What you need to know about: Paxlovid

There is a lot of information all over the internet regarding medications. My goal with Rxplanation has always been to offer clear, practical and easier-to-understand information on health topics. “What you need to know about…” posts like this one aim to offer a condensed overview of certain medications. While I may not cover every single detail, the hope is that this post can answer the more frequently asked questions and serve as a great starting point in your personal research.


What is Paxlovid?

Paxlovid, which is a medication that contains two agents (nirmatrelvir and ritonavir), is a treatment for COVID-19 that has been approved for use in both Canada and the United States. It is one of the very first dedicated antivirals developed to treat COVID-19.

For a good part of the pandemic, the treatment of COVID-19 has revolved primarily around repurposing drugs that were developed for other illnesses. Some of these have turned out to be very useful (e.g. dexamethasone, tocilizumab, remdesivir), some are potentially useful (e.g. fluvoxamine), and some have not panned out at all (e.g. hydroxychloroquine, ivermectin).

The first agents that specifically targeted the virus were the monoclonal antibodies. However, those are only available in injectable form and don’t necessarily treat all variants. Paxlovid is one of the first two antivirals available in pill form that were developed to specifically to treat COVID-19.


How does Paxlovid work?

The main active ingredient in Paxlovid is the antiviral nirmatrelvir. Nirmatrelvir is classified as a SARS-CoV-2 protease inhibitor. It works by preventing one of the early steps in how the virus reproduces, which will prevent it from making more copies of itself.

In order for viruses to build copies of themselves, they first need to produce the building blocks required. One of these steps is when a viral enzyme (protease) will “chop up” material in order to prepare for future steps in the process of building a new copy of itself.

A protease is almost like an saw or an axe. In order to build a house, you need to first chop up the raw material to refine your building materials.

So, to build a new house (new virus), you first need to prepare the building materials. By stopping the viral protease, we are essentially preventing the virus from refining the building materials it needs to make copies of itself.

The other component of Paxlovid, the antiviral ritonavir, is not used for its antiviral activity. Ritonavir is actually a protease inhibitor that targets HIV. The only reason it’s being used in Paxlovid is because of one of its more problematic side effects.

If you think creatively, a glitch/bug can easily become a feature. Just ask any programmer or good salesperson!

The main problem with ritonavir, which made it mostly obsolete to use on its own, is the fact that it can significantly reduce how well your liver can process certain medications. As I mentioned in my article on the effects of smoking on caffeine metabolism, some drugs can significantly impact the metabolism/processing of other substances.

It’s not essential that you know the specific enzymes affected (if you must know, CYP3A4 is the main one); the main thing you need to know is that adding ritonavir will slow down how fast the body processes nirmatrelvir (which is the antiviral that’s actually having an effect on the virus). If it wasn’t for this effect, it probably wouldn’t be possible to use nirmatrelvir, as the body would clear it too quickly for it to work properly.


How effective is Paxlovid?

Before I get started, I want to be as transparent as possible: there is very little data evaluating Paxlovid. The data we have on the use of Paxlovid to treat COVID-19 is limited to only one trial: the EPIC-HR study.

This study was done with a total of 2246 people, where half of the participants received Paxlovid and the other half received a placebo. The average age of the participants was only 46 years old; however, they all had at least 1 pre-existing condition putting them at higher risk for severe illness, and all were unvaccinated. To be eligible for the study, participants had to have symptoms for no more than 5 days.


Why does Paxlovid have to be taken within 5 days of symptoms starting?

Participants had to be within 5 days of their symptoms starting because COVID-19 is a tale of two separate diseases in one infection.

  • The first phase of COVID-19, in the first 5 to 7 days, is when the virus is actively reproducing itself and the immune system is trying to fight it off.
    • This is when antivirals would be expected to help the most
  • The second phase is a hyper-inflammatory phase; where the immune response goes a bit haywire and causes disproportionately more inflammation.
    • This is when people typically deteriorate and require hospitalization. At this point antivirals are not expected to help as much

For those who are more visual, check out this infographic (the middle pulmonary phase is what they coined for the in-between of the two distinct stages of COVID-19):

This is why Paxlovid should be taken as soon as possible after the onset of symptoms; the longer you wait, the less likely that it will have a meaningful impact.

After 5 days, your body has likely fought off most of the virus… So adding an antiviral is less likely to do as much.


What did they observe?

This study measured the rates of hospitalization or death in both groups. What they observed was that the group who received Paxlovid was less likely to be hospitalized or die than those who received placebo:

GroupHospitalizations or Deaths
Paxlovid 8 out of 1039 participants
(0.77%)
Placebo66 out of 1046 participants
(6.31%)
Paxlovid lowered the absolute risk by 5.54%

This means that you would need to treat about 19 people in order to prevent one hospitalization or death due to COVID-19.

Another way to look at the results is that Paxlovid reduced the risk of hospitalization or death by approximately 88%. So, if your baseline risk is really low, the absolute drop in risk won’t be that high. However, if your baseline risk is really high, then the potential benefit is much higher. In other words, an 88% reduction of a 20% baseline risk is much more significant than an 88% reduction for someone who only had a 0.5% risk to start off.

I mention the relative risk because this study was done at a time where the primary variant causing infections wasn’t Omicron.

As we already know, the Omicron variant is less likely to cause severe illness than the Delta variant. So the statistic of treating 19 people to prevent 1 hospitalization or death is no longer accurate when looking at Omicron.

As I already described in my previous article on the risk of hospitalization with the Omicron variant, the risk is lower but it is not zero. In that article I shared the following graph; which details hospitalization risk with the Omicron variant according to age, vaccine status, and preexisting conditions:

Source: Government of British-Columbia – COVID-19: Hospitalization Risk
*Note: estimates only, based on real-world data

Although the graph above doesn’t explain the potential benefit of Paxlovid for Omicron infections, it could at least help people determine their approximate risk of being hospitalized.

  • If you’re already at very low risk for hospitalization (e.g. otherwise healthy 25 year-old with 3 vaccine doses), then taking Paxlovid probably won’t move the needle that much for your absolute risk of hospitalization.
  • If you’re at very high risk (e.g. unvaccinated 75 year-old with a bunch of preexisting medical conditions), then there is a lot of potential benefit to be derived from taking Paxlovid.

What are the side effects of Paxlovid?

In the study, they observed that Paxlovid was well tolerated in most people. There were just as many side effects reported in the Paxlovid group (22.6%) as there were in the placebo group (23.9%).

When looking at side effects that were more common for Paxlovid than with placebo, the following 4 were noted:

  • Unpleasant taste (5.6%)
  • Diarrhea (3.1%)
  • Muscle pain (0.7%)
  • Blood pressure elevation (0.7%)

The investigators also looked at the rates of serious/severe side effects. There were actually less serious/severe side effects in the Paxlovid group than there were in the placebo group.

Since our knowledge on Paxlovid is limited to this single trial where only just over 1000 people received the drug, it’s possible that more rare (and possibly severe) side effects are not known.

This is why it’s essential to properly weigh the possible risks vs. the possible benefits.


Can Paxlovid interfere with other medications?

The biggest concern with the use of Paxlovid is its ability to interact with many other medications. One of the 2 active ingredients, ritonavir, can significantly reduce how your liver can process several medications. This means that they can’t be eliminated as efficiently; which could lead to rapid accumulation (and potential toxicities).

Think of your body as a bathtub, and the amount of drug you take as the water being turned on.

Adding on Paxlovid will reduce the clearance of certain drugs, so it’s like if you all of a sudden almost completely clogged the drain.

If you don’t stop adding water, or at least reduce the amount you’re adding in, it can rapidly accumulate (and potentially cause some problems).

Which medications are affected by Paxlovid?

There are too many medications that can be impacted by taking Paxlovid to be able to list them all. Some commonly encountered problematic agents include:

  • Some blood pressure medications (e.g. amlodipine, nifedipine)
  • Some blood thinners (e.g. rivaroxaban, apixaban, clopidogrel)
  • Many cholesterol medications (e.g. atorvastatin, simvastatin, rosuvastatin)
  • Some anxiety/insomnia medications (e.g. clonazepam, alprazolam, zopiclone)
  • Some antipsychotic medications (e.g. quetiapine, risperidone, aripiprazole)
  • Paxlovid can even affect how your body processes cannabis.
  • Many others…

For some of these agents, modifications can be made in order to give them safely with Paxlovid (usually decreasing the dose).

However in the case of certain drugs it’s just not safe, or feasible, to give Paxlovid safely. Talk to your doctor or pharmacist for more information on if Paxlovid is safe with your current medications.

Can some medications affect how well Paxlovid works?

Not only can Paxlovid affect other medications, but certain medications can also reduce how well Paxlovid can work. The most commonly encountered problematic agents include some anticonvulsants (e.g. carbamazepine, phenytoin), the antibiotic rifampin, and even St John’s Wort (a natural health product).

These agents have the opposite effect of what ritonavir does; by inducing the metabolism, they will actually increase how well the liver can process nirmatrelvir.

Remember the bathtub analogy earlier?

In this setting with an inducer, instead of clogging the drain, it’s like we just created a large hole in the bottom of the tub. It’s draining so much that we can’t even fill it if we tried.

This means that anyone taking one of these inducers will not be able to take Paxlovid, since their body will clear the nirmatrelvir component way too quickly for it to benefit them (and could even lead to viral resistance).


Who should consider taking Paxlovid?

Paxlovid should be considered for those people with symptomatic COVID-19 at the highest risk of progressing to severe illness. This includes older adults who aren’t fully vaccinated (i.e. 3 doses), those with preexisting medical conditions who aren’t fully vaccinated, and those with a significantly weakened immune system.

An argument could also be made to give Paxlovid to any elderly person (e.g. over the age of 70 or 80) who has preexisting conditions, regardless of whether they are vaccinated or not, since they are at the highest risk of severe illness when looking at the fully vaccinated population.

Since supply may still be limited in some areas, health authorities in your region may have specific eligibility criteria for Paxlovid. Check with your primary healthcare provider to see if you are eligible.


Who shouldn’t take Paxlovid?

There are a significant number of people who should not take Paxlovid, these can include:

  • Anyone who can’t swallow pills whole (Paxlovid can’t be chewed or crushed)
  • Advanced kidney failure, including dialysis patients (risk of toxicity)
  • Advanced (end-stage) liver disease (risk of toxicity)
  • Someone who is asymptomatic or has already recovered (little benefit to be derived from taking it)
  • Women who are pregnant or breastfeeding (no safety data for this population; could consider, on a case-by-case basis, if at VERY high risk)
  • Anyone taking other medications that cannot be combined with Paxlovid (where adjustments to those other medications cannot be made)
  • Children (under 12 in the United States; under 18 in Canada)

The Bottom Line

Paxlovid represents a welcome addition to the ever growing arsenal of treatments that we have for COVID-19. It can help reduce the risk of severe illness in those at high risk of hospitalization or death from COVID-19.

Since Paxlovid is still quite new (with very little clinical data), anyone considering this treatment should weigh the potential risks vs. the potential benefits. Check with your primary healthcare provider for more information.


More information on Paxlovid:

For healthcare providers:

For patients:

Dan Landry

Daniel (Dan) Landry, founder of Rxplanation.com, is an infectious diseases pharmacist at the Dr-Georges-L.-Dumont University Hospital Centre in Moncton, NB, Canada.

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