Paxlovid vs Molnupiravir (Lagevrio) vs Ivermectin: What are the Differences?

If you are confused about the recommendations made by different professional groups for the COVID-19 pandemic, you've come to the right place. 

The number of options for the treatment of COVID-19 has increased drastically in recent months, thus making it complicated when it comes to choosing the right combination. In general, there are 3 broad categories of medical interventions:

1. Prevention or Prophylaxis e.g. vaccine
2. Early out-patient treatment
3. Hospital treatment

All these treatments come with various technologies and jargons, thus could be overwhelming and confusing for you as a layperson. Generally, multiple treatments and strategies are used in combination to achieve the best possible outcome.

The medical community themselves are battling over repurposed drugs like ivermectin and hydroxychloroquine on whether they should be used to treat and prevent COVID-19. On one side are experts telling you that more research is needed before the treatment can be fully authorized and confirmed. On the other, are experts telling you that the potential benefits outweigh the risk and a 'wait and do nothing' position is not acceptable. Confused? 

How do you deal with different expert groups dishing out conflicting guides? A common issue is that certain groups have pre-defined narrative that they would like to support. Therefore, only studies that support that pre-defined narrative are picked and cited as references. This is what we call as 'cherry-picking'. Cherry picking will naturally lead to a 'biased' and 'manipulated' decision. In order to get the truth out, scientific information needs to be analyzed in a comprehensive, updated and non-biased manner.

In this article, we will do a roundup and cover 3 popular oral anti-viral treatments i.e. Paxlovid, Molnupiravir and Ivermectin.

Contents:

• Paxlovid and COVID-19
• The NIH COVID-19 Treatment Guidelines for High-Risk, Non-hospitalized Patients With Mild to Moderate COVID-19
• Molnupiravir and COVID-19
• Ivermectin and COVID-19
• Ivermectin and FLCCC I-CARE Early Treatment Protocol
• Molnupiravir vs Ivermectin
• Paxlovid vs Ivermectin vs Molnupiravir

Paxlovid and COVID-19

How to Get Paxlovid Without a Medical Doctor

In March 2022, the Biden administration launched the Test to Treat initiative. The initiative’s goal was to allow people to be tested for COVID-19 at pharmacies or health centers that have an on-site clinic, like CVS MinuteClinic. If you had a positive test, you’d then receive an antiviral prescription at the pharmacy before leaving the building.

While well-intentioned, there were many roadblocks that made the Test to Treat initiative difficult to roll out. One big barrier was the fact that most pharmacies don’t have clinics in the same building. In late May 2022, there were only about 2,500 Test to Treat locations in the entire U.S. This left many Americans still struggling to get a prescription from their healthcare providers in enough time to benefit from Paxlovid.

In response to this, the FDA updated Paxlovid’s EUA in July 2022. This change allows pharmacists to prescribe Paxlovid directly to people who have tested positive for COVID-19. This means that you might be able to head over to your local pharmacy for the medication without having to make other stops along the way. Keep in mind that not all pharmacies may offer this service.

To get Paxlovid from your pharmacist, you must bring the following documents with you to the pharmacy:

• Your current health records, which must be less than a year old (either electronic or printed records are fine)
• Your most recent liver and kidney function tests, which must be less than a year old
• A complete list of all medications that you take, including any over-the-counter (OTC) medications, vitamins, and supplements

If you don’t have all of this information available, or your records aren’t recent enough, there may be a delay in getting Paxlovid. A pharmacist can reach out to your provider by phone to get this information, but that takes time. In this case, pharmacist-prescribed Paxlovid might not be much faster than seeing your healthcare provider or visiting a Test to Treat location.

How much will Paxlovid cost? 

The U.S. will pay about $500 for each course of Pfizer’s treatment, which consists of three pills taken twice a day for five days. Two of the pills are Paxlovid and the third is a different antiviral that helps boost levels of the main drug in the body.

New Paxlovid Dose Pack Author​ized by FDA

On April 14, 2022, the U.S. Food and Drug Administration (FDA) revised the Emergency Use Authorization (EUA) for the COVID-19 oral antiviral therapeutic Paxlovid to authorize an additional dose pack presentation with appropriate dosing for patients with moderate renal impairment within the scope of the EUA. As a result, Paxlovid will soon be available in two package presentations:

1. ​The standard packaging that is currently in distribution: 300 mg nirmatrelvir;100 mg ritonavir - Each carton contains 30 tablets divided in 5 daily-dose blister cards. Each blister card contains 4 nirmatrelvir tablets (150 mg each) and 2 ritonavir tablets (100 mg each). Nirmatrelvir tablets and ritonavir tablets are supplied in separate blister cavities within the same child-resistant blister card.
2. The new packaging option that will be in distribution later this month: 150 mg nirmatrelvir; 100 mg ritonavir - Each carton contains 20 tablets divided in 5 daily-dose blister cards. Each blister card contains 2 nirmatrelvir tablets (150 mg each) and 2 ritonavir tablets (100 mg each). Nirmatrelvir tablets and ritonavir tablets are supplied in separate blister cavities within the same child-resistant blister card.

The updated provider Fact Sheet, Letter of Authorization, and Dear Healthcare Provider Letter​ are available for reference.

Precaution: PAXLOVID is not recommended (the appropriate dose has not been determined) in patients with severe renal impairment (<30 mL/min). (Source)

Paxlovid Doesn’t Work for Healthier Patients, Pfizer Says (Time.com - June 2022)

Pfizer Inc. plans to stop enrollment in a study of its COVID-19 drug in patients who aren’t at high risk of severe disease after the pill didn’t help alleviate their symptoms, a major setback for broader use of the treatment.

The New York-based drugmaker said Tuesday that it would stop adding new participants to a highly anticipated study testing Paxlovid in a broader population of COVID patients who are at low risk of hospitalization and death. The decision comes after the study failed to demonstrate that the drug reduced COVID symptoms among relatively healthy patients and wasn’t able to show a statistically significant reduction in hospitalization and death.

Since Paxlovid works by blocking a protease enzyme, should I be concerned about taking digestive enzymes that contain proteases? (ConsumerLab)

No, you should not be concerned. The proteases produced by your body and found in digestive enzyme supplements, which help digest protein in foods, are different from the viral protease (3CL) that is needed by coronaviruses to replicate (Zhang, Science 2020) and is the target of the antiviral protease-inhibitor drug Paxlovid. Taking a supplement that contains proteases to digest food is not likely to affect the course of COVID-19 infection or the activity of antiviral drugs.

The COVID-19 Treatment Guidelines Panel’s Statement on Therapies for High-Risk, Non-hospitalized Patients With Mild to Moderate COVID-19 (Last Updated: August 8, 2022)

This statement contains the Panel’s recommendations for treating these non-hospitalized patients using the currently available therapies.

For Patients Who Are at High Risk of Progressing to Severe COVID-19
Preferred therapies. Listed in order of preference:

• Ritonavir-boosted nirmatrelvir (Paxlovid)
• Remdesivir

Alternative therapies. For use ONLY when neither of the preferred therapies are available, feasible to use, or clinically appropriate. Listed in alphabetical order:

• Bebtelovimab
• Molnupiravir

Paxlovid Rebound

In late May 2022, the CDC issued a health advisory about “COVID-19 rebound” after Paxlovid treatment. The CDC described it as “a recurrence of COVID-19 symptoms or a new positive viral test after having tested negative.”

At the same time, the CDC wrote, “a brief return of symptoms may be part of the natural history of [coronavirus] infection in some persons, independent of treatment with Paxlovid and regardless of vaccination status.”

The CDC said there is no evidence for more treatment in rebound cases, though people should isolate again for at least 5 days so they won’t pass COVID-19 to others.

People who have a rebound after taking Paxlovid can report their cases to Pfizer’s adverse event reporting page.

Paxlovid's Contraindications and Drug Interactions

Pfizer anti-COVID pill's interaction with common drugs will narrow its benefit, experts say | National Post:

The buzz around PAXLOVID™ has largely obscured one major downside of this treatment. Ritonavir can interact dangerously with a slew of commonly used medications, pumping up the potency of blood thinners, heart-arrhythmia therapies, epilepsy drugs and others. And the patients targeted for its use – those most at risk of serious COVID disease because of age and other health issues – are also the people most likely to be taking those “contraindicated” medications. 

In some cases, the interactions could be managed, but it’s clear the problem will limit the pool of potential recipients, experts say. “It has a utility, it has a use,” said Dr. Gerald Evans, head of the Infectious Diseases Division of the Queen’s University medical school. “(But) I certainly would not call it a game-changer.” “A patient on blood thinners could end up with spontaneous bleeding in the gastrointestinal tract or brain”, noted Evans. 

“Someone taking pills for hypertension might see their blood pressure fall so much they pass out”, said Dr. Andrew Hill, a pharmacology researcher at the U.K.’s Liverpool University. “There are all kinds of ways that PAXLOVID™ could cause serious harm,” he said. 

Ritonavir is also used in HIV treatments, so there is a wealth of knowledge about those potential drug interactions. The U.S. Food and Drug Administration (FDA) product monograph for PAXLOVID™ lists over 100 drugs that it says should not be taken with the COVID pills, or whose use ought to be carefully monitored. The figure below lists a few of these drugs as well as liver enzymes whose functions are impacted by Ritonavir.

See Sections 4 and 7 of the FACT SHEET FOR HEALTHCARE PROVIDERS and a publication on JAMA by Ross et al. Pharmacists as prescribers may be a problem since they are not authorized to manage, deprescribe and be responsible for the OTHER drugs.

Molnupiravir and COVID-19

Associated Press (December 1, 2021) — A panel of U.S. health advisers narrowly backed Molnupiravir from Merck:

“I see this as an incredibly difficult decision with many more questions than answers,” said panel chair Dr. Lindsey Baden of Harvard Medical School, who voted in favor of the drug. He said FDA would have to carefully tailor the drug’s use for patients who stand to benefit most.

The recommendation came after hours of debate about the drug’s modest benefits and potential safety issues. Most experts backing the treatment stressed that it should not be used by anyone who is pregnant and called on FDA to recommend extra precautions before the drug is prescribed, such as pregnancy tests for women of child-bearing age.

Merck said final study results showed molnupiravir reduced hospitalization and death by 30% among adults infected with the coronavirus, when compared with adults taking a placebo. That effect was significantly less than the 50% reduction it first announced based on incomplete results.

For many panelists, the modest effect wasn’t enough to outweigh the drug’s potential toxicity to human fetuses.

“Given the large potential population affected, the risk of widespread effects on potential birth defects has not been adequately studied,” said Dr. Sankar Swaminathan of the University of Utah School of Medicine, who voted against the drug.

FDA scientists told the panelists earlier Tuesday that company studies in rats showed the drug caused birth defects when given at very high doses. FDA staffers concluded the data “suggest that molnupiravir may cause fetal harm when administered to pregnant individuals.”

The agency is weighing a blanket restriction against any use in pregnant women or allowing doctors to use the drug in rare cases. Some panelists said that option should be left open for pregnant mothers who have high-risk COVID-19 and may have few other treatment options.

Dr. Janet Cragan, who backed the drug, said that even with tight restrictions some pregnant women would inevitably take the antiviral.

“I don’t think you can ethically tell a woman with COVID-19 that she can’t have the drug if she’s decided that’s what she needs,” said Cragan, a panel member and staffer with the Centers for Disease Control and Prevention. “I think the final decision has to come down to the individual woman and her provider.”

Merck’s drug uses a novel approach to fight COVID-19: It inserts tiny errors into the coronavirus’ genetic code to stop it from reproducing. That genetic effect has raised concerns that the drug could spur more virulent strains of the virus. FDA regulators said Tuesday that risk is theoretical but many panelists said it should be carefully tracked in follow-up studies.

Antiviral pills have long been seen as a key advance beyond currently used antibody drugs, which must be injected or infused by health professionals. But given the shortcomings of Merck’s data, several experts said they would prioritize patients to receive the older drugs.

Ivermectin and COVID-19

Ivermectin is a well-known, FDA-approved anti-parasite drug that has been used successfully for more than four decades to treat onchocerciasis “river blindness” and other parasitic diseases on humans. It’s been used for decades for this purpose by over 3.7 billion people, and is considered safe and effective. 

Ivermectin has also being researched for it's potential effectiveness for dengue viral infection (Ref, Ref) and even colo-rectal cancer (Ref). Similarly, ivermectin has also been shown to possess antiviral activity against a whole host of other RNA viruses (Zika, yellow fever, human immunodeficiency virus type 1) (Ref).

It has an increasing list of indications due to its antiviral and anti-inflammatory properties, and is included on the WHO’s Model List of Essential Medicines.

Is ivermectin a zinc ionophore? Although there are many articles stating it is but most articles do not provide scientific references to support the claim. We have found studies that showed that ivermectin has a probable ionophore nature: 

• Ivermectin, antiviral properties and COVID-19: a possible new mechanism of action (Naunyn Schmiedebergs Arch Pharmacol. 2020).
• The multitargeted drug ivermectin: from an antiparasitic agent to a repositioned cancer drug (Am J Cancer Res. 2018)

Ivermectin Peer Reviewed and Other Studies

For a comprehensive review on ivermectin, please refer to the peer-reviewed publication; Review of the Emerging Evidence Supporting the Use of Ivermectin in the Prophylaxis and Treatment of COVID-19 and the included references.

For an up-to-date overview of all published studies on ivermectin in the treatment and prevention of COVID-19 we recommend visiting c19ivermectin.com; in addition, a meta-analysis of all studies can be found at ivmeta.com (constantly updated). For adoption and regulatory status of ivermectin globally, check out "Countries using Ivermectin".

Ivermectin and FLCCC's I-CARE Early Treatment Protocol

The Front Line COVID-19 Critical Care (FLCCC) Alliance was initially formed as a working group during the early COVID-19 pandemic days in response to multiple early reports of COVID patients with an inexplicably high need for prolonged mechanical ventilation and an excessive death rate.

Based on rapidly emerging clinical trials evidence, the FLCCC team has developed the I-MASK+ protocol for prophylaxis and at home treatment of early stage COVID-19.

For updated early outpatient protocol (COVID-19 positive), please check out FLCCC I-CARE protocol.

For post-covid or long covid syndrome, check out FLCCC (Front Line COVID-19 Critical Care Alliance) I-Recover Post-COVID Protocol. 

Concerns and Cautions:

• Ivermectin has a number of potentially serious drug-drug interactions. Please check for potential drug interaction at Ivermectin Drug Interactions - Drugs.com. The most important drug interactions occur with cyclosporin, tacrolimus, anti-retroviral drugs, and certain anti-fungal drugs. 
• Ivermectin is also lipophilic and therefore, bioavailability is maximised on a full stomach; or best to be taken with meal.

Related: 

• List of Doctors that will prescribe Ivermectin

• List of Pharmacies that will fill Ivermectin

Ivermectin vs Molnupiravir

Retired nurse lecturer John Campbell, Ph.D., makes a critical comparison of the two in a YouTube video. To be upfront, Campbell says he is pro-vaccine and pro-antiviral.

Ivermectin, he says, is one of the most-studied, repurposed drugs and, it’s not only FDA-approved for humans, but it won a Nobel prize as it “revolutionized the human treatment of a parasitic disease.” It also has demonstrated “broad spectrum antiviral activity against many viruses including HIV, Zika and MERS” and it inhibits the replication of the SARS coronavirus, and in fact got rid of 99.98% of SARS-viable particles in 48 hours.

Like ivermectin, molnupiravir is an oral drug, but it’s converted in the liver, and there is a safety concern that the metabolite action could also be mutagenic — cancerous — in mammalian cells as well as a trigger for birth defects in a fetus. While Merck says that’s not going to be a problem, Campbell says evidence he’s looking at shows “it at least needs looking into” because “if it stops the normal replication of RNA is it going to stop the normal replication of our DNA?”

Ivermectin, on the other hand, binds to the spike protein to stop it from going into your cells. It’s also an anti-inflammatory with high efficacy that inhibits cytokines and has very few side effects reported in its years of usage.

 

Dr John Campbell further reports on a comparative analysis of molnupiravir and ivermectin published in the Austin Journal of Pharmacology and Therapeutics. The advantage molnupiravir has over remdesivir is that it is administered orally and can be used for early treatment in an outpatient setting.

In the video above,  Campbell reviews a paper published in the Austin Journal of Pharmacology and Therapeutics that was a chemical comparison of the pharmacological effects of molnupiravir and ivermectin. Looking at the two ways science uses to develop new treatments when a new condition arises, Campbell explains the first is to create a new drug and the second is to repurpose medications used for other conditions. For example, aspirin originally was used to treat fever. Once it became evident that it was also effective against pain, doctors began recommending it to relieve headaches and other minor aches and pains. Subsequently, it was found that aspirin was an effective antiplatelet, as well, and this function was added to the known uses for aspirin. 

According to the paper, Ivermectin is the "most studied, 'repurposed' medication globally, in randomized clinical trials, retrospective studies and meta-analysis." Ivermectin is an FDA-approved, broad spectrum antiparasitic with known anti-inflammatory properties.

The data in the comparison paper show molnupiravir is more potent in-vitro than ivermectin, which means it needs less drug to work with a lower tissue concentration. The amount of time the maximum drug dose is found in the serum is one to 1.75 hours for molnupiravir and four to six hours for ivermectin.

Interestingly, the half-life for Merck's drug is seven hours and the half-life for ivermectin is 81 to 91 hours. This is the amount of time it takes for your body to reduce the active ingredients in the drug by half. Campbell also reviews the following factors:

Safety — No matter how well a drug works, if it's not safe for use, it cannot be effective. Offering some examples of how ivermectin's safety compares to other drugs, according to Campbell the global database of the World Health Organization, VigiBase, recorded 5,593 adverse events from ivermectin after 3.7 billion doses were administered to humans. 

For comparison, VigiBase recorded 136,222 adverse events for amoxicillin and 165,479 for ibuprofen. At this time there is no VigiBase data available for molnupiravir, so no comparisons can be made for that drug yet. To take the example one step further, an outside look at acetaminophen adverse events shows that this drug (aka Tylenol) is many times more dangerous than ivermectin.

In the U.S. alone the National Institutes of Health's STATPearls manual reports that there are 2,600 hospitalizations, 56,000 emergency room visits and 500 deaths each year for acetaminophen overdoses as of July 2021. And, the drug is the second leading cause of liver transplantation worldwide and the leading cause of transplantation in the U.S.

Efficacy — According to interim data from Merck, molnupiravir reduced hospitalizations or deaths by 50% in 385 participants who had at least one risk factor associated with poor disease outcome. A meta-analysis of 15 trials that included 2,438 participants demonstrated that ivermectin could reduce the risk of death by 62%.

Paxlovid vs Molnupiravir vs Ivermectin

Is Paxlovid like Ivermectin? Clinical evidence to date has reported promising results for Ivermectin in prevention, early treatment as well as late treatment for COVID-19. 

Both Paxlovid and ivermectin are protease inhibitors. However, Pfizer's Paxlovid (Generic Name: Nirmatrelvir / Ritonavir) and Merck's Molnupiravir (UK Brand Name: Lagevrio) have been issued Emergency Use Authorizations (EUAs) by the US FDA for high risk COVID-19 patients whereas ivermectin has not been authorized to be used for COVID-19.

Note: On December 22 and 23, 2021, the Food and Drug Administration (FDA) issued Emergency Use Authorizations (EUAs) that allow Paxlovid and Molnupiravir to be used in high risk patients.

According to GoodRx Health (Jan 26, 2022): Studies suggest that Paxlovid can lower the risk of severe COVID-19 for high-risk people by almost 90%. Studies suggest molnupiravir can lower this risk by about 30% in high risk people.

According to AP News (Dec 23, 2021): Pfizer’s drug is all but certain to be the preferred option because of its mild side effects and superior effectiveness, including a nearly 90% reduction in hospitalizations and deaths among patients most likely to get severe disease.

Pfizer’s drug is part of a decades-old family of antiviral pills known as protease inhibitors, a standard treatment for HIV and hepatitis C. They work differently than Merck’s pill and haven’t been linked to the kind of mutation concerns raised with Merck’s drug.

According to AP News (Dec 1, 2021): Pfizer said that its drug shouldn’t be affected by the omicron variant’s mutations.Both drugs require patients to take multiple pills, twice a day for five days.The U.S. government has agreed to purchase 10 million treatment courses of Pfizer’s drug, if it’s authorized. That’s more than three times the government’s purchase agreement with Merck for 3.1 million courses of molnupiravir.

Update: Effectiveness of Monoclonal Antibodies and Antiviral Drugs against Omicron BA.2.12.1, BA.4, and BA.5 Subvariants

A lab study published in July 2022 (NEJM) using the live-virus Focus Reduction Neutralization Testing (FRNT) method revealed that bebtelovimab seems to be the most promising monoclonal antibody against the BA 5 subvariant.

Overall, the study data also revealed that the three antiviral drugs remdesivir, molnupiravir, and nirmatrelvir (Paxlovid) may still have therapeutic value against the sublineages BA.2.12.1, BA.4, and BA.5 of SARS-CoV-2 omicron variants.

Do take note of the limitation of this study as this is a non-clinical study (not in humans). There is lack of clinical data on the efficacy of these monoclonal antibodies and antiviral drugs for the treatment of patients infected with BA.4 or BA.5 subvariants. Therefore, the selection of monoclonal antibodies or anti-virals to treat patients who are infected should be carefully considered based on the potential risks as compared to its potential benefits.

Related: Paxlovid vs Monoclonal Antibodies

Summary 

The important key takeaway is 'early' treatment. As anti-virals, Paxlovid, Molnupiravir and Ivermectin all need to be given early (within five days of symptoms appearing). That said you should never attempt to self medicate without the guidance of a licensed medical provider. If you are not a medical doctor, you are likely to find the above information overwhelming and complicated. The aim of this article is to empower you with a better understanding of the options available and to discuss the options with your medical doctor.

Updates: 

COVID antibody drugs have saved lives — so why aren’t they more popular?

China approves Genuine Biotech's HIV drug for COVID patients

Pfizer's softly, COVID marketing approach continues with COVID-Fighting Pill Ad

Test to Treat initiative - Assistant Secretary for Preparedness and Response (ASPR)