Day 9/10 – ranitidine and famotidine

This post is a part of a series on drug shortages.

I spent my day investigating two drugs. We were contacted by a CBC reporter asking about shortages of Ranitidine and Famotidine, both drugs used for reflux (why these drugs were chosen by the CBC… that’s an exercise left for the reader). Here is a link (alternate link) to the article published today .

The question we were asked was whether there was an association between a recent shortage in ranitidine (Zantac) and an even more recent shortage in famotidine (Pepcid). Let’s look at the timelines:

Availability of Ranitidine and Famotidine over time

Qualitatively, I’m not sure what I see here. It’s tricky because there is clearly a jump in shortages of both drugs in 2019, but I’m not sure I could say too much more about it. I’m also not entirely sure how to model the idea of the knock-on effect of shortages (called “domino shortages” in the article) so I’m not sure how to measure any causal effect statistically.

In any case, the chart also illustrates a stagnation/decline in the number of available versions of each of these drugs. One thought could be that this represents a shift away from prescribing these drugs to other, similar drugs. If so, perhaps the impact of shortages of ranitidine and famotidine may be buffered by the availability of these other drugs.

To explore, let’s first look at other drugs with the same mechanism of action: histamine-blockade. We can do this by looking at the 4th-level ATC class that they both belong to: A02BA. First chart is the whole class together, and the second is broken out by ATC code (ranitidine is A02BA02, and famotidine is A02BA03)

Okay, so a huge drop in marketed drugs, right around the same time that we also see an increase in the number of shortages. If I squint at the top chart, it looks like the number of shortages starts increasing through 2016 just before the drop in 2017. Now, I’m suspicious of the completeness of our shortage data around 2017 since this is also when the shortage database itself came online. The error bars are likely quite large at that point. In any case, we can say that in 2017 there was a drop in marketed h2-blockers, and then in 2019 we see a spike in the number of shortages, especially so for ranitidine. (The drug with the very significant drop in marketed versions is cimetidine, an h2-blocker on the WHO Model essential medicines list.)

Note that what we don’t see is evidence of a “buffering” via increased availability of other H2-blockers. That is, the shortages of ranitidine and famotidine really do impact the availability of H2-blockers.

Let’s zoom out further. H2-blockers themselves are part of a larger group of antacids and other drugs used for reflux: The 3rd-level ATC class A02B:

Availability of peptic ulcer drugs

You can clearly see that any effect is really from two classes of drugs: the h2-blockers (A02BA) and the proton-pump inhibitors (A02BC). The PPIs do not have the same sudden loss of marketed drugs and have a smoother increase in shortages over time. But again, we don’t see any evidence of increasing access to alternatives drugs to manage reflux as the shortages roll in. That is, there is no evidence the market is adapting to shortages, and this suggests that these shortages really do matter for access to medications that treat reflux.

Going back to our two drugs under investigation, we wondered whether the drop in marketed drugs had to do with manufacturers getting out of the business of producing these drugs entirely or whether it was just a decrease in the number of formulations being marketed. To explore this, we can plot the number of manufacturers over time:

Manufacturers of marketed products over time

Looks to be that famotidine had its heydey in the early 00s and has since lost manufacturers, where as ranitidine did not. We see that 20 year trend of losing manufacturers is reflected in the decline in the number of marketed famotidine products (see the first chart, note the decline). What we don’t see is a sudden drop in the number of manufacturers around 2017 corresponding to the drop in marketed H2-blockers. This suggests the drop in marketed H2-blockers comes from manufacturers producing fewer versions of the drugs.

Are you dazzled and overwhelmed by my myriad of charts? My summary is this: both drugs have experienced recent shortages that continue to this day, ranitidine to a greater extent. I don’t know that we can draw conclusions about the shortage of ranitidine being a causal factor in the subsequent shortage of famotidine, but we can say that there hasn’t been much wiggle room in the market to deal with shortages, and in fact the market has been shrinking. And that can’t help.

Postscript: I think getting a feel for the data is important. In that spirit, here is the data we have on shortages and discontinuations for ranitidine and famotidine:

Timeline of famotidine and ranitidine