug-drug interactions prior to prescribing Inhibits CYP1A2 (strong), CYP2C19 (moderate), CYP2C9 (weak), CYP2D6 (weak), CYP3A4 (weak)Can enhance the serotonergic effects of other SSRIs or MAOIs leading to serotonin syndrome
Comments	Unpublished data from EPIC-HR trial indicates lower risk of COVID-19 hospitalization or mortality compared to placebo Not authorized for treatment of patients requiring hospitalization due to severe or critical COVID-19 Not authorized for use as pre/post-exposure prophylaxis for prevention of COVID-19Not authorized for use for ≥5 consecutive days	NOT recommended for use in pregnancy due to findings of fetal harm in animal studies Requires pregnancy test Contraception must be used during treatment & for 4 days after last dose Do not breastfeeding during treatment & for 4 days after last dose Males of reproductive potential should use contraception during treatment & for 3 months after last doseDo not use in patients ≤18 years – affects bone & cartilage growth Not authorized for treatment of patients hospitalized for COVID-19Not authorized for use as pre/post-exposure prophylaxis for prevention of COVID-19Not authorized for use for ≥5 consecutive days	In a murine sepsis model, fluvoxamine was found to bind to immune cells resulting in reduced production of inflammatory cytokines Ongoing studies are establishing whether anti-inflammatory effects are observed in humans with COVID-19 Screen for drug-drug interactions with CYP3A4Benefits in pregnancy must outweigh the risks (limited data available)

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	Overview of Evidence
Author, year	Design/ sample size	Intervention, Comparison, & Population	Outcome
(EPIC-HR Study) Unpublished data	Phase 2/3 double-blind study N= 2246	Intervention: Paxlovid™ or placebo x5 days Population: Enrolled within 5 days of symptom onset≥1 risk factor for progression to severe diseaseaNo prior COVID-19 vaccine or infectionStandard of care treatment allowed but primary analysis population was limited to subjects who did NOT receive COVID-19 monoclonal antibodies	COVID-19 related hospitalizations/death through day 28: 0.8% Paxlovid™ vs. 6.3% placebo when treated within 5 days of symptom onset   Paxlovid™ reduced risk of hospitalization or death by 89% (within 3 days of symptom onset) and 88% (within 5 days of symptom onset)
Caraco, 2022 Phase 2/3 Study	N= 302	Intervention: molnupiravir 200, 400, or 800 mg twice daily vs placebo x5 days (1:1:1:1) Population: Mild or moderate, laboratory confirmed Covid-19 with onset of symptoms up to 7 days before randomization and required to be at risk for severe illnessa	Proportion of patients who were hospitalized and/or died through day 29: Molnupiravir 3.1% vs. placebo 5.4%   Molnupiravir was not associated with dose-limiting side effects   Highest clinical benefit for patients treated early in the Covid-19 disease course (symptom onset ≤5 days before care with risk factors for severe Covid-19 illness)
Bernal, 2022 (MOVe-OUT Study)	Double-blind, RCT N= 1433	Intervention: 800 mg of molnupiravir or placebo x5 days Population: Administered within 5 days after the onset of symptoms in non-hospitalized, unvaccinated adults with mild-to-moderateb, laboratory confirmed COVID-19 and at least 1 risk factora for severe illness	Hospitalization or death at day 29 (intention-to-treat population): Molnupiravir 7.3% vs. placebo 14.1%   Hospitalization or death at day 29 (all participants): Molnupiravir 6.8% vs. Placebo 9.7%   Incidence of adverse events: 30.4% molnupiravir vs.  33.0% placebo
Reis, 2022 (TOGETHER Trial)	Placebo-controlled, RCT conducted at 11 clinical sites in BrazilN= 1,497	Intervention: Fluvoxamine 100 mg twice daily x10 days or placebo Population: Patients ≥ 18 years at an outpatient care setting with COVID-19 symptoms beginning within 7 days of the screening date, a positive rapid test done at the time of screening, or patient with positive diagnostic test within 7 days of symptom onset	Composite endpoint of medical admission to a hospital setting due to COVID-19c: 11% fluvoxamine vs. 16% placebo   No statistically significant difference in mortality between study arms in the intention-to-treat population
Lenze, 2020 STOP COVID	Double- blind RCT in United States	Intervention: Fluvoxamine 50 mg x1 dose, then fluvoxamine 100 mg twice daily, then fluvoxamine 100 mg three times daily through day 15 or placebo	Clinical deterioration within 15 days of randomization: 0% fluvoxamine vs. 8.3% placebo   Fluvoxamine reduced the proportion of patients who experienced clinical deterioration
Wen Wen, 2022	Meta-analysisIncluded 8 studies	Inclusion criteria: Articles with clinical results, total number of participants, and deaths/hospitalizations of patients receiving molnupiravir, fluvoxamine, or Paxlovid English literature	Odds ratio (OR) for death or hospitalization in the drug vs. placebo group was 0.33 Oral drugs are effective for COVID-19 patients reducing mortality or hospitalization by ~67%   OR adverse events drug vs. placebo group was 0.85 No significant difference between groups

^a Risk factors – age >60 years; cancer; chronic kidney disease; chronic obstructive pulmonary disease; obesity (BMI ≥ 30); serious heart conditions (heart failure, coronary artery disease, or cardiomyopathies); or diabetes mellitus

^b Defined based on Food and Drug Administration and World Health Organization (WHO) guidance

^c Defined as COVID-19 emergency setting visits with participants in observation for >6 h or referral to further hospitalization due to the progression of COVID-19 within 28 days of randomization

^d Defined as dyspnea or being hospitalized for dyspnea or pneumonia & having SpO2 <92% on room air or requiring supplemental oxygen to attain SpO2 ≥92%

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Conclusions

• Paxlovid is currently in limited supply and should be prioritized for higher risk populations
  • Determine drug-drug interactions prior to prescribing
  • To assess for drug-drug interactions with Paxlovid™, please review:
    • https://www.covid19treatmentguidelines.nih.gov/therapies/statement-on-paxlovid-drug-drug-interactions/
    • https://www.covid19-druginteractions.org/
• Molnupiravir should be used when other options are not available due to lower efficacy
  • Not recommended in pediatrics or patients who are pregnant/breastfeeding 
• There is insufficient evidence for the COVID-19 Treatment Guidelines Panel to recommend either for or against the use of fluvoxamine for the treatment of COVID-19

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References

1. Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved January 17, 2021, from http://www.micromedexsolutions.com/
2. Nirmatrelvir & ritonavir (Paxlovid™) [package insert]. New York, NY: Pfizer Inc.; 2021. https://www.fda.gov/media/155050/download
3. Pfizer announces additional phase 2/3 study results confirming robust efficacy of novel COVID-19 oral antiviral treatment candidate in reducing risk of hospitalization or death. News release. Pfizer Inc. Published December 14, 2021. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-announces-additional-phase-23-study-results.
4. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19
5. Mahase E. Covid-19: Pfizer’s paxlovid is 89% effective in patients at risk of serious illness, company reports. BMJ. 2021;375:n2713.
6. https://clinicaltrials.gov/ct2/show/NCT04960202
7. Molnupiravir [package insert]. Kenilworth, NJ: Merck & Co., Inc.; 2021-2022. https://www.fda.gov/media/155054/download
8. Caraco Y, Crofoot GE, Moncada PA, et al. Phase 2/3 Trial of Molnupiravir for Treatment of Covid-19 in Nonhospitalized Adults. NEJM Evidence. 2022; 1 (2).
9. Jayk Bernal A, Gomes da Silva MM, Musungaie DB, Kovalchuk E, Gonzalez A, Delos Reyes V, Martín-Quirós A, Caraco Y, Williams-Diaz A, Brown ML, Du J, Pedley A, Assaid C, Strizki J, Grobler JA, Shamsuddin HH, Tipping R, Wan H, Paschke A, Butterton JR, Johnson MG, De Anda C; MOVe-OUT Study Group. Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients. N Engl J Med. 2022 Feb 10;386(6):509-520.
10. Reis G, Dos Santos Moreira-Silva EA, Silva DCM, Thabane L, Milagres AC, Ferreira TS, Dos Santos CVQ, de Souza Campos VH, Nogueira AMR, de Almeida APFG, Callegari ED, de Figueiredo Neto AD, Savassi LCM, Simplicio MIC, Ribeiro LB, Oliveira R, Harari O, Forrest JI, Ruton H, Sprague S, McKay P, Glushchenko AV, Rayner CR, Lenze EJ, Reiersen AM, Guyatt GH, Mills EJ; TOGETHER investigators. Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial. Lancet Glob Health. 2022 Jan;10(1):e42-e51.
11. Lenze EJ, Mattar C, Zorumski CF, et al. Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: a randomized clinical trial. JAMA. 2020;324(22):2292-2300. 
12. Rosen DA, Seki SM, Fernandez-Castaneda A, et al. Modulation of the sigma-1 receptor-IRE1 pathway is beneficial in preclinical models of inflammation and sepsis. Sci Transl Med. 2019;11(478).
13. Wen W, Chen C, Tang J, Wang C, Zhou M, Cheng Y, Zhou X, Wu Q, Zhang X, Feng Z, Wang M, Mao Q. Efficacy and safety of three new oral antiviral treatment (molnupiravir, fluvoxamine and Paxlovid) for COVID-19：a meta-analysis. Ann Med. 2022 Dec;54(1):516-523.