Episode 80 - Oral Meds for COVID-19 - a podcast by Rio Bravo Family Medicine Residency Program

Episode 80: Oral Meds for COVID-19. 

The US department of human health and services recently launched the COVID19 Therapeutics Locator website to allow providers find locations where they can send prescriptions for Paxlovid and Molnupiravir. Find the COVID19 therapeutics locator online: https://arcg.is/iuuW50

Yasmin and Arti discuss oral medications under emergency use authorization for COVID-19: Paxlovid and Molnupiravir. 

Introduction: Meds for COVID-19.  
By Hector Arreaza, MD.  

For the last 2 years, humanity has faced the challenge to find an effective way to fight COVID-19. This pressing charge has not been free of obstacles. It has been hindered by politics, misinformation, greed, jealousy, and many other not-so positive human traits. For me, living through the pandemic has been somewhat frustrating and shaming. Stupidity, vulgarity, and mediocrity are a few of the attributes that have flourished during the last 2 years all around us. 

But not everything about the pandemic has been negative. Many talented people with good intentions have engaged in serious research and have made tremendous contributions to science and humanity. Vaccines have been developed using cutting-edge technology and their efficacy has been very positive so far. Many medications have been tried to fight COVID-19 since the beginning. Some clinicians have tried to repurpose old medications in their honest desires to fight COVID-19. Examples include ACE inhibitors, statins, azithromycin, hydroxychloroquine, and chloroquine, which have not proven to be effective against this virus so far. 

Ivermectin, for example, has been very controversial since the beginning of the pandemic. Ivermectin is not approved by the FDA for the treatment of COVID-19. Until today, the National Institutes of Health do not have enough data to recommend for or against using ivermectin for COVID-19. “Results from adequately powered, well-designed, and well-conducted clinical trials are needed to provide more specific, evidence-based guidance on the role of ivermectin in the treatment of COVID-19.” Ivermectin is still being used by some clinicians in the United States based on personal experience and opinions.

At this time, remdesivir (brand name Veklury®) is the only medication approved by the FDA to treat COVID-19. IV remdesivir won full FDA approval in October 2020 for hospitalized patients, and its use has been expanded a couple days ago to include use in non-hospitalized high-risk patients. 

The NIH recommends against IL-6 inhibitors, such as tocilizumab or sarilumab, in COVID-19 patients who are not in the ICU. At this moment, there is not enough data for the NIH to make a recommendation for patients who are in the ICU. Baricitinib is an oral medication used to treat rheumatoid arthritis authorized in November 2020 to be used in combination with remdesivir for the treatment of COVID-19 in certain hospitalized children and adults who require supplemental oxygen, mechanical ventilation, or Extracorporeal membrane oxygenation (ECMO). Baricitinib is now authorized to be used without remdesivir against COVID-19 in hospitalized patients. We cannot forget the use of dexamethasone in hospitalized patients requiring oxygen.

Today we want to give you a little taste of two oral medications: Paxlovid® and molnupiravir. You will listen to two brave medical students presenting what they have found about these medications. 

This is Rio Bravo qWeek, your weekly dose of knowledge brought to you by the Rio Bravo Family Medicine Residency Program from Bakersfield, California. Our program is affiliated with UCLA, and it’s sponsored by Clinica Sierra Vista, Let Us Be Your Healthcare Home. 

Paxlovid®.   
By Yasmin Fazli, MS3, Ross University School of Medicine.  

What is it?

Paxlovid® is the first oral treatment for mild-to-moderate coronavirus disease (COVID-19) in patients over 12 years-old to be issued by the FDA. The FDA issued an emergency use authorization (EUA) on December 22, 2021. It is made up of two different medications: nirmatrelvir and ritonavir. Nirmatrelvir is a protease inhibitor while ritonavir helps decrease the breakdown of nirmatrelvir. 

 

The combination authorized is nirmatrelvir 300 mg plus ritonavir 100 mg. You may remember ritonavir use in combination with other antiretrovirals for the treatment of HIV/AIDS.

 

At the end of the 2021, Pfizer announced that results from a trial comparing between Paxlovid® versus a placebo revealed that Paxlovid® reduced proportion of mortality and morbidity by 88% compared to placebo after a 5-day course.

 

When and how to prescribe it?

To use Paxlovid® some criteria must be met by the patient. First, a positive result of COVID-19 viral testing, second, the patient must be at high risk for illness progression to a more severe state, including hospitalization and death; and third, the patient must be 12 years or older. 

 

Paxlovid® should be started as soon as possible after diagnosis of COVID-19 and within 5 days of symptom onset. It is to be taken by mouth 2 times a day for 5 days straight with or without food. You take 3 pills twice a day. It is not authorized for more than 5 days. 

 

It is not authorized for the pre-exposure or post-exposure prevention of COVID-19. It’s not meant to be a replacement for the vaccine. 

 

Side effects?

Possible side effects of Paxlovid® include dysgeusia (altered or impaired sense of taste), diarrhea, increased blood pressure, and myalgia (muscle aches). Nirmatrelvir and ritonavir, which comprise Paxlovid®, also interact with other medications, which may lead to serious or life-threatening adverse reactions. 

 

It’s contraindicated in patients taking medications that are dependent on CYP3A metabolism for clearance, for example, warfarin, amiodarone, clozapine, midazolam, sildenafil (for pulmonary hypertension), etc. A list of these medications has been reviewed by the FDA and you can find it online. 

 

Liver problems have occurred in patients receiving ritonavir. Therefore, caution should be exercised when administering Paxlovid® to patients with pre-existing liver diseases, liver enzyme abnormalities, or hepatitis. Furthermore, Paxlovid® is not recommended for patients with severe kidney problems, and if they do use it, the dose should be adjusted.

Because nirmatrelvir is co-administered with ritonavir, there may be a risk of HIV-1 developing resistance to HIV protease inhibitors in individuals with uncontrolled or undiagnosed HIV-1 infection. 

As for pregnancy or lactation, there currently is no data available for it to understand any potential effects on miscarriages, birth defects, or maternal and fetal outcomes. 

Considering all of this, please review your patients’ list of medications and supplements and medical history prior to initiating Paxlovid®.

Concerns?

Due to its limited clinical data availability, other adverse effects that have not been reported may also occur while using Paxlovid® on top of the side effect list we are aware of. Ritonavir is a well-known medication, but nirmatrelvir is brand new. 

 

Another concern is its limited availability. So even though it has shown positive results, it is not widely available yet, which leads to having to prioritize certain populations such as the unvaccinated patients. This may prove to be a moral and ethical concern. 

 

Effectiveness?

There is no long-term data on Paxlovid® yet; however, from what we do know, it is proving to be effective more than placebo by almost 90% which shows much promise. It works against current or previous variants of COVID-19. 

 

EPIC-HR is the randomized, double-blind, 2-arm study done to prove Paxlovid®. It included 2246 patients with laboratory-confirmed SARS-CoV-2 infection, mild to moderate symptoms, and at least one comorbidity with increased risk of developing severe illness from COVID-19. Patients were randomly assigned 1:1 to receive either Paxlovid or placebo orally every 12 hours for 5 days.

 

Results: Paxlovid significantly reduced the risk of COVID-19-related hospitalization or death from any cause by 89% (within 3 days of symptom onset) compared with placebo. Through day 28, 0.7% (5/697) of patients in the Paxlovid® arm were hospitalized compared with 6.5% (44/682) of those in the placebo arm. The study also showed that nobody died taking Paxlovid® while 12 people died taking placebo. These are promising results and Pfizer will be announcing more information on the effectiveness as time passes by. 

 

Pricing?

The original pricing was announced to be $530.00; however, it’s been added that it’ll be at no cost to the people in the United States. 

 

Molnupiravir.   
By Arti Patel, MS3, Ross University School of Medicine.  

1. What is molnupiravir? 

Molnupiravir is an antiviral medication that can be used to treat COVID-19. Molnupiravir is a nucleoside analog that inhibits viral replication. The active drug of molnupiravir (N-hydroxycytidine) tricks the RNA polymerase enzyme into incorporating the drug instead of uridine or cytidine. Nucleobases continue to get added to the RNA chain and eventually the new RNA molecule has accumulated enough errors that the virus cannot replicate further. 

 

 

 

2. When and how to prescribe it? 

Molnupiravir is available for Emergency Use Authorization for “mild to moderate COVID-19 disease in adults with positive results of direct viral testing who are at risk of developing severe COVID-19, including hospitalization or death or those in whom alternative COVID-19 treatment options approved by the FDA are not accessible or clinically appropriate.” 

 

FDA provided EUA status on December 23, 2021. It should be taken as soon as COVID-19 is diagnosed, and within 5 days of symptom onset. It is not to be used as a method to prevent COVID-19 disease. Not for prophylaxis. 

 

Benefits of treatment have not been seen after hospitalization, so administration of molnupiravir in patients hospitalized due to COVID-19 is not recommended. Adults above the age of 18 should take 800 mg orally every 12 hours for 5 days, with or without food. Use for longer than 5 days has not been studied. 

 

3. Side effects? 

Most common adverse effects are diarrhea, nausea, and vomiting. 

 

4. Concerns? 

Pediatric patients: Molnupiravir may not be used in patients under the age of 18 due to effects on bone and cartilage growth. Studies in rats with repeated doses of molnupiravir showed bone and cartilage toxicity. 

 

Pregnancy: Fetal toxicity was observed when given to pregnant individuals in animal reproduction studies. Risk of adverse maternal or fetal outcomes or birth defects have not been studied in humans as of now. Use of molnupiravir in pregnant individuals may be considered once the prescribing physician has assessed the potential risks and benefits. Prior to initiating treatment of molnupiravir, if clinically indicated, assess whether a patient is pregnant. If a patient is having irregular menstrual cycles, first day last menstrual period is unknown, or patient is not using an effective method of contraception, a pregnancy test is advised. 

 

Females of childbearing age are advised to use an effective method of contraception while under treatment of molnupiravir and for 4 days after the final dose. Effects of molnupiravir on sperm are not known, thus effective contraception must be used while under treatment of molnupiravir and for 3 months after the last dose. 

 

Additionally, breastfeeding is not recommended during treatment and for 4 days after the last dose. 

 

5. Effectiveness? 

Although molnupiravir is not substitute in patients for whom COVID-19 vaccination and booster are recommended, it can be used for treatment of non-hospitalized patients with COVID-19 who have a high risk of progression to severe disease. 

 

In, MOVe-OUT, a randomized, double-blind, placebo-controlled clinical trial, almost 7% of about 700 individuals who received molnupiravir were hospitalized compared to almost 10% of 700 individuals who received the placebo. During the follow up period, one person who received molnupiravir died compared to 9 people who received the placebo. The safety and effectiveness of molnupiravir continues to be studied. 

 

Availability and pricing?

Not available in pharmacies yet, and preliminary pricing for a 5-day course of molnupiravir was about $700.

 

Conclusion of episode:

Now we conclude our episode number 80 “Oral Meds for COVID-19.” We hope you got enough information about these two medications: Pax-lovid and Mol-nu-pira-vir. Remember that they are authorized (not approved yet) by the FDA for the treatment of COVID-19. They are both oral medications, taken twice a day for 5 days. Their use in pregnant patients is not recommended yet. Paxlovid can be used in patients older than 12 years old, and molnupiravir in patients older than 18 years old. We’ll keep learning together about these medications in the future. Even without trying, every night you go to bed being a little wiser.

Thanks for listening to Rio Bravo qWeek. If you have any feedback about this podcast, contact us by email RioBravoqWeek@clinicasierravista.org, or visit our website riobravofmrp.org/qweek. This podcast was created with educational purposes only. Visit your primary care physician for additional medical advice. This week we thank Hector Arreaza, Arti Patel and Yasmin Fazli. Audio edition: Suraj Amrutia. See you next week! 

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References:

F.D.A. Approves Remdesivir for Patients Not Hospitalized, The New York Times, nytimes.com, January, 21, 2022, https://www.nytimes.com/2022/01/21/world/remdesivir-fda-approval-expanded-covid.html.

 

“Frequently Asked Questions on the Emergency Use Authorization for Paxlovid for Treatment of COVID-19”, U.S. Food and Drug, December 22, 2021, https://www.fda.gov/media/155052/download. Accessed on Jan 24, 2022.

 

“Pfizer Receives U.S. FDA Emergency Use Authorization for Novel COVID-19 Oral Antiviral Treatment,” pfizer.com, December 22, 2021. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-receives-us-fda-emergency-use-authorization-novel. 

 

Ahmad, B., Batool, M., Ain, Q. U., Kim, M. S., & Choi, S. (2021). Exploring the Binding Mechanism of PF-07321332 SARS-CoV-2 Protease Inhibitor through Molecular Dynamics and Binding Free Energy Simulations. International journal of molecular sciences, 22(17), 9124. https://doi.org/10.3390/ijms22179124

 

Coronavirus (COVID-19) Update: FDA Authorizes Additional Oral Antiviral for Treatment of COVID-19 in Certain Adults, fda.gov, December 23, 2021. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-additional-oral-antiviral-treatment-covid-19-certain. Accessed on January 24, 2022.

 

Fact Sheet for Healthcare Providers: Emergency Use Authorization for Molnupiravir, fad.gov, December 23, 2021, https://www.fda.gov/media/155054/download, accessed on January 24, 2022. 

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