Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. This podcast is Narrator - ? 00:12 provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 This podcast contains general information for educational purposes only. This is not professional advice and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - ? 00:27 And now on to the show. Dr. Sean Kane 00:31 Welcome to HelixTalk episode 143 I'm your co host, Dr. Kane, and I'm Dr. Patel, and the title of today's episode is the low down on hypothyroidism, the essentials of what healthcare providers need to know. So obviously, we're talking about hypothyroidism today. And what's interesting, Dr. Patel, is that this was actually a listener request, multiple listener requests. So we got questions from listeners asking about hypothyroidism to do an episode on it, specifically about how to interpret some of those thyroid panel numbers, and also what the difference is between different thyroid medications like brand versus generic Synthroid or levothyroxine, armor thyroid, liothyronine. You know, when are we supposed to be using these non levothyroxine products, and what is the difference between them? Dr. Khyati Patel 01:18 And, you know, I think over the years, this has become a little bit more clear. However, there's still some controversy, and we'll talk about why there is a controversy. But all in all, dr, Kane, I just love doing episodes that are requested by our listeners, because it feels like we're giving back, right? So I'm excited for this Dr. Sean Kane 01:36 one, yeah. And for listeners, if you do have a topic that you would like us to cover you can reach out to us. So HelixTalk.com has our contact information, or even on Twitter at HelixTalk. Dr. Khyati Patel 01:47 So it seems like hypothyroidism is everywhere. You know, I have few family members who have it, and levothyroxine is probably top 200 medication that's dispensed, right? Is it? Right? Dr. Sean Kane 01:59 Oh, yeah. So this is literally the second most prescribed medication in the US. So it's extremely common. Every healthcare provider is going to encounter patients that are on this medication. And it's important to know facts about the medication and also the disease state in general, prevalence is about 2% of all women and point 2% of all men in the US have this disease and the risk of having it increases with age. So as you get older, you're more likely to have it. So it is interesting that prevalence is literally 10 times more common in women than in men, as we'll talk about it is essentially, in most cases, an autoimmune disorder. And we do see women tend to have more autoimmune disorders than men, so it's not surprising that hypothyroidism is in that boat as well, Dr. Khyati Patel 02:44 and so some of the symptoms that patients with hypothyroidism may present with are changes in the skin system and integumentary changes such as dry skin, or they may find their hair to be a little bit more coarse, or maybe even shutting off the hair because it's become coarse. Dr. Sean Kane 03:02 And then, from a metabolism standpoint, you your body regulates metabolism through the thyroid hormone system. So if you don't have enough thyroid hormone in your blood, essentially all of the tissues in your body start slowing down or not burning as many calories as they normally would. So of course, we think about weight gain from a slower metabolism. But we also think about things like cold intolerance, because you're not generating as much heat as you normally would, constipation, because your GI tract, peristalsis is kind of slowing down, feeling weak, not having a lot of energy, low heart rate, everything in your body is kind of slowing down because you lack the amount of thyroid hormone that your body needs to have a normal functioning metabolism. Dr. Khyati Patel 03:45 And going with the you know, theme of slowing down your central nervous system is slow as well, so that fatigue, the lethargy, just the feeling of not wanting to do anything. And in patients who have, you know, underlying depression, maybe this exaggerates it, or it feels like that they're having a nuance at depression. And then Dr. Sean Kane 04:07 kind of the thing that makes a little bit less sense are we can see muscle cramps and myalgias. So this isn't so much about, you know, the muscle system revving its metabolism down. But for whatever reason, muscle cramps and myalgias are fairly common complaints among patients that do have hypothyroidism. Dr. Khyati Patel 04:23 Well, symptoms are good to understand. You know what patients presenting with? And you know what this might be, however, kind of going back to the drawing board and understanding what's the normal physiology of our thyroid hormones and just the system in general, it's really important so kind of to start with. You know, we have two thyroid hormones that have effect in our tissues in the body, that's our t3 and t4 Dr. Sean Kane 04:50 and these are produced from your thyroid gland, but your thyroid gland needs to get signaling from elsewhere in your body to know how much of this stuff to produce. It's actually your pituitary gland in your hypothalamus that detect how much thyroid hormone you have. And if it's not enough, your hypothalamus is going to release something called TSH, thyroid stimulating hormone. This is important because this is the thing that we check in your blood to actually see what your thyroid status is. So TSH is going to trigger more thyroid hormone to be produced. So it's t3 and t4 from the thyroid gland. And that also means that if your TSH is really, really high, that means that you are hypothyroid. It's kind of the opposite of what you might expect. So high TSH means that you are hypothyroid because your body is trying to stimulate more thyroid hormone. TSH is thyroid stimulating hormone. Dr. Khyati Patel 05:40 And I think the t3 and t4 and their composition and origin is also something important to learn. All of our body's t4 is coming from the thyroid gland, while small amount of t3 is made in the thyroid gland, the rest is kind of converted from t4 to t3 in our body's peripheral tissues. This is more than 80% of the t3 is available to us via this conversion. Dr. Sean Kane 06:07 And what's interesting Dr. Patel, is that the t3 is kind of the the more potent thing. So t3 is 10 to 15 times more potent than t4 and it's interesting because your thyroid gland primarily makes t4 that later on in the periphery, gets converted to t3 and that conversion is mostly regulated by nutrition, other hormones in your body, the room temperature, ambient temperature, other medications that you're on, other chronic illnesses that you have. So really, a lot of the magic isn't necessarily happening in the thyroid gland, but it's happening in the periphery, where you're converting t4 almost like a pro hormone, into t3 which is a much more potent version of a thyroid hormone. Dr. Khyati Patel 06:47 So what really goes wrong in the hypothyroidism in most of the cases, it's chronic autoimmune thyroiditis, as you laid it out Dr. Kane earlier, it is an autoimmune disease more common in women. We also call this Hashimoto thyroiditis, or Hashimotos disease, basically, our immune system attacks the thyroid cells, and thyroid cells that are making these hormones are now not making them. We could go ahead, just like, to check antibodies for any autoimmune condition. We could go ahead and check specific antibodies to Hashimoto thyroiditis. These are anti thyroid peroxidase and anti thyroglobulin antibodies, but because this is the most common cause in practice, usually these antibodies are not conducted just because it takes a little bit longer to come back, and even if they come past, if they come positive, it doesn't really change the treatment. Course, you know, the treatment is still the Dr. Sean Kane 07:47 same in the United States, the kind of second most common cause of hypothyroidism is some issue with the pituitary gland, where the hypothalamus not making enough TSH, this is way less common. And generally speaking, it's kind of obvious that a patient has a problem with their pituitary gland. So this would be someone with a tumor in their brain, or a traumatic brain injury, or some structural problem in their pituitary or hypothalamus, that would lead you to suspect that the hypothalamus or pituitary are not producing adequate hormones in general, TSH included, Dr. Khyati Patel 08:21 and other medications or iodine can also cause hypothyroidism, especially with iodine. You know, it's either too much or too little dietary iodine can cause it. Iodine is part of the structure of our T3/T4 hormone, so it's important for its composition in itself. Lithium and amiodarone are some of the other examples of medications that can cause hypothyroidism, and it kind of becomes monitoring parameters for checking for, you know, TSH, when patients are on these medications. Dr. Sean Kane 08:52 So from a diagnostic standpoint, if you go back to kind of the symptoms of hypothyroidism, they are fairly non specific, where lots of things causes fatigue, lots of things cause constipation. So obviously you need to have laboratory testing to confirm a diagnosis of hypothyroidism. And for autoimmune thyroiditis, the most common cause, we're looking for TSH levels. And again, TSH levels in hypothyroidism will be high, so normal values around point four to four, and we'll talk more later about how that's a little bit controversial, but I like point four to four because it's easy to remember. You know, different lab assays will be slightly different, but roughly speaking, that's our normal level. Dr. Khyati Patel 09:34 And as the hypothyroidism kind of progresses, this translates the effect of this high TSH will eventually translate to the production of our t4 levels. So the t4 levels is eventually going to turn up low as well, and then kind of follows the t3 because of t4 converting to t3 these will be the last one to be impacted, but eventually they can also turn enough to be low. Dr. Sean Kane 10:01 And just for completeness sake, there are t3 and t4 levels that we obtain, and we can also get a free t3 and a free t4 and basically this is kind of like phenytoin or valproic acid, where t3 and t4 are extensively protein bound, like more than 99.5% of t3 and t4 are bound to proteins, but only that point 5% the unbound or the free t3, and t4 are physiologically active, where they cross membranes, cross the blood brain barrier, and can actually impact gene expression on target tissues. So there is some argument that perhaps we should check free t3, and t4 the physiologically active t3, and t4 to kind of make sure that we have a good understanding of a patient's thyroid status. But again, at the end of the day, the main thing that we look at is the thyroid stimulating hormone, or TSH. That's how we assess for hypothyroidism in general, and also generally, how we are going to titrate our therapy. Dr. Khyati Patel 10:58 And so talking about therapy, let's start with how hypothyroidism is treated, as we kind of laid out earlier. You know, levothyroxine is the drug of choice, and it's probably the second most prescribed drug. This levothyroxine, aka l thyroxine. There are a lot of brand names out there. More common ones that you may have heard are Synthroid, levoxel, but there is plenty more out there, Dr. Sean Kane 11:23 and this is essentially just synthetic t4 so it's literally the same stuff that your body makes, called t4 but it's a synthetic version, so it's not dry from animals. It's made in a lab. And just like the t4 in your body has a really long half life of about seven days. And that's relevant for a couple of reasons. One, if you miss a dose, probably not the end of the world. And two, it takes a long time to get to steady state. So when you initiate someone on levothyroxine, it's going to take, you know, four to six weeks for you to be able to see the impact of whatever dose of levothyroxine that you're on, to see the impact on the TSH levels for that patient. Dr. Khyati Patel 11:59 And so kind of keeping that in mind. You know, that principle is then moving into how we dose it. We normally start at a lower dose and then titrate slowly by checking the levels every four to six weeks. And you know, we try to get to that TSH goal level, the point four to four normally, we don't do too quick or fast increase in doses, because it can cause side effects. Obviously, some of the serious one can lead to, you know, symptoms of angina as well. So that that low dose is really the 12.5 microgram, another low dose is 25 microgram, or even 50 microgram. Now we gave you a good range. And you may wonder, okay, well, that's a big range. What do we do? Dr. Sean Kane 12:45 So really, for the the older patient, the elderly patient, or those that have pre existing cardiovascular disease or arrhythmias, you do worry that being too aggressive upfront is going to cause them to have some cardiovascular side effect. So for those older patients or those with cardiovascular disease, you're going to start at 12 and a half or 25 for that younger patient that has very few chronic comorbidities, especially cardiovascular ones, maybe you could start at 50, and that would be okay. Dr. Khyati Patel 13:12 And then what does that slower titration mean? And that's going to be just kind of increase it by either 12.5 to 25 micrograms every four to six weeks. So let's say a patient was on 50 micrograms and the TSH level was not in that point four to four range. I probably would add another 12.5 and then check again in four to six weeks. And of Dr. Sean Kane 13:35 course, we're thinking both about that TSH level goal, point four to four ish. We'll talk more about that in a bit, and also symptoms. So especially if they had a specific symptom, like fatigue, we're going to want that to get better. That's a whole point. We're not just treating the number. We're treating the patient too. So it's important to talk to the patient about their symptoms and also assess their lab value as well. Dr. Khyati Patel 13:57 So is there a goal level that we are aiming for, like, you know, like eventual dose of levothyroxine. And the answer is, the usual dose for any patient is based on ideal body weight, and so it will be 1.5 microgram per kilogram per day. So on an average being adult, it's going to be somewhere around 125 micrograms per day. But that being said, some patients are controlled very well on the lower doses, like 88 microgram or even 100 microgram. Dr. Sean Kane 14:30 And conversely, Dr. Patel, I've seen plenty of patients that are on ridiculous doses of levothyroxine, 200 to 300 micrograms per day. So obviously there's a variability here, and that's why we titrate every four to six weeks, and we're checking those levels Dr. Khyati Patel 14:43 right absolutely. And as you mentioned earlier, too, a lot of different factors would change that conversion rate. You know this t4 that we are taking our body is still converting to that active t3 in the periphery. So all of those reasons or factors that would impact this conversion. Would also dictate how the dose is different for each patient. Dr. Sean Kane 15:04 Now the good news, though, is that for the most part, once you pick the right dose for a patient, when you get a steady state TSH level, things look good. For the most part, you don't have to really reassess extremely frequently, unlike something like warfarin, where even once you pick the best Warfarin dose for that patient, you have to keep frequently checking and potentially adjusting. For the most part, once you get the right dose, for a patient, you don't have to check as often, and for the most part, that dose isn't really going to change. Dr. Khyati Patel 15:31 Right I think in in practice, Dr. Kane, what I've seen is if, if we've gotten patient to a good dose and TSH level is good, and their symptoms of hypothyroidism are now controlled. We would check them, you know, every six months to even once a year. Check. I've seen that obviously, you know, if there are other medications or drug interactions or new health conditions they're developing, this could end up affecting thyroid, like, one example is prednisone, and so the levels of TSH might be a little bit different, and you want to always be careful, as you know, if the number is off, don't jump to conclusion and say, I need to change the dose. Always evaluate what's going on in patient's life in terms of other medical conditions and changes in medications that could be affecting this. And so sometimes it's not about just changing the levothyroxine dose, but just maybe giving it a little bit of a time for us to recheck the level again. Dr. Sean Kane 16:29 And in terms of that level, as we said, the easy answer here, in terms of our goal level, is around point four to four micrograms per milliliter. And I like that Dr. Patel, because it's easy to remember point four but this is a surprisingly weirdly controversial thing in terms of what is the goal level for a patient. So some experts would advocate for a basically a lower TSH goal for younger patients, something like point four to two and a half, instead of point four to four. And conversely, for the older elderly patients maybe a higher TSH level, something like point four to six, as opposed to point four to four. And a lot of this argument comes from this condition called sub clinical hypothyroidism. And these are patients that have slightly elevated TSH levels, but they have minimal or no symptoms. And really the debate is, if they have very few symptoms, if you give them levothyroxine, are you really benefiting the patient, aside from changing the level? So for sure, if the TSH level is more than 10, you definitely have to treat but around like the four to six to eight to 10 mark for their TSH level, it's a little bit controversial in terms of, what is the clinical benefit of treating those patients, assuming they have very few symptoms. Dr. Khyati Patel 17:44 And I can understand why the controversy is there, especially for these, you know, sub clinical hypothyroidism patients. Why rock the boat? If you don't need to, you know, rock the boat, basically. Dr. Sean Kane 17:57 So, you know, obviously patients need some counseling regarding these medications. And my number one counseling point, Dr. Patel, is take it the same way at the same time every day, the medication, in terms of how it's absorbed into your body, can change based on how you take it and when you take it. Therefore, if you take it the same time every day, we can pick the right dose based on how you take it, as long as you're consistent, right? Dr. Khyati Patel 18:21 And I think this is one of the most important aspect of levothyroxine. As a pharmacist, we're going to come across is educating patients on how to take it. I get questions all the time in terms of them they're starting new medication, or if their schedule is changing, or they got another medication that needs to take, you know, around the same time I get questions about this, and there is lot of information out there that has to be taken in the morning, as you nailed it. Dr. Kane, the answer is the same time in the same manner. So if it was two hours after dinner, which you can do, it has to be two hours after dinner every day. Because if there was supposed to be any interference from medications or other food, it would be consistent. So kind of like staying consistent, you know, don't change it three hours after meal one day. Or, you know, five hours after meal one day. Just stay at two if that's what you're normally doing. Dr. Sean Kane 19:20 Dr. Patel I actually view this very similar to how we counsel patients on warfarin regarding vitamin K containing foods like salads. It's a misconception with Warfarin that you need to avoid salad or avoid green leafy vegetables. The proper thing to say is, if you want to have five salads a week, go for it. But we're going to pick a five salad a week. Warfarin dose for you, and you have to be consistent with the amount of salad that you take every week. The same is true with levothyroxine. Consistency is the key, absolutely. Dr. Khyati Patel 19:50 And you know, if you look at the manufacturer label, they're going to say, Take empty stomach 30 to 60 minutes before breakfast. So kind of following that, PDR. Reference, you know, these are, these are the instruction moving into patient sake, when the prescription arrives at the pharmacy, and that's how patients are taking it. But again, going back to what you said, Yeah, same time every day. That makes sense. Some of the other literature, I'm suggesting, it can be taken three to four hours after dinner. The most important thing is to, you know, help patient find a time in the day that they can stick to to be able to take it, you know, same time every day, obviously, when they're starting on certain interacting medications, for example, calcium carbonate, you know, then there needs to be that two hour separation for the drug to be absorbed properly. But other than that, they need to follow their regular routine, and Dr. Sean Kane 20:41 in terms of when you initiate therapy and you're counseling patients about what to expect with the medication, some of the precautions, I think, are certainly things that you would want to counsel on. You know, we kind of alluded to it, but one big precaution is that, especially if you're too aggressive in your dosing, that patients could potentially have cardiovascular adverse effects. So we're talking about palpitations, arrhythmias, angina, things like that. This is mainly in the older patient population or those with pre existing cardiovascular disease, but it's still something to mention at a minimum, palpitations to a patient, or if they have angina that they need to call their doctor immediately, Dr. Khyati Patel 21:17 and kind of going from this milder precaution for which we're going to probably do dose adjustment, a box warning on thyroid medication is is to not use it for obesity and weight loss. And I always found this box warning really interesting. Dr. Kane, you know, it wouldn't make sense for somebody to use thyroid for weight loss, although we know that hyperthyroidism causes the opposite of hypothyroidism, so your metabolism is ramped up and you could end up losing weight. So I think that therefore there is this warning here that you know if you are euthyroid, normal, healthy individual, by taking this medication, it can turn your euthyroid state into hyperthyroid state, and can cause some life threatening toxicities, especially when it's combined with certain stimulants like phentermine, which is normally used for weight loss too. So this combo is just kind of like a no go, perfect. Dr. Sean Kane 22:14 And you know, related to that, you know that box warning is for levothyroxine, which is an FDA approved drug, one fascinating area, and I think an area that really contributes to the confusion about hypothyroidism treatment, is that there's a bunch of other thyroid hormone supplements and drugs on the market. And one thing that again, was the listener question is, what is the difference between levothyroxine and then all of the other thyroid products that are on the market, and I would, Dr. Khyati Patel 22:43 I would say, this is a very common question I get as well, even from the prescriber perspective too, because these, these formulations are available, you know, if not over the counter, agents and supplements containing thyroid, even thy armor thyroid, or Leo thyron In or cytomel, are kind of the prescription products available. So good. To clarify this definitely, as we talked about earlier. You know, we normally like to go for leave with the rocks, and which is a t4 because it's a pro hormone our body takes care of converting it to the t3 as it needs. The guidelines are not really clear in supporting anything else besides levothyroxine, because there is kind of no data supporting t3 or even combination of t3 and t4 products. Dr. Sean Kane 23:31 So despite the guidelines saying you should use levothyroxine because there isn't good data supporting anything else, Dr. Patel, I'm sure you would agree with me. In clinical practice, we still see patients that are taking armor thyroid, for example, or other thyroid products. What's interesting is that the reason that these are still in the market is that they were present before 1938 and for any pharmacy student listening that took a pharmacy law class, 1938 was kind of a big deal in the pharmacy world, right? Dr. Khyati Patel 24:00 That's right because we had the fdnc Act of 1938 passed, which required all medication to submit that new drug application in order for a full FDA review. Dr. Sean Kane 24:12 So any drugs that were pre 1938 could be grandfathered in, which means that they don't have to go through all of the things that a new drug has to so in terms of verifying that the manufacturer has good manufacturing practices in terms of a generic equivalent cannot exist if it's not a drug, because we don't have data to prove bioequivalency, data supporting its use in terms of efficacy and safety. Some of these medications were grandfathered in, and they're still in the market. They've never truly undergone a full FDA new drug application review, so they're considered unapproved drugs that are widely available and used on the market. Dr. Khyati Patel 24:50 And so one of this one is liothyronine. Brand name is Cytomel. This essentially is a synthetic t3 it's. Pure syntactic t3 the half life is a little different, shorter than our t4 levothyroxine. It's 1.5 days instead of seven days with our levothyroxine. Again, as we discussed earlier, there is a reason to give t3 as our body pretty well converts t4 to t3 as it's needed. Dr. Sean Kane 25:19 And the listeners might be wondering, well, what if the body doesn't do a good job of converting t4 to t3 wouldn't it make sense to give t3 and essentially, that condition, in terms of not converting t4, to t3 appropriately, is exceptionally rare and usually involves genetic mutations and things like that. So the normal run of the mill, hypothyroidism patient does a great job converting t4 to t3 in the periphery, better than what we can do in terms of providing the patient with t3 so that is the preferred way is to give the body t4 and let the body figure out how much does it want to convert to t3 and Dr. Khyati Patel 25:53 the additional kind of hiccup that comes with dosing t3 is because most of the dosing and attaining The TSH goal levels are based on t4 dosing, right? So with this different half life, with t3 it just becomes that much harder to kind of say, like, Can Can we get to that TSH level? When do we monitor the levels? Because the half life is a little bit different all in more the confusion. So it's better just to stick with t4 Dr. Sean Kane 26:20 then the other commonly used product on the market is thyroid USP. USP stands for United States Pharmacopeia, which means that any product under thyroid USP has certain requirements that they need to make. It doesn't mean that every product is equivalent to every other product that is a thyroid USP, but it means that the requirement in this case is that they have to have a specific amount of t3 and t4 per grain of the product. And grain is a weight of measure. The typical brand names that you're going to see here are going to be armor thyroid, which I think is probably the most common, but there are other ones, like NP, thyroid, westeroid nature thyroid, all of these are under the thyroid USP umbrella because they meet the criteria of what the United States Pharmacopeia says should be a thyroid product. Dr. Khyati Patel 27:08 And despite that, you know, these products, because they're coming from natural sources, can have different amount of t3 and t4 ratio. So essentially, these products are desiccated, as in dry thyroid glands containing t3 and t4 these thyroid glands are coming from animal sources, more commonly pigs, but in history, has come from other sources, such as bovine and sheep. Again, there is higher risk for allergic reaction because it's an animal based product, plus, there is some religious observation where, you know, patients might not be able to use these medication because it's coming from animal sources. One thing I remember very vividly Dr. Kane from my days in working in community pharmacy, is the smell. We used to actually take turns on counting armor thyroid, because it smelled pretty Dr. Sean Kane 28:02 awful, and that's not surprising, right? It's coming from an animal product, right? Yes, that's right. So essentially, we should not be using thyroid USP, including Armour Thyroid and other products. We should not be using liothyronine, and the other question that we got from the listeners was, does it matter if you pick brand name Synthroid, or is it okay if you do a generic product, just generic levothyroxine? Dr. Khyati Patel 28:29 This is another question that comes across all the time, and I think it has to do with something that the manufacturer of Synthroid, which we won't name, by the way, had created some controversy. Is that, right? Dr. Sean Kane 28:43 Oh, this is the most amazing story I've come across in a long time. Dr. Patel. So essentially, like in the 1990s the manufacturer of Synthroid took a lot of steps to basically encourage drug reps to talk to prescribers about their branded product is better, and they didn't really have data showing that it was better, but they just made suggestions that they had a superior product compared to other branded products like Levoxyl or even the generic, just normal, generic levothyroxine that was on the market. And one of the arguments here was the FDA does have specific criteria for what's called bioequivalence, so when a generic product wants to come to the market, it can, and it just has to show that the C max and the AUC of the product is similar, and they have criteria for what similar means, but it just has to show that the drug levels are similar over a 48 hour period. And in this case, that would mean t4 levels. Remember, levothyroxine or L thyroxine, is t4 so bioequivalence just had to prove that t4 levels were similar over a 48 hour period. And that's problematic, because it would be nice to show that the physiologic effects in terms of your TSH levels, your symptoms over a longer period of time. Because, remember, it's a. Half Life of seven days. It would be nice to show a longer period of time that these are similar in effect, and also that your TSH levels over a longer period of time are similar. But that wasn't what the FDA mandated for bioequivalence. So for a long time, the manufacturer said, even though there are bioequivalent products out there, we think our product is the best, and there's no data suggesting otherwise, Dr. Khyati Patel 30:24 and that's really, really interesting. Until in 1997 a JAMA article looked at four different products and looked at the bioequivalence of these four products. And this was more of a four way crossover study that looked at two brand formulations and two generic formulations of levothyroxine and found that, you know, they were bioequivalent, and the thyroid hormone levels over six weeks period, as you just suggested, Dr. Kane, that's the more appropriate way of doing bioequivalence testing was no different. They were the same. And this was a big deal, because essentially that means that any four of the levothyroxine formulation could effectively help patients, you know, hypothyroidism, and that the brand name, Synthroid wasn't necessarily better than the other other brand or generic equivalents out there. Dr. Sean Kane 31:17 Now Dr. Patel at face value, you might say, okay, these four products are the same or similar to each other. Not that controversial, but it gets crazy controversial, and the reason is that the company that sponsored that trial comparing the four different products was the maker of Synthroid. So if you imagine, they just spent a bunch of money hiring a researcher to compare these four products, and it basically threatened their market share. So they were hoping to show or prove that Synthroid was better. But in fact, they spent money to show that four different products were equal or similar to each other in terms of treating hypothyroidism. We can't cover everything of kind of what happened after that, and the podcast, if you want on our website, HelixTalk.com Again, Episode 143, we have a link to an article called thyroid storm, which was an editorial or commentary posted at the same time as this JAMA article that goes through the entire thing, but kind of the cliff notes version of it was the manufacturer sponsored the study when they found out that the data didn't support their product being better, they basically prevented, for several years, the author being able to publish the data. There were some contractual issues of legal issues in terms of how they were able to prevent the author from publishing. During that time, where they prevented publication, they played all sorts of other shenanigans in terms of publishing that data in a different format to make it look like, almost discrediting the data if it was ever to come out. And eventually, over many, many years, the manufacturer was pressured, kind of, by the FDA, to allow Jama to publish the manuscript, and Jama did in the original form of what the author had originally wanted to publish. The entire ordeal ended up making its way to a class action lawsuit, and the manufacturer actually paid out more than $80 million to patients who purchase brand name Synthroid because the manufacturer knowingly suppressed data to protect their market share and protect their profit. And if that story isn't interesting enough. The icing on the cake here is in the issue in JAMA, where they published both the article and the editorial outlining this whole thing. Jama ran an ad like apparently, a full page ad, advertising Levoxyl. And Levoxyl was the other branded product that was tested in the four way study that was cheaper. So not only was there this gigantic issue in terms of, you know, suppressing the publication of the article, kind of in a tone deaf fashion, Jama allowed for a levoxel ad to be part of that issue of Jama at the same time. Dr. Khyati Patel 33:56 Now, Dr. Kane, I felt like just relaxing, having a box of, you know, popcorn on my lap, and just watching this pharma drama on Netflix like that was the most interesting story of bad practices from the pharma and how there was some punishment thereafter. But that boils down that your branded Synthroid is no better than some of the other brands or generics that are out there. Dr. Sean Kane 34:22 And with that in mind, it still would make sense to kind of stick to the same product. So when you initiate levothyroxine, sure, pick the cheapest one, they're all fine to do. But once you start on a given formulation, given the consistency talk that we had earlier in terms of taking it the same way every day. Consistency of the manufacturer is probably also a good idea. So even though we have bioequivalence data, it probably makes sense to stick to the same manufacturer with whatever you've been on for months or years. If you're in the hospital for a couple days, not a big deal. But on the outpatient side, in terms of your refills. You would like to stick to the same manufacturer. Dr. Khyati Patel 35:01 And then there is something else to pay attention to, and it's the, you know, FDA Orange Book that would allow pharmacists to interchange any AB‑rated or AB‑compatible levothyroxine products. If you just take the 25 microgram tablet of levothyroxine for an example, there is about nine A B compatible formulation. Now with the A B rating, there's like four categories, so A, B, 123, and four. And you can only kind of change it or interchange it. And when we say interchange it, this is interchanging without calling the provider to be able to change it within the same categories. And there's, you know, there's nine formulation that have different compat, you know, combination of a b compatibilities. But it kind of gets confusing. You know, you have four A B categories, and they have nine formulation. I think the bottom line over here is probably to just kind of even ignore that, because I've seen some pharmacists get in the weeds of this A B rating and interchangeability of levothyroxine products, and then just kind of take that initial approach, initial prescribing approach, as you mentioned, kind of pay attention to it for the first fill, and then kind of stick to the same product for all the refills thereafter. Dr. Sean Kane 36:17 And Dr. Patel, in my opinion, the only time I would really reference the orange book for this would be if a patient is receiving a levothyroxine product from a given manufacturer, and if it's on shortage or it's been discontinued, I might use the orange book to recommend the closest alternative product, and then obviously we'll do more frequent TSH testing to make sure that we're titrating that in, but that's really the only time that I would really first see myself using that specifically for levothyroxine. So certainly, a lot of controversy here, Dr. Patel, and a lot of kind of nuances to treating a fairly straightforward medical condition of hypothyroidism. You know, some key take home points for me, I don't treat a lot of hypothyroidism in the ICU, but I see plenty of patients on it. I didn't realize, to be honest with you, that the most common cause of hypothyroidism was autoimmune thyroiditis, and we do call that Hashimotos disease, or Hashimotos thyroiditis. But I like the term autoimmune thyroiditis because it really refers to the pathophysiology of the body attacking the thyroid glands themselves. Also, just of note, we're looking at TSH levels, and those are going to be high in hypothyroidism, and those t3 and t4 levels can be normal ish, but eventually they'll go down to a low status of hypothyroidism is not corrected over a period of time, Dr. Khyati Patel 37:38 and in order to correct the levels of thyroid. Levothyroxine is the drug of choice. This is the synthetic t4 and the dosing approach should be, you know, start low and go slow to avoid any kind of cardiovascular effects. And we're going to titrate the dose based on that goal TSH level. Dr. Sean Kane 37:59 Then there are other thyroid products that are on the market, but these are all not approved by the FDA and not recommended by the guidelines. So thyroid USP, Armour Thyroid, liothyronine and all of that stuff, we should not be using that in hypothyroidism, but you will still see patients taking these in clinical practice. There is no data showing that this is a more effective approach than just using levothyroxine, which is the recommended therapy, Dr. Khyati Patel 38:23 and last but not the least, the generic versions of levothyroxine are just as effective and safe as the brand name Synthroid, as we learned from that JAMA article. And although there are several different versions of generic levothyroxine formulations are out there that are AB compatible, and can be interchanged by the pharmacist whenever possible. Patients should be maintained on the same formulation unless there is a, you know, drug shortage situation. Dr. Sean Kane 38:52 So again, this topic came from multiple listener requests. So if you have a topic you'd like to learn more about in podcast form, go to helix, talk.com and find our contact information and let us know what you think. We still love the five star reviews in iTunes. We're still on Twitter at HelixTalk, where we release clinical pearls from previous episodes. So with that, I'm Dr. Kane and I'm Dr Dr. Khyati Patel 39:12 Patel, and as always, study hard. 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