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The history of Thyroxine and Thyroid

Written by Nora.Heime.net

 

About the history of Thyroxine and Thyroid, Erfa Thyroid (formerly: Pfizer Canada) dessicated thyroid, Thyreoidum, Thyreodinum etc.


The standard is Thyroid, dried pig gland. All research on Thyroxin was actually done on Thyroid, because in the old days there was no T4, but diligent research was done on Thyroid, which was also called Thyroxine because people didn't know any better.


This is called Thyroid USP (United States Pharmacopeia) where the content of thyroxine and liothyronine is now strictly regulated. In the old days, T4 and T3 were not known, so it was regulated according to iodine content. A 10% deviation in strength is permitted. (90%-110%) This applies to all Thyroxine preparations, and all other medicines. For generics, 80-125% applies.


There is no generic for Thyroid, therefore the 10 percent applies. (Updated: it's been changed now, to 95-105%)


Thyroid was standardized early on and produced as brands. An example available on the internet is Merck thyroidinum.


In the beginning, the requirement was that it should be analyzed for iodine content, later when it was possible, of course, the amount of Levothyroxine and Liothyronine was measured.


Here is an interesting Cuban website where they list all the old names and manufacturers of Thyroid: http://www.sld.cu/servicios/medicamentos/medicamentos_list.php?id=399


List of old and new medicines:

Name

Country

Manufacturer

Thyranon

Sweden

Thyreoïdum

Denmark, Netherlands

Biofac Kastrup, imported to Netherlands by BUFA/Fargo

Thyroidin

Germany

Armour Thyroid

USA

Several over times: USV, Pfizer, Forest, now acquired by Activas Pharmaceuticals

NP Thyroid

USA

Acella Pharmaceuticals

Nature-Throid, Westhroid Pure

USA

Western Reseach Laboratories http://www.rlclabs.com these got a central approval in the 2000's of Nature-throid in the UK and went throught all these approval procedures

http://getrealthyroid.com

ERFA Thyroid

Canada

Parke-Davis, acquired by Erfa (flagship: Belgia)

Thyroid Powder, USP

Canada

Medisca (only available through compounding pharmacies)

Cinetic

Italy

Teofarma SRL

Thyreoid

Germany

Tiroides

Spain

?

Japan

Thyroidine

France

Thyroid-S

Thailand

Sriprasit

Thiroyd

Thailand

Greater Pharma

Thyroid API

Spain

Bioiberica

Adthza

USA

Azurity Pharmaceuticals

Thyrid Extract

Australia

Australian Custom Pharmaceuticals

Compound Thyroid

Denmark

Glostrup Apotek

Thyreogland

Germany

Klösterl-Apotheke, Munchen

Schilddruesen-Extrakt

Germany

Receptura

Whole Thyroid

New Zealand

Pharmaceutical Compounding New Zealand

Diotroxin

South Africa

Aspen Pharmacare Ltd

Generic Thyroid

USA

Major Pharmaceuticals

Qualitest

USA

Time-Caps Labs

Thyrolar

USA

Forest Labs

Thyrogold

USA

Natural Thyroid Solution (non prescr. but recommended by Dr. Lowe)


Some of these are no longer available on the market.


Thyroid USP has content of T4 and T3 that is strictly regulated, that's what USP means, United States Pharmacopeia. The specification zone is that 1 grain contains 38 mcg T4 plus 9 mcg T3, plus or minus 10%. This is completely reliable. 1 grain = 60 mg.

In Europe, Thyreoïdum and other similar products do not have this requirement, but all batches of Thyreoidum from Denmark are analyzed and the amount of T4 and T3 is specifically stated. So there is not even 10% wiggle room. There is a higher proportion of T3 in Thyroidum. This is probably what Wiersinga is getting at.


But his statement is being used about the unreliability of Armor Thyroid by Welsh in Australia and William Harper in Canada here.

Wiersinga is based in Holland, Welsh in Australia, and Harper in Canada.

In Australia there is no Armour, they use powder from the USA and the pharmacies make capsules.

In Holland they use Thyreoïdum, and in Canada there is no Armour, they make their own, but from imported raw material.


(It was Pfizer that owned Armor Thyroid at the time, and then Pfizer split up into Canada and the US and so Canada got the original old Armor formulation before all the reformulations. Armor got no rights for marketing abroad, it was Thyroid in Canada who received.

Then Erfa bought up a bunch of rights, and bet on Thyroid based on patient wishes. It is approved by Health Canada, which is important for us in Europe since it is often a prerequisite that the medicine must be approved in the country of origin for it to be approved in Europe at all)


Here in Europe we had Merck Thyroidin according to their own website, but I don't have an overview of all the brands that existed, I have found a brand from Switzerland as well. Thyroidum is still made in Denmark, it is what the Dutch patients use today.

Armor Thyroid from Forest does not have rights outside the US, not even Canada. It came about because Pfizer, who owned the rights, was split up in the US and Canada and they split up the rights to Armor and Thyroid. Thyroid from Canada is the original Armor due to the old rights.

Western Research Laboratories has been approved (central approval, but everyone must apply for a registration exemption, which is called named-patient program in foreign languages) for their brand Nature-Throid here in Europe, they went through the approval procedure in England and it therefore applies throughout Europe. It is just as reliable. Everything comes from the same raw material.

What distinguishes the American USP (United States Pharmacopeia) Thyroid from the European one is that the ratio between T4 and T3 is constant and that the strength is the same all the time, which is an advantage when making pills from it. (Comment from a pharmacist at Stenlake Pharmacy in Australia).


The European Thyroidum has varying strengths and ratios of T4 to T4 for each batch, which lasts approximately one year. On direct request to the users, they say that it has no consequences (the forum in Holland). In addition, Thyroid is still available in Japan and Thailand.


Updated: According to their own forum, Erfa says that they obtained Thyroid raw material in Europe. It may well be from biofac in Denmark, and tens of millions of pig glands are exported from Denmark, according to a Dane on Sonja's Stoffskifteforum. They can therefore presumably make Thyroid with USP specifications as well.


In any case, the effect is absolutely excellent according to all patients who have tried it. The amount of active ingredient is also stated as less than Armour had, but the effect is the same as old Armor from when it was good. Other patients have also noted that for Levothyroxine, the effect of European tablets was stronger than that of American ones.


Now it was thought that thyroxine (=t4) was the active substance in Thyroid, and levothyroxine (=t4) came on the market. It was claimed to be exactly the same as Thyroid. Double blind tests were never conducted to prove that Levothyroxine worked as well on the patients as Thyroid for that reason (Note that at least 14 comparison studies have been done).


That is the reason why today we cannot show double blind tests that Armor Thyroid is as effective as Thyroxin, or that patients in such tests felt better or worse. It comes from the makers of Thyroxin who all along claimed it was the same as Thyroid.

Update: Dr. Lowe has found at least 14 direct comparisons of Thyroid vs Thyroxin in the literature. He says it is wrong, a repeated lie, that there are no comparative studies between the two. Thyroid was recognized as stable and effective.


Then came a clean-up of medicines in the United States. All that had been used for many years and proved effective were given the status of approved on historical grounds. Note that when applying for approval in Norway, an exception may be granted to submit documentation in clinical trials, namely historical use. Digitalis and Thyroid are just such remedies.


Synthroid, as thyroxine was called in the US, claimed historical status and referred to Thyroid, that it was the same as Thyroid. They managed to get away with it until the FDA cut through and decided that all Levothyroxine products were new drugs and that they had to go through new approval procedures and prove their shelf life and dose stability.


Synthroid was notorious for repeatedly changing the ingredients and active substances and that the strength could be much more or less than stated. Many patients were very dissatisfied because they became so unwell that they functioned poorly at work etc.


A bigger scandal was also the case where Knoll, who owned Synthroid, then prevented a research report that was to be printed, stating that Synthroid was no better than other brands. It was such a big scandal when it came out that they fired the researcher and prevented the publication of correctly conducted research.


And then there was a larger compensation case in the wake of this, where the patients got back a few dollars for the overcharge they had to pay, when in reality all Levothyroxine preparations were equal. The patients had paid a huge premium because Synthroid had claimed to be far superior to the others. Synthroid costs about 52 dollars for 90 tablets compared to Thyroxine in England about £2.50 and Levaxin here about NOK 70 for 100 tablets.


Synthroid is known to be inconsistent, not Thyroid. If you search the database for recalls in the USA, it is Levothyroxine that has been recalled, not Thyroid.

The different brands of Levothyroxine, despite the fact that they should contain the same, should not be used interchangeably because they will give different blood values. If you switch, you must take new blood tests after 6 weeks.


The various manufacturers of Levothyroxine fought for many years against having to apply for approval. They constantly claimed that their product was identical to Thyroid, which was recognized as stable and with good effect.


NDA = New Drug Application. Approval on historic grounds is called "Grandfathered In".


  • 1891: Murray treats patients with Thyroid extract injections. Soon after, oral agents are used and tablets are made.

  • 1915: Kendall makes a crystalline powder from Thyroid. It is assumed that Thyroxin is the active substance in Thyroid.

  • 1950-tallet: T3, liothyronine was isolated and made chemically. It was not realized that there was more to Thyroid USP than T4 until then.

  • 1950: Thyroxin-Natrium registered in Norway.

  • 1952: T3 was discovered, important information because Thyroxin-Natrium was introduced as identical to Thyroid extract before anyone knew anything about the active ingredient T3, and that it was missing in Thyroxin-Natrium. But from before it was known that T2 was 80% of the amount of Thyroxine types in Thyroid extract, but it did not work in trials so this was written off as not important.

  • 1958: Synthroid enters the US market.

  • 1962: Medicines that were recognized as effective before that did not need to apply for new approval later. This is a principle known as "Grandfathered In".

  • 1997: The FDA decides that all Thyroxin preparations are new drugs and must submit an application for approval of a new drug. Not long after, Thyrolar, a T4/t3 combination preparation (Liotrix) is approved as the first preparation.

  • 2000: Unithyroid is approved as the first levothyroxine preparation in the USA. Note that Thyrolar (a T4/T3 combo owned by Forest) sought and received approval long before any Levothyroxine preparations. Armor Thyroid and all Thyroid USP were always approved.

  • 2001: Abbott which now owns Synthroid submits an NDA application.

  • July 2002: Synthroid approved.


References:


Have followed closely the questions about metabolic drugs.


Note that the Federal Register is the most official thing that can be done in the US, it is where new laws are registered. A rather important document on the instability of Levothyroxine. Nobody can come here and come here and say that it is a lie that Levothyroxine is unstable. It is Levothyroxine and not Thyroid USP that is unreliable and unstable.



About the history, Thyroid extract etc.

A brief overview of medications in the United States including Thyrolar.


More on the Synthroid and Boots/Knoll scandal and trial.

"In April of 1997, the Journal of the American Medical Association (JAMA) published a study, commissioned by Knoll, that concluded that Synthroid -- a synthetic thyroid hormone -- is no better than two generic alternatives or the brand-name drug Levoxyl . Knoll disagreed with the study, and considered suing to stop its publication. Betty Dong, the researcher at the University of California at San Francisco who conducted the study, told the journal that Knoll had suppressed her findings for more than six years."


Unithyroid approved as the first L-Thyroxine preparation in 2000.


2001 "Levothyroxine sodium tablets are also currently not listed in the Orange Book. In the words of the FDA, "Levothyroxine sodium was first introduced into the market before 1962 without an approved NDA, apparently in the belief that it was not a new drug. "

See also below for an explanation of bioequivalence.


2001 Synthroid still not approved: FDA is penalizing companies that filed late for approval of Levothyroxine Sodium products by forcing reductions in distribution over the next 2 years.


Synthroid approved 2002


Among other things:


IV. Formulation Change

Because orally administered levothyroxine sodium products are marketed without approved applications, manufacturers have not sought FDA approval each time they reformulate their products. In 1982, for example, one manufacturer reformulated its levothyroxine sodium product by removing two inactive ingredients and changing the physical form of coloring agents (Ref. 6).


The reformulated product increased significantly in potency. One study found that the reformulated product contained 100 percent of stated content compared to 78 percent before the reformulation (Ref. 7).

Another study estimated that the levothyroxine content of the old formulation was approximately 70 percent of the stated value (Ref. 8).


This increase in product potency resulted in serious clinical problems. On January 17, 1984, a physician reported to FDA: ''I have noticed a recent significant problem with the use of [this levothyroxine sodium product]. People who have been on it for years are suddenly becoming toxic on the same dose. Also, people starting on the medication become toxic on 0.1 mg [milligram] which is unheard of.''


On May 25, 1984, another physician reported that 15 to 20 percent of his patients using the product had become hyperthyroid although they had been completely controlled up until that time. Another doctor reported in May 1984 that three patients, previously well-controlled on the product, had developed thyroid toxicity. One of these patients experienced atrial fibrillation.


There is evidence that manufacturers continue to make formulation changes to orally administered levothyroxine sodium products. As discussed in section V of this document, one manufacturer is reformulating in order to make its product stable at room temperature.


In a 1990 study (Ref. 5), one manufacturer's levothyroxine sodium tablets selected from different batches showed variations in chromatographs suggesting that different excipients had been used.

V. Stability Problems

FDA, in conjunction with the United States Pharmacopeial Convention, took the initiative in organizing a workshop in 1982 to set the standard for the use of a stability-indicating high-performance liquid chromatographic (HPLC) assay for the quality control of thyroid hormone drug products (Ref. 3).


The former assay method was based on iodine content and was not stability-indicating. Using the HPLC method, there have been numerous reports indicating problems with the stability of orally administered levothyroxine sodium products in the past several years. Almost every manufacturer of orally administered levothyroxine sodium products, including the market leader, has reported recalls that were the result of potency or stability problems.

Since 1991, there have been no less than 10 firm-initiated recalls of levothyroxine sodium tablets involving 150 lots and more than 100 million tablets. In all but one case, the recalls were initiated because tablets were found to be subpotent or potency could not be assured through the expiration date.


The remaining recall was initiated for a product that was found to be superpotent. During this period, FDA also issued two warning letters to manufacturers citing stability problems with orally administered levothyroxine sodium products.

At one firm, potency problems with levothyroxine sodium tablets resulted in destruction of products and repeated recalls. From 1990 to 1992, the firm destroyed 46 lots of levothyroxine sodium tablets that failed to meet potency or content uniformity specifications during finished product testing. In August 1989, this firm recalled 21 lots due to subpotency. In 1991, the firm recalled 26 lots in February and 15 lots in June because of subpotency.

An FDA inspection report concerning another manufacturer of levothyroxine sodium showed that 14 percent of all lots manufactured from 1991 through 1993 were rejected and destroyed for failure to meet the assay specifications of 103 to 110 percent established by the firm.

In March 1993, FDA sent a warning letter to a firm stating that its levothyroxine tablets were adulterated because the expiration date was not supported by adequate stability studies. Five lots of the firm's levothyroxine sodium tablets, labeled for storage within controlled room temperature range, had recently failed stability testing when stored at the higher end of the range.


The warning letter also objected to the labeled storage conditions specifying a nonstandard storage range of 15 to 22 degrees C. FDA objected to this labeling because it did not conform to any storage conditions defined in United States Pharmacopeia (USP) XXII. In response, the firm changed the labeling instruction to store the product at 8 to 15 degrees C. The firm informed FDA that it would reformulate its levothyroxine sodium tablets to be stable at room temperature.

The five failing lots named in FDA's warning letter were recalled in April 1994. Previously, in December 1993, a lot of levothyroxine sodium tablets was recalled by the same firm because potency was not assured through the expiration date. In November 1994, the renamed successor firm recalled one lot of levothyroxine sodium tablets due to superpotency.

Another firm recalled six lots of levothyroxine sodium tablets in 1993 because they fell below potency, or would have fallen below potency, before the expiration date. The USP specifies a potency range for levothyroxine sodium from 90 percent to 110 percent. Analysis of the recalled tablets showed potencies ranging from 74.7 percent to 90.4 percent. Six months later, this firm recalled another lot of levothyroxine sodium tablets when it fell below labeled potency during routine stability testing. Content analysis found the potency of the failed lot to be 85.5 percent to 86.2 percent.


Subsequently, an FDA inspection at the firm led to the issuance of a warning letter regarding the firm's levothyroxine sodium products. One of the deviations from good manufacturing practice regulations cited in that letter was failure to determine by appropriate stability testing the expiration date of some strengths of levothyroxine sodium. Another deviation concerned failure to establish adequate procedures for monitoring and control of temperature and humidity during the manufacturing process.

In April 1994, one manufacturer recalled seven lots of levothyroxine sodium products because potency could not be assured through the expiration date. In February 1995, the same manufacturer initiated a major recall of levothyroxine sodium affecting 60 lots and 50,436,000 tablets. The recall was initiated when the product was found to be below potency at 18-month stability testing.

In December 1995, a manufacturer recalled 22 lots of levothyroxine sodium products because potency could not be assured through the expiration date.

In addition to raising concerns about the consistent potency of orally administered levothyroxine sodium products, this pattern of stability problems suggests that the customary 2-year shelf life may not be appropriate for these products because they are prone to experience accelerated degradation in response to a variety of factors. Levothyroxine sodium is unstable in the presence of light, temperature, air, and humidity (Ref. 4).


One study found that some excipients used with levothyroxine sodium act as catalysts to hasten its degradation (Ref. 5).


In addition, the kinetics of levothyroxine sodium degradation is complex. Stability studies show that levothyroxine sodium exhibits a biphasic first order degradation profile, with an initial fast degradation rate followed by a slower rate (Ref. 4).


The initial fast rate varies depending on temperature. To compensate for the initial accelerated degradation, some manufacturers use an overage of active ingredient in their formulation, which can lead to occasional instances of superpotency."

I got comments on the above on the thyroid.about.com forum when I posted this text that Mary Shomon has on her website. They asked if I was aware of what the Federal Registry was. It is where all laws and everything that is important and official is recorded in the United States, the most official that exists in America. "The document you quote is the Federal Register notice that declared all T4s marketed in the US to be unapproved drugs and in need of NDAs. It's a very significant document and should be required reading for all thyroid patients, in my honest opinion. (Since you're not in the US, you may not know that the Federal Register is the publication organ of the US government. If something's an official decision by any federal agency, it's published in the Federal Register.)"

During the same period, no problems with Thyroid were reported.


Levothyroxine a new drug? Since when? How could that be? (paylink)


"The US Food and Drug Administration (FDA) states that all approved levothyroxine sodium preparations should be considered therapeutically inequivalent unless equivalence has been established and noted in FDA's Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book)."


How is levothyroxine tested? Not on sick people. One gives healthy people high doses and measures how high the blood tests go: http://www.medscape.com/viewarticle/472917

"For pharmacokinetic studies designed to measure the bioavailability of LT4 formulations, the Food and Drug Administration (FDA)[8] recommends that a single dose be administered to healthy subjects at a strength several times the normal therapeutic dose.


The objective is to raise serum concentrations of the hormone sufficiently above endogenous baseline levels to achieve meaningful pharmacokinetic measurements."...


"The most recent clinical practice guidelines from the American Association of Clinical Endocrinologists (AACE) and the American Thyroid Association recognize that the various brands of LT4 have not been proven bioequivalent and recommend that the patient's brand not be changed during therapy.."


In this study, they used data from 31 healthy people who received a larger dose of thyroxine twice 44 days apart.


More about innovative drugs og generic drugs "In 1980, the FDA first published a list of approved drugs, consisting of innovator drugs approved through the NDA process and the generic products considered by the FDA to be therapeutically equivalent to these innovator products."

http://www.fda.gov/foi/warning_letters/g4190d.html (no longer exists, has been replaced by a new warning) an example of an FDA warning that one must apply for approval


PDF about the application process from the FDA


Letter to FDA from Finland about Armor Thyroid


About a patient who prefers Armor Thyroid over synthroid etc.


Here from page 15 in this link at findarticles.com: Objections to the Use of Armour Thyroid

The main objections voiced in textbooks and editorials 1,73 regarding the use of desiccated

thyroid are: (1) its potency varies from batch to batch, and (2) the use of T3-containing preparations causes the serum T3 concentration to rise to supraphysiological levels.


Regarding between-batch variability, there may have been some problems with quality control a half-century or more ago, and in a 1980 study a number of generic versions of desiccated thyroid were still found to be unreliable in their potency. The amounts of T4 and T3 in Armour thyroid, on the other hand, were found to be constant.74


Moreover, two-year old tablets of Armour thyroid contained similar amounts of T4 and T3 as did fresh tablets. Three studies are typically cited to support the contention that T3 containing preparations should not be used. Smith et al reported a levothyroxine-plus-T3 product caused adverse side effects in 46 percent of patients; whereas, side effects occurred in only 10 percent of those receiving levothyroxine alone.75


In that study, however, the combination product and the levothyroxine product differed substantially in potency. For the combination treatment, each 100 mcg of levothyroxine was replaced by 80 mcg of levothyroxine plus 20 mcg of T3. Considering 20mcg of T3 is equivalent to 80 mcg of levothyroxine, the total hormone dose in the combination product was 60-percent greater than that in the levothyroxine preparation. Therefore, the high incidence of adverse side effects may not have been due to the T3, but to the higher total dose of thyroid hormones.


In the second study, by Surks et al, the administration of T3-containing preparations to

hypothyroid patients caused the plasma T3 concentration to become markedly elevated for several hours after ingestion of the medication.76


In most cases, however, the amount of T3 administered (50-75 mcg) was considerably greater than that contained in a typical dose of desiccated thyroid (9 mcg T3 per 60 mg),77 and/or the total dose of thyroid hormones given was excessive (180 mcg of levothyroxine plus 45 mcg of T3).


By contrast, in a patient given 60 mg of desiccated thyroid, the plasma T3 concentration increased from a hypothyroid level to a euthyroid level. Of two hypothyroid patients treated with 120 mg per day of desiccated thyroid, one showed a relatively constant plasma concentration of T3.


In the other patient, the T3 level increased by a maximum of 80 percent, to the bottom of the range seen in hyperthyroid patients, and returned to the baseline value within 24 hours. In that patient, the pre-dose plasma T3 concentration was near the top of the normal range, suggesting that this patient may have been receiving too high a dose of desiccated thyroid.


Finally, Jackson and Cobb reported that the serum T3 concentration (measured 2-5 hours

after a dose) was above normal in most patients receiving desiccated thyroid.2 They concluded there is little use for desiccated thyroid in clinical medicine. Most of the patients (87.5%) in that study, however, were taking a relatively large dose of desiccated thyroid (120-180 mg daily).


Moreover, 57.5 percent of the patients were not being treated for hypothyroidism, but rather to suppress the thyroid gland. Nearly half of the patients continued to have an elevated serum T3 concentration after they were switched to levothyroxine, even though the equivalent dose was reduced in 62.5 percent of patients.


Thus, the elevated serum T3 concentrations found in this study can be explained in large part by the high doses used and by the selection of patients, the majority of whom

were not hypothyroid. What this study does suggest is that desiccated thyroid should not be used for thyroid-suppression therapy.


Although the oral administration of T3 causes a transient increase in serum T3 concentrations, that fact does not appear to be of significance for hypothyroid patients receiving usual replacement doses of Armour thyroid. In this author's experience, reports of post-dose symptoms of hyperthyroidism are extremely rare, even among patients taking larger doses of desiccated thyroid.


An occasional patient reports feeling better when he or she takes Armour thyroid in two divided doses daily. The nature of that improvement, however, is usually an increase in effectiveness, rather than a reduction in side effects.


For patients taking relatively large amounts of desiccated thyroid (such as 120 mg daily or more), splitting the daily dose would obviate any potential concern about transient elevations of T3 levels. In practice, however, splitting the daily dose is rarely necessary.


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