#MSCOVID2019. Interacting with your drugs

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How do you know if your drug is likely to interact with Paxlovid, which is one of the anti-viral drugs for SARS-CoV-2

You can ask your Doctor?

They may go to the latest advice for the NHS and for some MS drugs you get the “avoid like the plague message” given in Doctory language. We know that paxlovid can affect the breakdown of some drugs and this is because it contains an anti viral drug called ritonavir.

Ritonavir inhibits cytochrome p450 enzymes called CYP3A4 and CYP2D6 meaning that any drug that is broken down by CYP3A4 that is taken at the same time as ritonovir, it will now not be broken down as quickly and so the effects of the drug may be enhanced and this could be dangerous if the drug is potentially toxic. Sidenafil is broken down by CYP3A4 so if you had sidenafil and paxlovid you may have something for a long, long time…P.S. Sidenafil is also known as Viagra, which is used to treat heart problems:-).

You could go to a drug checker site. Here is one from a “Drug Interaction Checker”

Check out cladribine and paxlovid and there is no issue, do the same with siponimod and there is no issue but now do ritonavir and you get a warning. That’s not good as paxlovid contains ritonovir.

OK, so let’s go to another trusted site The Liverpool COVID-19 Drug interactions checker and oh dear it doesn’t have cladribine, or siponimod or fingolimod or dimethyl fumarate or etc despite by being funded by an MS drug manufacturer:-( So that is not going to help.

You can do your own Searching

So the way you check the interactions with CYP3A4 and 2D6 is to Read the label in the US or the Summary of (medical) Product characteristics in Europe

Search (product name) and INN and label. This gives you sites to look at you can choose the FDA site if you live in the US (www..accessdata.fda.gov) or EMA sites in Europe (www.ema.europa.eu › medicines › human › EPAR). This should give you accesss to a pdf.

Press Control (Ctrl) f together which is the search function and then type in CYP and the search function with find every time CYP is mentioned

For cladribine it says (pg 14)

“Cladribine is not a relevant substrate (target) to cytochrome P450 enzymes and does not show significant potential to act as inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1
and CYP3A4. Inhibition of these enzymes or genetic polymorphisms (e.g. CYP2D6, CYP2C9 or
CYP2C19) are not expected to result in clinically significant effects on cladribine pharmacokinetics or
exposure. Cladribine has no clinically meaningful inductive effect on CYP1A2, CYP2B6 and
CYP3A4 enzymes”

so this says cladribine’s breakdown will not be affected by ritonavir’s action on CYP3A4 or CYP2D6

For Siponimod (EMA) it says

“Siponimod is metabolised primarily by cytochrome P450 2C9 (CYP2C9) (79.3%) and to a lesser
extent by cytochrome P450 3A4 (CYP3A4) (18.5%)…….Because of a significant increase in exposure to siponimod, concomitant use of siponimod and medicinal products that cause moderate CYP2C9 and moderate or strong CYP3A4 inhibition is not recommended. This concomitant drug regimen can consist of a moderate CYP2C9/CYP3A4 dual inhibitor (e.g. fluconazole) or a moderate CYP2C9 inhibitor in combination with a separate moderate or strong CYP3A4 inhibitor.

In the label

It says ” Because of a significant increase in exposure to siponimod, concomitant use of MAYZENT and drugs that cause moderate CYP2C9 and moderate or strong CYP3A4 inhibition is not recommended. This concomitant drug regimen can consist of a moderate CYP2C9/CYP3A4 dual inhibitor (e.g., fluconazole) or a moderate CYP2C9 inhibitor in combination with a separate – moderate or strong CYP3A4 inhibitor.

The and is underlined, does in mean avoid use of drugs that inhibit both CYP2C9 and CYP3A4 or CY2C9 or CYP3A4. As ritonavir is not an inhibitor of CY2C9, it is not an inhibitor of CYP2C9 and CYP3A4 and potentially would not be covered by the warning…..but as there is a warning about CYP2C9 and CYP3A4 inhibitors and siponimod, I suspect people will stay clear and use an alternative anti-viral treatment, despite the fact that the COVID-19 drug is only taken for 5 days, and higher siponimod doses have been tested and are relatively safe in humans.

Now I have questioned the significance of the AND with the Medical Liason Officiers, so I know the answer, but surely it is up to the manufacturers to make a call about their own compounds.

Why write this post….Well it is for you AND especially for some doctors, as it is is interesting to see which products they are recommending to the UK Government that they should be avoided if use of paxlovid is considered (NHSE advice 29 January 2022).

COI: Multiple

Disclaimer. This is the opinion of the author of this post and does not represent the views of any instituion. This should not be taken as medical advice.

About the author

MouseDoctor

9 comments

  • Hello MD- Your write-up is labelled as “easy read”. I don’t know about that. In a very subjective sense, it feels good knowing that there are some very bright people around (you) pointing things out and working to improve upon them. Just saying…

    • Sorry since ProfG left to go do his own thing I have not been using the labels much, but if you think it is helpful I will be more diligent. Likewise I have not been particulalry bothered about the labelling of posts as so many were ProfGisms e.g. “clinicspeak” and in my opinion need to go when we give the blog a overhaul.

  • thank you, this is a really important post! first, because you have to be fairly tuned in to even know about the ritonavir interactions, but also because I personally looked fingolimod up weeks ago and DIDN’T FIND the potential interaction you describe above for siponimod.

    • We have contacted Novartis and there is evidence that a CYP3A4 inhibitor did not unduly influence siponimod, but it is for them to question the ruling, we have told Novartis and Merck about the information. For fingolimod if you look at the SpMC it says “Fingolimod is metabolised mainly by CYP4F2. Other enzymes like CYP3A4 may also contribute to
      its metabolism, notably in the case of strong induction of CYP3A4……Caution should be exercised with substances that may inhibit CYP3A4 (protease inhibitors, azole antifungals, some macrolides such as clarithromycin or telithromycin)”.

  • This is all so confusing. If I get covid and am offered an antiviral, I would just take it because I’d trust whoever was prescribing it. Now I’m worried about interactions, I’m on Gilenya. Since the start of the covid pandemic, I’ve been very much wishing I wasn’t! Thanks MD though, I am grateful for the time you spend on the blog.

    • In terms of drug interactions with Gilenya Fingolimod is metabolised mainly by CYP4F2 this is not affected by paxlovid. In the label it says “Caution should be exercised with substances that may inhibit CYP3A4 (protease inhibitors, azole antifungals, some macrolides such as clarithromycin or telithromycin). So you may think that paxlovid would be avoided, but this is not the case in some of the information online for UK Doctors. However, ther are alternatives so dont worry.

      David et al.Clin Pharmacol Drug Dev. 2018 Aug; 7(6): 575–586. “CYP3A4, have no or little contribution to fingolimod metabolism. Earlier, we reported that coadministration of ketoconazole and fingolimod results in increased fingolimod and fingolimod‐P exposure by 1.7‐fold through the inhibition of CYP4F2”. [Ketoconazole can affect CYP3A4 but if it only increases the level by 2 fold that means the effect of a CYP3A4 inhibtor that does not target $F2 is going to be less than 2 fold and remember ten times the clinical dose was safe in phase II trials]. There is some information about CYP3A4 inducers but paxlovid is not an inducer.

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