7. Outpatient COVID-19 Therapeutics

I hope you find this information useful to your patients and your practice. I know personally, I’ve had some issues figuring out what I should use for some patients, or when I should use what, and how do I go about getting some of those things, so we hope to answer those questions for you. Along with me today is Dr. Alavi.

Mustafa Alavi, MD:

All right, thank you Dr. Ott. My name is Dr. Mustafa Alavi. I’m a full-scope delivering family physician at Erie Family Health Centers. I graduated residency from Oregon Health & Science University in 2019, so I don’t have as many years of experience as you, Dr. Ott, but I’m super excited to talk about all the
COVID therapeutic options we have for our patients today.

Timothy Ott, DO, FAAFP:

Thank you. Thanks for joining us. We really haven’t had many treatment options in 2020 and 2021, and it seems like now we have many options out there to choose from, and maybe not all our listeners are aware of the options. I think we have at least four treatment options for our patients who are not hospitalized, so have mild to moderate COVID-19. Dr. Alavi, can you tell me about where we are now with treatment options?

Mustafa Alavi, MD:

Yeah, no problem. Yes, we have four treatment options available for our outpatients. A lot of them are tongue twisters, so I’m just going to go through each of them, so paxlovid, remdesivir, bebtelovimab, and molnupiravir. I’m not going to be able to say those four times fast, but those are our treatment options, and something I think we each need to know about. You’re right, we did not have many treatment options for our patients with COVID, but now, as of December 2021, we now have a slew of treatment options that really are hard to navigate through as a provider, so at the end of the summer, as we all remember, that’s when omicron was surging, and we were struggling to help treat all these patients suddenly getting COVID.

But at the same time, the FDA put under emergency use authorization paxlovid, on December 22nd, so these medications became available to us as providers, but there were so many logistical issues to solve, like supply issues, where can our patients get these medications? How do we get these medications? How do you dose them? How do you need to adjust them? What medications are contraindicated? Each medicine has its own nuances, and it was, and still is as a provider, really hard to know about each of these medicines. So hopefully, we can help teach the listener how to navigate these medications and feel comfortable prescribing them.

Even our treatment options back then, like our monoclonal antibody option, has changed. Bebtelovimab was not previously used for omicron, but now it is. So treatment options are changing, and we need to keep up with what is currently recommended. And actually, as you’ve probably been seeing in the news, some of these treatment options are being unused, sitting on pharmacy shelves, and we need to get the word out about these medications. We need to help push to actually prescribe them for patients that it’s indicated for, because they can be helpful to reduce hospitalization of our patients.

I recently just heard on NPR, that the White House is also pushing to have these test and treat options, where patients can have easy, seamless options to get tested for COVID and get the treatment option for them right then and there, which is the ideal that we need to get to. So I hope after you listen to this podcast, we’ll make you as a listener comfortable with prescribing these medications.

Timothy Ott, DO, FAAFP

That’s great, so let’s work on getting the word out. Dr. Alavi, if you had a patient in front of you right now, how do you decide which of these options is the best for that patient?

Mustafa Alavi, MD:

Great question. That’s question number one all of us are going to ask as providers when we’re seeing that patient in front of us with COVID-19 and we want to get them the help they need and a therapeutic option. So first, I will refer everyone to the NIH treatment algorithm. This was developed by the NIH as a decision aide tool, to help the provider in the moment, to answer the question, “Which medication should I use?” It first goes through does this patient meet criteria to be hospitalized? If yes, then these treatment options are not for your patient in front of you. But if they’re not meeting those criteria, then if there’s symptom onset within five to seven days, then it goes through the four medications. They prioritize paxlovid and remdesivir as your first two treatment options, and I’ll go into later why those are your first two treatment options, and then if those two aren’t options, then it goes into going towards the monoclonal antibody versus molnupiravir. And we’ll put the link to this therapeutic decision aide in our show notes. It is also something you can Google by just honestly Googling COVID-19 NIH treatment guidelines.

Timothy Ott, DO, FAAFP:

I’ve noticed that your treatment options don’t include things that some of our listeners may have heard about, like ivermectin and hydroxychloroquine. Why aren’t they on the list?

Mustafa Alavi, MD:

That’s a great question, but it is not a mistake. The NIH has reviewed the data behind ivermectin, and hydroxychloroquine, and chloroquine, and there are actually some trials studying ivermectin for COVID-19. Currently, they recommend, and they write this in bold, they recommend against using these treatment options for COVID-19. Right now, there hasn’t been enough data to substantiate benefits from these medications, and these medications do come with a lot of unwanted side effects.

Timothy Ott, DO, FAAFP:

Great. Thank you. So if we use the algorithm and we figure out which medicine to use, how do I find it?

Mustafa Alavi, MD:

Also, that’s question number two for your provider, “Where do we get these medications from?” First, meant to mention this earlier. Each drug has an emergency use authorization data sheet that I would highly recommend that if you’re prescribing this, quickly look up that EUA for these medications. They’re pretty easy to use to get the information you need about the drug, to just make yourself comfortable with each drug once you’re in the moment, needing to prescribe that medicine.

Once you decide which medicine to use, to find where to get that medication, they have also developed this great treatment locator, and we’ll put the link in our show notes as well, but there is this COVID-19 therapeutic locator, which all you have to do is put in your zip code or the zip code of where the patient lives, and it will show you, in real time, which drugs are available where. When I put in my home zip code, it shows me Walgreens, and CVS, and some clinics around me, and it tells me, to the number, how much supply of paxlovid they have, if there’s Evusheld available, if there’s molnupiravir available, and it updates in pretty real time, meaning when I look at it, it tells me what the stock was yesterday. So that’s pretty accurate and helpful, so it will help tell you where to prescribe, say, paxlovid for your patients.

When you look at these treatment locators, you’ll notice that supply for drugs like molnupiravir are far more than paxlovid, but in general, compared to where we were two months ago, stock and supply has ramped up greatly. [inaudible 00:08:08] paxlovid to prescribe for your patients. But I would suggest looking where you live and your current location first.

Timothy Ott, DO, FAAFP:

Great, so we have some help picking a drug and we have some help locating the drug, but as you said, we need to know a little more about these drugs, so let’s dive into these medications a little bit. It looks like with the algorithm, that paxlovid is one of the first medications to consider. What can you tell us more about paxlovid?

Mustafa Alavi, MD:

Exactly. If there is one medicine you’re going to take away from this podcast, it is paxlovid. It is a great treatment option for COVID-19. It’s two drugs in one, actually. It’s nirmatrelvir, which is the main drug that inhibits… is a protease inhibitor for COVID-19, and then ritonavir, which is actually a CYP3 inhibitor that’s just meant to increase the drug concentrations of the main drug, nirmatrelvir.

So it’s indicated for your patients who are 12 and older and at least 40 kilograms, or over, with mild to moderate disease of COVID-19, so they have to have proven COVID-19, and are at high risk of progression to severe disease.

And you can look on the CDC website of what meets criteria for high risk, but that would be many of our patients, for like obesity, hypertension, diabetes, heart failure. Any of these high-risk criteria really makes them a candidate for paxlovid.

Paxlovid has to be initiated within five days of symptom onset, and it is really effective from the main studies out, granted it emergency use authorization. So in a main study, it showed an 88% relative risk reduction of hospitalization or death if started within the first five days, which is a phenomenal relative risk reduction for any study, which is why it likely gained the EUA, and why the algorithm has it as one of the first treatment options.

The medication comes in a box with five blister packs. Each pack contains six tablets, so you take three tablets. Two of nirmatrelvir, one of ritonavir in the morning, and then in the evening, you take the same three tablets. So it’s almost similar to Tamiflu. You’re taking medicine twice a day for five days. It’s just that with paxlovid, you’re doing three tablets twice a day for five days.

Biggest thing to know about, or one of the biggest things to know about, is that this medicine does have to be renally adjusted, so if you have a patient with CKD, with GFR between 30 to 60, then you do actually have to take away one of the tablets of nirmatrelvir in the morning and the evening, so they’re just taking two tablets twice a day. Logistically, that means you would just have to notate that when you prescribe this to the pharmacy, and that tells the pharmacist to take away a tablet from the blister pack physically. They just physically remove two tablets from each blister pack, and they put a sticker over the hole from the blister packet. So you do have to specify that, and you do have to be aware of… It is good to be aware of your patients’ renal function.

The most common side effects are diarrhea, elevated blood pressures, muscle aches, dysgeusia. The biggest thing that I also want people to be aware of is that paxlovid comes with a lot of drug interactions. That’s because there’s ritonavir in it, which is a CYP3 inhibitor, meaning if you remember from med school, there’s a lot of drugs that get metabolized by that enzyme, so highly recommend that you have to look at each medicine your patient is on and run it on a drug interaction calculator. There is a lot out there, and we can put a link in the show notes for one of the drug interaction calculator, but make sure there aren’t any significant drug-drug interactions, and you have to counsel your patient on how to modify. I know Epic has a feature that allows you to look through medications, and it does give you a warning if there is a drug-drug interaction, so that’s a nice feature as well.

Best medicines to know about, though, that cause drug interactions, one of the most common is a statin, is actually, it’s recommended that most statins, like you’ll want to hold while the patient is taking paxlovid. There’s drug interactions with amiodarone, sildenafil, colchicine. A lot of immunosuppressant drugs, there’s interactions with, warfarin or anticoagulation, so it is really important that you look at what drugs your patients are on, and you’ll have to make some modifications or decide that these drug interactions are too much and you need to think about another agent. If you need a little bit more guidance, the EUA

also goes through each class of medicine that might have a drug interaction, and gives you suggestions as well, such as lower the dose of this drug, or hold this drug for five days, that can be helpful.

That’s my quick info about paxlovid. It is a really good drug, and plug the patient’s zip code into the COVID therapy locator, and you’ll likely find doses of paxlovid nearby, that you can prescribe to.

Timothy Ott, DO, FAAFP:

Great. That was a lot of very important information about this drug, that apparently has very strong effect for patients who are at risk, so can you tell us more about remdesivir?

Mustafa Alavi, MD:

Yeah, no problem, and I’ll just go to say that I personally have taken paxlovid for COVID. It does not taste good. It leaves this awful residue in your mouth, and I don’t think it’s just the COVID-19-altered taste. Like, when I took the tablet, I just had this awful chalky taste in my mouth pretty much until I was about to take the next tablet, so that is something to look forward to if you take or prescribe paxlovid.

Timothy Ott, DO, FAAFP

:But if it can save my life and keep me out of the hospital, I’ll put up with the bad taste, right?

Mustafa Alavi, MD:

Yeah. That is probably a risk-benefit that will highly weigh towards the altered taste. Yes, I can tell you more about remdesivir. Your treatment algorithm then prioritizes remdesivir. This actually isn’t even on emergency use authorization. It’s already FDA approved, and was being used on the inpatient hospitalized side for your patients with COVID-19. But on January 21st, the FDA expanded the use of remdesivir for your outpatients. This medicine can be initiated within seven days instead of five days for paxlovid. It’s meant for patients 12 and older, for similar criteria. They have to have mild to moderate COVID-19 with high risk of progressive disease, and it also, in the studies, has a pretty similar relative risk reduction for hospitalization or death to paxlovid, so the study was 87% relative risk reduction.

The difference obviously with remdesivir is that we used to be getting it in the hospital, but now that it’s approved for outpatient, it’s an IV infusion that has to be given once a day for three days, so most clinics don’t have remdesivir. But that means you need to partner or find someone in the community that has the capabilities to do IV infusions and that the patient can go to this infusion center for three days. So the biggest warnings for this medication was that it can cause an infusion site reaction, a rash. There is, in the FDA pamphlet, a talk about transaminase elevation, and requiring that you check kidney function, LTs and PTs, [inaudible 00:15:43] and time prior to initiating, and then kind of at your discretion, talking LFPs after treatments, and it’s not recommended for a DFR less than 30.

The benefits of this medicine, though, is that there aren’t significant drug-drug interactions like paxlovid, but like I mentioned, you have to find a infusion center that has remdesivir available. At least in Illinois, remdesivir is not managed by IDPH, so it’s managed by local hospitals and infusion centers, so you actually can’t put this drug into the COVID therapy locator. It won’t tell you where there’s remdesivir available, so just requires partnering with your local community.

Timothy Ott, DO, FAAFP:

With most of those medications, you’ve mentioned that they have to be at high risk for progression. Can you briefly mention what makes someone high risk for progression to more severe disease? Am I putting you on the spot?

Mustafa Alavi, MD:

Doc Ott, that’s a fantastic question, and that’s a question every clinic and institution has asked itself, about which patients are at highest risk? Who would benefit the most from these limited therapies and limited supply of drugs?

When these medications first came out, when omicron was surging, each institution developed its own sort of prioritization about which patients should get these medications. The NIH developed a prioritization table, tiered one through four, that most institutions have kind of adopted or modified to kind of fit their own population’s needs. The top, in tier one, are your patients who are immunocompromised or not expected to mount an adequate immune response to vaccination, or your unvaccinated folks who are at highest risk of severe disease, meaning like age over 75 or age over 65 with additional risk factors, being like high blood pressure, diabetes. And then each tier moves down a little bit, so then in tier two, it’s anyone who’s unvaccinated, who are at high risk of severe disease, so basically anyone over age 65 or age less than 65 with clinical risk factors, and then in tier three, you have your vaccinated folks who are individuals at high risk for severe disease, so anyone age over 65 with risk factors or age greater than

75. And then in tier four is your vaccinated patients at high risk of severe disease, which they define as anyone age over 65 or anyone less than 65 with risk factors.

The CDC has a nice list of different risk factors, and many, many medical conditions are considered risk factors, high blood pressure, diabetes, obesity, overweight, so BMI greater than 25 is considered a risk factor, CPD, heart failure. Pretty much every diagnosis that we see in primary care or family medicine is what is on this list. And then I would just implore you to look at your own local institution, if they have prioritization guidelines. I know at least what I’m hearing in the media, that now that we have so much stock sitting on the shelves, we do need to really get these medicines out to our patients with COVID, because it can help with these hospitalizations.

Timothy Ott, DO, FAAFP:

We’ve talked about the first two drugs. The third one is a tongue twister, bebtelovimab. Can you tell us about that one?

Mustafa Alavi, MD:

I don’t know if I’m pronouncing it right either, but yeah. Bebtelovimab is how I think it is pronounced, but yeah, it is a monoclonal antibody that has emergency use authorization for COVID-19. We’ve had a slew of different monoclonal antibodies over the past year, year-and-a-half, but this is the one the is recommended, at least right now, as of May 4, 2022, for our current strains of COVID. It is shown that this monoclonal antibody works for omicron.

And who is it approved for? I’m sure you’re going to notice a theme here, but it’s approved for anyone with mild to moderate COVID-19, in adults and pediatrics age 12 and older, at lest 40 kilograms or over, who are at high risk for progression, but then with the caveat for whom alternative treatments are not available, meaning paxlovid or remdesivir are not options for them.

So this is dosed by a single IV injection over 30 seconds. It’s 175 mg. They have to get it within seven days of symptom onset. There are also no known contraindications or drug interactions with the monoclonal antibody, similar to remdesivir. There also is no clinical efficacy data for these monoclonal antibodies. And the biggest reactions to this medication are infusion-related reactions, itching, a rash at the site, and they do also talk about, in the EUA, about potentially clinical worsening after infusion of the monoclonal antibody, meaning worsening fever, hypoxia, shortness of breath, but it does mention in the EUA that they’re unclear if this is related to the monoclonal antibody infusion versus just natural disease from COVID-19, and what was going to happen.

It’s just like remdesivir. Getting these monoclonal antibodies requires working with your local community at the hospital, and seeing who has bebtelovimab available for your patients. I know during the peak of the surge for omicron, when we had a different monoclonal antibody available, my local hospital was so backed up on these monoclonal antibody infusions that they were booking out one to two weeks out, which honestly is not helpful for your patients with COVID in the moment. They need COVID treatment as soon as possible, so that just requires seeing who’s doing this in your community.

Timothy Ott, DO, FAAFP:

Great, thank you Dr. Alavi. One more drug to talk about, another oral medicine, molnupiravir.

Mustafa Alavi, MD:

Yep, last one. I never thought I would be talking about pharmacology when I was at med school, but here I am. The last drug is molnupiravir. It is a nucleoside analog that is meant to inhibit COVID-19. The indications for this are a little bit different than the other three drugs, so it has to be given within five days, but it’s only for adults aged 18 and over with mild to moderate disease, and it also has a stipulation when alternative COVID-19 therapeutics aren’t available. That’s because the main trial for molnupiravir showed a relative risk reduction of 30% for hospitalization or death, which is far different than the 85, 87, 88+% that we saw for paxlovid and remdesivir.

The dosage for this is 800 milligrams twice a day for five days, so it’s actually four 200 milligram capsules. The biggest thing to be aware of, and I personally have not prescribed molnupiravir, because it is an alternative treatment, but it’s not recommended in pregnancy, and if you’re breastfeeding, it’s not recommended to be taken during breastfeeding and four days after the final dose. But otherwise, there are no drug interactions or dosage adjustments needed for renal function, but I highly, highly recommend that if you will be prescribing this, that you read the EUA for this drug, because there’s a lot of criteria that you actually have to document in your notes.

You have to document if they’re within childbearing potential. If they are, you have to advise contraception. You have to advise sexually active individuals use contraception for at least three months after the last dose of molnupiravir. You have to make them aware that there is a pregnancy surveillance program.

Obviously, all of these, like if you have a system that allows you to do dot phrases, like read the EUA, make this a dot phrase, so that you know that you meet these FDA requirements for prescribing this medication, and make sure you have the EUA and give the patient a… There’s the patient EUA for these drugs.

So that was a lot. I talked a lot of boring pharmacology, and we talked about a lot of medications to treat COVID-19, but Dr. Ott, is there anything we can do to prevent COVID-19 in some of our most high-risk patients and in our patients who may already be vaccinated?

Timothy Ott, DO, FAAFP:

Yes, there is. That’s the good news. This medication is marketed as Evusheld, and it is a preexposure prophylaxis that’s composed of two monoclonal antibodies that hang around in the system for quite a while, and I’ll get to their names in a minute, but the idea with this medication is if you have somebody that’s really immune compromised, meaning that they have an immune- compromising disease, that they’re currently on chemotherapy for active cancer, that they’ve had severe allergic reaction to the COVID vaccine, and therefore haven’t been able to get the COVID vaccine, that they’re transplant recipients on immunosuppressive drugs, or have a primary immunodeficiency syndrome or active AIDS with a CD4 count of less than 200, or stage IV CKD, or dialysis patients, or neutropenia from any cause. These are really severely immune compromised people that maybe can’t mount a response to the vaccine or can’t tolerate the vaccine, so the idea with Evusheld is to give them antibodies, since they can’t develop their own antibodies.

To qualify, you have to be 12 years old or older. This medication was also approved in December of 2021 for emergency use authorization. You have to have not had recent COVID exposure or be COVID positive, because it’s a preexposure prophylaxis for these very high-risk patients, and you have to be at high risk if you would get COVID. It’s two shots that are given at the same time. The two drugs are… There’s 150 milligrams of tixagevimab and 150 milligrams of cilgavimab. They’re two shots given at the same time, intramuscularly, so one in each buttcheek, and they are only available at specialty care centers, infusion

centers, hospitals around the state, and I don’t think they’re on the locator, so this would be something else that would be required to partner with your local hospitals, health departments, and stuff to figure out where you can get it.

But I would also recommend, I have had two patients now that have got this, and both of them were under the care of an oncologist, and the oncologist did not bring this up with them, but I brought it up with my patients, but I looped the oncologist in, and I think with these sort of most critical patients, that we need to keep our specialists looped in when we make decisions about something like Evusheld. So if you’re dealing with an immunologist, or an oncologist, or a HIV specialist, that I think you ought to loop them in on agreeing with the Evusheld and obtaining that for your patient. It’s also good to have the specialist buy-in to help convince the patient to get the Evusheld.

Mustafa Alavi, MD:

Wow. Thank you, Dr. Ott, for teaching me about Evusheld. I have not personally prescribed that for my highest risk patients, and I need to start thinking about that more. To your point, Evusheld is actually on the COVID therapy locator, but you’re right, you do have to know which institutions have them, which infusion centers, because it has to be an infusion that’s given, so you have to know who has it in your community. So the therapy locator will just kind of guide you which institutions you reach out to.

Timothy Ott, DO, FAAFP:

Thank you, Dr. Alavi, and thank you for leading us through the treatment options and teaching us about the COVID-19 algorithm. That’s all great information, and I know I’ve learned a lot, and I hope our listeners have learned a lot, and I hope this’ll help all of our listeners be more comfortable in providing outpatient therapeutics for their COVID-19 patients. Any closing comments, Dr. Alavi?

Mustafa Alavi, MD:

Yeah, and I just want to really reiterate and summarize, like there is a lot of treatment options, and we went through a lot of information. Just to summarize, use the NIH treatment algorithm to help you as a provider, in the moment, know which medications are available to you, between paxlovid, remdesivir, bebtelovimab, and molnupiravir. In one of those four medications, to really know paxlovid is a great treatment option that you can easily electronically prescribe to a pharmacy that has it in stock. And, if you are going to prescribe any of the other medications, work with your local institution in your community. Use the COVID-19 therapy locator to know what’s available or around you, and read the emergency use authorization for the medications that have them for more detailed information, as you as a provider become more comfortable with it.

Timothy Ott, DO, FAAFP:

And the links for the tools that Dr. Alavi talked about will be there where you found the link for the podcast, and we hope you tune into additional podcasts.

Thank you, everyone.

Mustafa Alavi, MD:

Thank you. This was a lot of fun.

Resources Mentioned:

https://aspr.hhs.gov/COVID-19/Therapeutics/Documents/COVID-Therapeutics-Decision-Aid.pdf

https://covid-19-therapeutics-locator-dhhs.hub.arcgis.com/

https://dph.illinois.gov/covid19/community-guidance/covid19-treatment.html

https://www.cdc.gov/coronavirus/2019-ncov/your-health/treatments-for-severe-illness.html