Volledig artikel: ETA en TFI position statement interchangeability of Levothyroxine Products in EU Countries

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ineke
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Lid geworden op: 08 nov 2014, 17:53

Volledig artikel: ETA en TFI position statement interchangeability of Levothyroxine Products in EU Countries

Bericht door ineke » 02 nov 2018, 17:14

Joint Position Statement on the Interchangeability of Levothyroxine Products in EU Countries
Fliers E · Demeneix B · Bhaseen A · Brix T.H. | Onderwerp aangepast - volledig artikel te lezen - zie bericht 23 november
European Thyroid Association (ETA) and Thyroid Federation International (TFI)

Several European countries have seen major health issues after a switch from one levothyroxine brand to another, as well as following the introduction of several levothyroxine formulation changes.

While the relationship between these health issues and brand or formulation changes merits further investigation, the current position statement on behalf of both health-care providers and patients summarizes recent events in several European countries and provides a number of recommendations to limit the burden for patients, so as to prevent increased health-care consumption and health-care expenses in this context.

References
1. American Thyroid Association; Endocrine Society; American Association of Clinical Endocrinologists: Joint Statement on the U.S. Food and Drug Administration’s decision regarding bioequivalence of levothyroxine sodium. Thyroid 2004; 14: 486.

2. Gottwald-Hostalek U, Uhl W, Wolna P, Kahaly GJ: New levothyroxine formulation meeting 95–105% specification over the whole shelf-life: results from two pharmacokinetic trials. Curr Med Res Opin 2017; 33: 169–174.

3.Cerqueira C, Knudsen N, Ovesen L, Laurberg P, Perrild H, Rasmussen LB, Jørgensen T: Doubling in the use of thyroid hormone replacement therapy in Denmark: association to iodization of salt? Eur J Epidemiol 2011; 26: 629–635.

1e pagina view:
https://www.karger.com/Article/Abstract/493123#


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Laatst gewijzigd door ineke op 23 nov 2018, 13:04, 1 keer totaal gewijzigd.

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laura
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Lid geworden op: 11 sep 2013, 22:42
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Re: ETA en TFI position statement interchangeability of Levothyroxine Products in EU Countries

Bericht door laura » 03 nov 2018, 16:30

Het position statement is mede bedoeld voor patiënten.
Het is alleen niet toegankelijk voor die patiënten.
laura

Kijk voor meer informatie ook eens op Schildkliertje.

Raadpleeg altijd een arts als je twijfelt over je gezondheid.
Het Schildklierforum kan niet worden beschouwd als vervanging van een consult of een behandeling.

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laura
Berichten: 3127
Lid geworden op: 11 sep 2013, 22:42
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Re: ETA en TFI position statement interchangeability of Levothyroxine Products in EU Countries

Bericht door laura » 04 nov 2018, 15:39

ineke schreef:
02 nov 2018, 17:14
References
1. American Thyroid Association; Endocrine Society; American Association of Clinical Endocrinologists: Joint Statement on the U.S. Food and Drug Administration’s decision regarding bioequivalence of levothyroxine sodium. Thyroid 2004; 14: 486.

2. Gottwald-Hostalek U, Uhl W, Wolna P, Kahaly GJ: New levothyroxine formulation meeting 95–105% specification over the whole shelf-life: results from two pharmacokinetic trials. Curr Med Res Opin 2017; 33: 169–174.

3.Cerqueira C, Knudsen N, Ovesen L, Laurberg P, Perrild H, Rasmussen LB, Jørgensen T: Doubling in the use of thyroid hormone replacement therapy in Denmark: association to iodization of salt? Eur J Epidemiol 2011; 26: 629–635.
Hoi Ineke,

Van de referenties heb ik de links even opgezocht.
Het artikel van Gottwald-Hostalek heb je hier eerder genoemd: viewtopic.php?f=17&t=1304&p=11063&hilit ... lek#p11063
laura

Kijk voor meer informatie ook eens op Schildkliertje.

Raadpleeg altijd een arts als je twijfelt over je gezondheid.
Het Schildklierforum kan niet worden beschouwd als vervanging van een consult of een behandeling.

ineke
Berichten: 418
Lid geworden op: 08 nov 2014, 17:53

Re: ETA en TFI position statement interchangeability of Levothyroxine Products in EU Countries

Bericht door ineke » 05 nov 2018, 21:50

laura schreef:
04 nov 2018, 15:39
Hoi Ineke,

Van de referenties heb ik de links even opgezocht.
Het artikel van Gottwald-Hostalek heb je hier eerder genoemd: viewtopic.php?f=17&t=1304&p=11063&hilit ... lek#p11063

Het position statement is mede bedoeld voor patiënten.
Het is alleen niet toegankelijk voor die patiënten.
Hoi Laura,
Ja, die naam van Gottwald had ik al herkend :D en het verband met genoemd artikel.

Maar ik heb ook de naam van de hoofdauteur neergezet. ;)
Dat is Eric Fliers van het AMC Amsterdam.
Is hij medebepalend voor de sk-richtlijnen?

Ben benieuwd of het onderwerp over dat "gelazer" met al die veranderingen in de levothyroxine-producten ook wordt meegenomen in de - wanneer ?????? komt die nou ????? - nieuwe richtlijn schildklierfunctiestoornissen.

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laura
Berichten: 3127
Lid geworden op: 11 sep 2013, 22:42
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Re: ETA en TFI position statement interchangeability of Levothyroxine Products in EU Countries

Bericht door laura » 06 nov 2018, 15:03

Of Fliers in de richtlijnencommissie zit of zal zitten? Geen idee.
Hij is wel voorzitter van de MAR van SON.

En in die hoedanigheid vertelde hij dit: viewtopic.php?f=7&t=1292&hilit=fliers&start=60#p6702
laura

Kijk voor meer informatie ook eens op Schildkliertje.

Raadpleeg altijd een arts als je twijfelt over je gezondheid.
Het Schildklierforum kan niet worden beschouwd als vervanging van een consult of een behandeling.

ineke
Berichten: 418
Lid geworden op: 08 nov 2014, 17:53

Re: Volledig artikel: ETA en TFI position statement interchangeability of Levothyroxine Products in EU Countries

Bericht door ineke » 23 nov 2018, 13:41

Inmiddels een link gevonden met volledig artikel te lezen.

European Thyroid Association (ETA) and Thyroid Federation International (TFI) Joint
Position Statement on the Interchangeability of Levothyroxine Products in EU Countries

Eric Fliers

a Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, Location AMC,
Amsterdam, The Netherlands;
b Evolution des Régulations Endocriniennes, Département “Adaptation du Vivant”, UMR 7221 Muséum National d’Histoire Naturelle/CNRS, Paris, France;
c Montreal, QC, Canada
d Department of Endocrinology and Metabolism, Odense University Hospital, Odense C, Denmark

- A. Bhaseen: on behalf of the Thyroid Federation International.
- E. Fliers, B. Demeneix, T.H. Brix: on behalf of the Executive Committee of the European Thyroid Association.


Introduction
For the treatment of hypothyroidism, desiccated thyroid made from animal thyroid glands remained the mainstay of therapy until the 1970s.
Levothyroxine came to market in the 1960s in the form of sodium Lthyroxine, which was better absorbed than the free-acid thyroxine.
Levothyroxine is a drug with a narrow therapeutic index, which is the range of doses at which a medication is effective without unacceptable adverse events.
Drugs with a narrow therapeutic index have a slender window between their useful doses and those at which they produce adverse toxic effects.

As a consequence, whenever a pharmaceutical company decides to introduce a new levothyroxine formulation, great care should be taken to guarantee that bioequivalence and dosage form proportionality between the marketed formulation and the new formulation. In addition, generic levothyroxine may be substituted for - zie verder de link

Netherlands
In February 2016, it became clear that there was a shortage of Thyrax tablets, initially regarding the 25-μg tablets only but later the additional potencies (100 and150 μg) as well.

Of note, the Dutch Medicine Evaluation Board had transferred the trade license for Thyrax from MSD (Oss, The Netherlands) to Aspen Pharma Trading Limited in Ireland in 2014. In the same year, a technical transfer project was started to facilitate the reallocation of production to Aspen Bad Oldesloe (ABO) GmbH, a new production facility in Oldesloe, Germany.

In 2015, it became clear that Thyrax ABO tablets showed a more rapid degradation than Thyrax MSD tablets.
This led to various unsuccessful actions by Aspen to secure the availability of Thyrax on the market.

As a result, 350,000 patients using Thyrax in the Netherlands (i.e., 70% of the total number of levothyroxine users) were forced to switch to another formulation, principally levothyroxine Teva® or Euthyrox.
The number of reported side effects increased, and many family doctors and internists were confronted with patients mentioning health problems after switching to the new formulation (Netherlands Institute for Health Services Research, or NIVEL; www.nivel.nl/nl/thyrax).

The Dutch Endocrine Society together with the Dutch thyroid patient organization Schildklier Organisatie Nederland (SON) issued a general advice to check serum TSH concentration 6 weeks after any brand change, and the issue was covered by several national media.

The Dutch Ministry of Health, Welfare and Sport provided a small subsidy to run a telephone support service by SON.
Following an initiative by SON and the Dutch Endocrine Society, the Ministry provided a small grant to 2 Dutch health-care institutions (NIVEL and the Institute for Drug Outcomes Research PHARMO) to investigate the consequences of the Thyrax shortage in terms of laboratory results (2 separate databases) and online questionnaires.

The research projects were coordinated by a sounding board group comprising representatives of all stakeholders (Dutch Endocrine Society, SON, NIVEL and PHARMO, Medicine Evaluation Board, The Netherlands Pharmacovigilance Centre Lareb, and The Royal Dutch Pharmacists Association).
The NIVEL and PHARMO reports were published in April 2017 (https://www.schildklier.nl/onderzoek-na ... b-afgerond).

It appeared that 53% of the patients using > 100 μg daily (50,000 μg in total) showed biochemical signs of oversupplementation, clearly in excess of background observations before the switch had taken place (Fliers et al., in preparation).
In addition, 30% of the patients experienced more health problems than before the switch.
It should be mentioned that 25% experienced fewer health problems.

The initial advice to the patients was confirmed, but now with the additional remark that for patients using > 100 μg daily, an a priori dose reduction should be considered when switching from Thyrax to levothyroxine Teva or Euthyrox.
For the patient organization SON, these results strengthened their earlier position, i.e., to be strongly opposed to a forced brand switch for patients using levothyroxine preparations.
This was explicitly stated in a letter to the Dutch parliament dated February 21, 2017, on behalf of various patient platforms on the forced switch of pharmaceutical products for nonmedical reasons
(https://www.schildklier.nl/nieuws/43-ni ... zelfde-dag).

In their final report dated June 1, 2016, the Dutch Ministry of Health, Welfare and Sport (Inspectie Gezondheidszorg en Jeugd) concluded that Aspen Pharma Trading Limited had underestimated the transfer of the production of Thyrax to another location and should have taken more care to ensure the availability of Thyrax to fulfill patients’ needs (https://www.rijksoverheid.nl/documenten ... zoekthyrax).

The Dutch Medicine Evaluation Board approved the production process at the new location on March 30, 2017.

France
In France, as of March 2017, 2.6 million patients were being treated with Merck’s Levothyrox according to data from the French Agence Nationale de Sécurité des Médicaments (ANSM).
A switch was made to the new Merck formulation (with mannitol as opposed to lactose) as of late March/April 2017.
The justification given by the ANSM was the need for tighter specification (95–105%) over the whole shelf life, as for other thyroxine products (however, according to patient associations, the ANSM documents requesting the formulation change have yet to be released).

In January 2018, 17,310 reports of adverse effects had been received by - zie verder de link.


Denmark
In 2008, there were approximately 80.000 patients in Denmark treated with levothyroxine [3].
Since GSK had a monopoly position, all these subjects were treated with a GSK product, Eltroxin.
This product was well tolerated as reflected by the fact that the Danish Medicines Agency only received approximately 1 report per month on side effects.

By the end of 2008, GSK decided to switch to a new formulation to prolong the shelf life.
Although the new formulation meets potency specification guidelines and is bioequivalent, a growing number of patients began to complain of intolerance and several unspecific health problems after starting on this “new drug.”
The problem - zie verder de link

Fig. 1.
Number of reported side effects of Levothyroxine in Denmark in 2009 and 2010. Data obtained from the Danish Medicines Agency.
Status: by ultimo 2009, 919 patients had reported 5,015 possible side effects.

Conclusions
1. Several European countries have seen major health issues after a switch from one levothyroxine brand to
another, as well as following the introduction of several levothyroxine formulation changes.

2. Although it is not possible to ascertain what proportion of these health issues are biologically related to the
formulation change, the issues include increased prevalence of side effects as well as increased prevalence of
biochemical signs of inadequate dosing, and result in increased health-care consumption and health-care expenses

3. Testing bioequivalence does not guarantee continued euthyroidism after a formulation change of levothyroxine.

4. In at least 3 European countries, formulation changes have been introduced by manufacturers without adequate
communication with health-care professionals and patient organizations.

Recommendations
1. Patients should be maintained on the same formulation/brand name of levothyroxine.
If a change is necessary, a blood test after 6 weeks is recommended to determine, if any adjustment to dosage is required.

2. Manufacturers should carefully prepare the introduction of a formulation change together with representatives of relevant
(health-care professionals, national Endocrine Society, Medicine Evaluation Board, Pharmacovigilance Centre,
Pharmacists Association, national or – if not applicable – international patient organizations) to prevent insufficient
communication and coordination.

3. The preparation of a formulation change should include a monitoring plan to become active immediately after introduction.

4. Authorities should define the required levothyroxine potency specifications in an unambiguous way.

5. The method for determining the bioequivalence of levothyroxine preparations should be reevaluated.


Disclosure Statement
The authors have no conflicts of interest to disclose

Volledig artikel:
Statement ETA en TFI

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