Paxlovid vs Molnupiravir (Lagevrio): 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. 

paxlovid vs molnupiravir vs ivermectin

BQ.1.1 is a new Omicron subvariant descended from Omicron BA.5. BQ.1.1, along with its sister variant BQ.1, accounts for around 62.8% of new COVID-19 cases in the U.S. (CDC). Are the current treatment options still relevant?

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 SheetLetter 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)

The COVID-19 Treatment Guidelines Panel’s Statement on Therapies for High-Risk, Non-hospitalized Patients With Mild to Moderate COVID-19 (Last Updated: Sept. 26, 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.

In a retrospective cohort study of electronic health records (EHRs) of 92 million patients from a multicenter and nationwide database in the US, published as a preprint in June 2022:

“The 7-day and 30-day COVID-19 rebound rates after Paxlovid treatment were 3.53% and 5.40% for COVID-19 infection, 2.31% and 5.87% for COVID-19 symptoms, and 0.44% and 0.77% for hospitalizations.”

However, according to a new study (Oct 2022), this puzzling phenomenon can occur whether you take Paxlovid or not.

Researchers found that when patients received a placebo instead of treatment, a portion of them still experienced a rebound of their symptoms after they had initially improved.

“Symptom return is common,” said Dr. Davey Smith, the chief of infectious diseases and global public health at the University of California, San Diego School of Medicine, who led the study. “It doesn’t mean that things are going south. It’s just the natural way the disease goes.” What is surprising, however, is how many people may experience a rebound, he said. (Read More)

How to treat rebound COVID after Paxlovid

Dr. Paul Auwaerter, head of Infectious Diseases at Johns Hopkins said:

“I think when you're using drugs such as Paxlovid for only 5 days with one specific protease inhibitor, the nirmatrelvir component of the drug, it may be that that is not sufficient.”

Rather than relying on Paxlovid as a single agent drug, it makes sense to use a multi-agent approach. The synergistic potential of multiple therapeutics against Covid means that the effect of 1 + 1 can equal more than 2. Taking advantage of synergism is well-known in the use of both antibiotics and antivirals, and a mix of therapies has been published to have excellent efficacy against Covid.

Paxlovid for long COVID

A report from the Veterans Affairs health system (now in preprint), the largest in the United States, is the first study to look at longer term effects. Dr. Ziyad Al -Aly and colleagues, who have published many of the important papers on Long Covid in leading peer review journals, now studied over 9,000 paxlovid treated patients (within 5 days of symptom onset; in March-June 2022 during Omicron and subvariant waves) and compared the results to ~47,000 controls. Their mean age was 65 years and 12% were female. 

In summary, the results show that in people with SARS-CoV-2 infection who had at least 1 risk factor for progression to severe COVID-19 illness, treatment with Paxlovid (nirmatrelvir) within 5 days of a positive SARS-CoV-2 test was associated with reduced risk of PASC (Post Acute Sequelae of COVID-19) regardless of vaccination status and history of prior infection. The totality of findings suggests that treatment with Paxlovid during the acute phase of COVID-19 reduces the risk of post-acute adverse health outcomes.

The U.S. National Institutes of Health's $1 billion RECOVER Initiative has picked Pfizer Inc's (PFE.N) antiviral drug Paxlovid as the first treatment it will study in patients with long COVID, organizers of the study said on Oct 27, 2022.

The complex medical condition involves more than 200 symptoms ranging from exhaustion and cognitive impairment to pain, fever and heart palpitations that can last for months and even years following a COVID-19 infection.

According to details of the study, posted on Clinicaltrials.gov, the randomized, placebo-controlled trial will test Pfizer's treatment or a placebo in 1,700 volunteers aged 18 and older.

The Duke Clinical Research Institute is supervising the study, which is scheduled to start on Jan. 1, 2023.

The trial will investigate a leading theory of the cause of long COVID, which holds that fragments of the virus persist in the tissues of some individuals, causing prolonged symptoms.

Patients in several case studies have reported improvements in their symptoms after taking Pfizer's antiviral treatment, and several physicians have called for the drug to be studied in a large, scientifically rigorous study in patients with long COVID.

Paxlovid, which combines a new Pfizer pill with the old antiviral ritonavir, is currently authorized for use in the first days of a COVID infection to prevent severe disease in high-risk patients.

Estimates of long COVID prevalence range from 5 to 50% of people who have had a COVID-19 infection. It affects people who have had both mild and severe COVID-19, including children, and can be severe enough to keep people out of work.

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.

There are many Paxlovid drug-interaction checkers, but the one we find most useful is from the University of Liverpool summarized in the Table below. For most, the interactions can be avoided by holding the 'medication of concern' until the 5-day treatment course is completed.

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 (RefRef) 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 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: 

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.

Efficacy of Antiviral Agents against Omicron Subvariants BQ.1.1 and XBB | NEJM (Dec 2022)

BQ.1.1 is a new Omicron subvariant descended from Omicron BA.5. BQ.1.1, along with its sister variant BQ.1, accounts for around 62.8% of new COVID-19 cases in the U.S. (CDC).

A lab study published in December 2022 (NEJM) using the live-virus neutralization assay revealed that most of the monoclonal antibodies may not be effective against BQ.1.1 or XBB in the clinical setting.

Overall, the study data also revealed that the three antiviral drugs remdesivir, molnupiravir, and nirmatrelvir (Paxlovid) may still have therapeutic value against the omicron subvariants BQ.1.1 and XBB.

According to the authors:

"...These results suggest that imdevimab–casirivimab, tixagevimab–cilgavimab, sotrovimab, and bebtelovimab may not be effective against BQ.1.1 or XBB in the clinical setting...These results suggest that remdesivir, molnupiravir, and nirmatrelvir are efficacious against both BQ.1.1 and XBB in vitro..."

Key Takeaway

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 trusted medical doctor.


Related: 



10 Natural Alternatives for Paxlovid (2022)



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