Nieuwe artikelen over levothyroxine

Levothyroxine (thyrax, euthyrox, eltroxin), cytomel, schildklierremmers (strumazol, PTU), medicijnen schildklierkanker, en wisselwerkingen
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ineke
Berichten: 426
Lid geworden op: 08 nov 2014, 17:53

Nieuwe artikelen over levothyroxine

Bericht door ineke » 06 sep 2019, 14:01

Nieuwe artikelen over levothyroxine.


In het 2e artikel:
There are no equivalent European guidelines for the demonstration of LT4 formulation bioequivalence, but the FDA bioequivalence guidelines for LT4 are referred to in European countries [37, 38].
Instead, the relevant European guideline is the 2010 European Medicines Agency Guideline on the Investigation of Bioequivalence [10].





Voor beide artikelen:
© 2019 Springer Nature Switzerland AG. Part of Springer Nature.
Open Access
This supplement has been sponsored by Merck.

1e artikel
Review
First Online: 04 September 2019


Levothyroxine Dose Adjustment to Optimise Therapy Throughout a Patient’s Lifetime
1 Leonidas H. Duntas
2 Jacqueline Jonklaas

1. Unit of Endocrinology, Diabetes, and Metabolism, Thyroid Section Evgenidion Hospital Athens Greece
2. Division of Endocrinology Georgetown University Washington USA


Levothyroxine is the standard therapy for patients with hypothyroidism, a condition that affects up to 5% of people worldwide. While levothyroxine therapy has substantially improved the lives of millions of hypothyroid patients since its introduction in 1949, the complexity of maintaining biochemical and
clinical euthyroidism in patients undergoing treatment with levothyroxine cannot be underestimated.

Initial dosing of levothyroxine can vary greatly and may be based on the amount of residual thyroid function retained by the patient, the body weight or lean body mass of the patient, and thyroid-stimulating hormone levels.

As levothyroxine is usually administered over a patient’s lifetime, physiological changes throughout life will affect the dose of levothyroxine required to maintain euthyroidism.
Furthermore, dose adjustments may need to be made in patients with concomitant medical conditions, in patients taking certain medications, as well as in elderly patients.
Patients who have undergone any weight or hormonal changes may require dose adjustments, and the majority of pregnant women require increased doses of levothyroxine.

Optimal treatment of hypothyroidism requires a partnership between patient and physician. The physician is tasked with vigilant appraisal of the patient’s status based on a thorough clinical and laboratory assessment and appropriate adjustment of their levothyroxine therapy.
The patient in turn is tasked with medication adherence and reporting of symptomatology and any changes in their medical situation.
The goal is consistent maintenance of euthyroidism, without the patient experiencing the adverse events

Hypothyroidism, a reduction in thyroid hormone levels, is one of the most common diseases worldwide. The medication most used to treat hypothyroidism is levothyroxine, a compound that acts as a replacement for a person’s thyroid hormone. People with > zie verder artikel


Introduction
Thyroxine was isolated on Christmas Day 1914 by Kendall. Its chemical structure was determined in 1926 by Harington, and it was synthesised in 1927 by Harington and Barger [1, 2]. The acidity of the thyroxine molecule, which caused diminished absorption resulting in low bioavailability, was an unresolved problem for more than 20 years following > zie verder artikel


Methods
A search of the literature was conducted using the PubMed and CENTRAL (Cochrane) databases. Keywords relating to levothyroxine, hypothyroidism, treatment, levothyroxine dose adjustments, levothyroxine and concomitant conditions, levothyroxine and concomitant medications, and combined treatment with levothyroxine and liothyronine versus levothyroxine were searched. Only reviews and articles providing > zie verder artikel


When Levothyroxine Administration Is a Necessity
Thyroxine is secreted by the thyrocytes and is the main thyroid hormone in the circulation. Thyroxine is actively transported to the various organs where it is converted to triiodothyronine by the activity of the deiodinases [6]. Triiodothyronine, the active form of thyroid hormone, is secreted in small amounts by the thyroid but is > zie verder artikel



Initial Dosing and Dose Adjustment of Levothyroxine During Therapy
Initial Dosing
The levothyroxine dose initially required by a patient depends primarily on three factors: the amount of residual thyroid function retained by the patient, the body weight or lean body mass of the patient, and the target thyrotropin or thyroid-stimulating hormone (TSH) level to be achieved during therapy [8]. Additional factors such > zie verder artikel


Figuur 1
Example of body weight- and thyroid-stimulating hormone-based levothyroxine initial dose estimates. BMI body mass index, FT4 free thyroxine, LT4 levothyroxine, TSH thyroid-stimulating hormone
https://media.springernature.com/lw785/ ... 1_HTML.png


Dose Adjustment
Regardless of the method used to estimate the initial levothyroxine dose requirement, dose adjustment is frequently required. This may be due to multiple factors including limitations in the dose requirement predictions, inter-patient variation, levothyroxine absorption, or effects of concomitant medical conditions or medications [8].
Given the half-life of levothyroxine (approximately 1 week), reassessment of thyroid status by serum TSH levels, and free thyroxine levels if desired, is indicated after 6 weeks of therapy when the pharmacokinetic steady state is reached.
If the TSH is not at the desired goal, the levothyroxine dose can be adjusted up or down.
TSH values that are slightly out of range may be corrected by a single dose increment or decrement, such as increasing from 100 to 112 μg or decreasing from 175 to 150 μg. TSH values that are considerably out of range may require larger percentage changes.
Levothyroxine absorption is maximised, at about 75% of the administered dose, when it is ingested upon an empty stomach [8]. Therefore, if levothyroxine is taken at other times of the day for convenience, the dose requirement may be greater and potentially more variable [15].
Once the desired TSH value has been achieved, it could potentially be re-confirmed by laboratory testing in 3–6 months, and then checked on an annual basis thereafter.
A stable TSH while receiving levothyroxine therapy was inversely associated with the magnitude of the levothyroxine dose in one study, perhaps suggesting that residual thyroid function provided some buffer against TSH variations in those who required smaller levothyroxine doses [16].
Simple regimens that involve the same dose taken daily are ideal with respect to ease of adherence, although sometimes regimens that involve alternating doses or use of half tablets are needed to achieve the desired TSH value. A study comparing TSH values achieved with > zie verder artikel


Figuur 2
Example of how to address non-adherence to levothyroxine associated with elevated thyroid-stimulating hormone levels. 25 (OH) vitamin D 25-hydroxy vitamin D, FT4 free thyroxine, LT4 levothyroxine, TSH thyroid-stimulating hormone
https://media.springernature.com/lw785/ ... 2_HTML.png


Avoidance of Over- and Under-Dosing with Levothyroxine
Generally, hypothyroidism may be effectively treated via a constant daily dose of levothyroxine, and, for the majority of confirmed aetiologies, this needs to be lifelong. However, in this setting, there appear to be many cases of both levothyroxine over- and under-dosing and it may be that frequent adjustments of a dose are necessary. These adjustments need to be handled with caution and take into account the many contributing factors, as multiple levothyroxine > zie verder artikel


Factors Potentially Contributing to the Need for Levothyroxine Dose Adjustments Throughout a Patient’s Life Span
There are many factors encountered by patients across their life span that may be associated with an altered levothyroxine requirement. Newborns, children, and adolescents typically > zie verder artikel

Pregnancy
The dramatic increase in levothyroxine dose requirements associated with pregnancy, and the subsequent decrease in requirement post-partum are perhaps the best documented alterations in levothyroxine requirement [34]. The reason for the increased requirement is the need for an increased total body thyroxine pool associated with > zie verder artikel

Weight Changes and Hormonal Changes
As mentioned above, levothyroxine dose requirements are affected by body weight, ideal body weight, and lean body mass, with dose requirements increasing as these parameters increase [8, 13, 40].
However, if actual body weight is used to calculate the levothyroxine requirement in obese individuals, the dose may be overestimated, with ideal body weight being a better predictor [40].
Moreover, the studies regarding levothyroxine requirement in obese individuals often yield differing results of either > zie verder artikel

Ageing
Several studies have shown that the levothyroxine dose requirement is decreased in older individuals [8, 48, 49].
However, a recent study suggests that this decreased requirement may be mediated by the changes in weight that may accompany ageing [26]. Other important considerations regarding levothyroxine doses in older individuals include > zie verder artikel


Figuur 3
Example of application of age-adjusted thyroid-stimulating hormone reference ranges to patient treatment. LT4 levothyroxine, TSH thyroid-stimulating hormone

https://media.springernature.com/lw785/ ... 3_HTML.png


Levothyroxine Dose Adjustments Associated with Concomitant Medical Conditions and Medications
Levothyroxine is best absorbed when the stomach environment is acidic and is absorbed mainly in the jejunum and ileum [51].
It is primarily metabolised by de-iodination, but also is metabolised by conjugation, decarboxylation, and deamination. Based on this route into and out of the body, there are many medical conditions and medications that can impact these steps and alter the levothyroxine dose requirement. Two studies illustrate the combined impact > zie verder artikel


Medical Conditions
Generally speaking, although other chronic medical conditions such as cardiac disease, hepatic disease, osteoporosis, or diabetes do not directly impact levothyroxine dose requirements, some individuals with these conditions may be elderly or frail and thus extra caution may need to be exercised to avoid under- or over-dosing.
One specific medical condition in which levothyroxine doses that lower serum TSH may be intentionally employed is differentiated thyroid cancer [54]. If TSH suppression is the goal in patients with intermediate- or high-risk thyroid cancer, higher doses up to 2.2 μg/kg body weight may be needed [8]. However, TSH suppression is > zie verder artikel


Figuur 4
Example of balancing risks and benefits in order to choose a target thyroid-stimulating hormone value for a patient. LT4 levothyroxine, TSH thyroid-stimulating hormone

https://media.springernature.com/lw785/ ... 4_HTML.png


Medications, Supplements, and Food
Medications may alter a patient’s requirement for levothyroxine through a variety of mechanisms
(Table 1).
These mechanisms include altered levothyroxine absorption, altered thyroid hormone synthesis or release (theoretically relevant for those who still have some residual thyroid function), altered transport of levothyroxine, altered metabolism of levothyroxine, and altered TSH secretion.
A partial list of some of the implicated drugs is shown in Table 1, and more complete discussion of these drugs can be found > zie verder artikel


Tabel 1
Drugs affecting levothyroxine requirement and the mechanism of altered requirement
Drug Altered LT4 requirement Altered LT4 absorption Altered TH synthesis or release Altered transport Altered metabolism Altered TSH secretion
Oestrogen ↑ ×
Androgens ↓ ×
Glucocorticoids ↓ × ×
Phenobarbital ↑ ×
TKI ↑↓ ×
Rifampin ↑ ×
Sertraline ↑ ×
Amiodarone ↑↓ × ×
Iodine ↑↓ ×
Lithium ↑↓ ×
Dopamine, dobutamine ×
Bexarotene ↑ ×
Calcium carbonate ↑ ×
PPI ↑ ×
Ferrous sulphate ↑ ×
Cholestyramine ↑ ×
Phosphate binders ↑ ×
LT4 levothyroxine, PPI proton pump inhibitors, TH thyroid hormone, THS thyroid-stimulating hormone, TKI tyrosine kinase inhibitors >> zie ver artikel



Figuur 5
Example of how to adjust levothyroxine dose in patients receiving concomitant medications. LT4 levothyroxine, rT3 reverse triiodothyronine, T3 triiodothyronine, TSH thyroid-stimulating hormone

https://media.springernature.com/lw785/ ... 5_HTML.png


Figuur 6
Example of how to adjust levothyroxine dose in patients consuming foods that may impair absorption. LT4 levothyroxine, TSH thyroid-stimulating hormone

https://media.springernature.com/lw785/ ... 6_HTML.png


Controversies About Treatment Other Than Levothyroxine

No consistently strong evidence has been found for the superiority of any alternative preparation (e.g., levothyroxine/liothyronine combination therapy, thyroid extract therapy, or others) over monotherapy with levothyroxine in improving health outcomes [8]. Trials of such therapy show mixed results regarding patient preference for combination therapy or other alternative therapies [8]. On an anecdotal basis some patients may perceive > zie verder artikel


Figuur 7
Illustration of potential responses of a patient to a trial of combination therapy with levothyroxine and liothyronine. FT4 free thyroxine, LT3 liothyronine, LT4 levothyroxine, TSH thyroid-stimulating hormone, T3 triiodothyronine

https://media.springernature.com/lw785/ ... 7_HTML.png


Conclusion

This review highlights the complexity of maintaining biochemical and clinical euthyroidism in patients undergoing treatment with levothyroxine.
Challenges include the physiological changes that occur as adult patients progress through the stages of life as well as the alterations in levothyroxine needs that may be associated with concomitant medical conditions and medications.
Optimal treatment of hypothyroidism requires a partnership between patient and physician.
The physician is tasked with vigilant appraisal of the patient’s status based on a thorough clinical and laboratory assessment and appropriate adjustment of their levothyroxine therapy.
The patient in turn is tasked with medication adherence and reporting of symptomatology and any changes in their medical situation.
The goal is consistent maintenance of euthyroidism, without the patient experiencing the adverse events and negative health consequences of under- or overtreatment


Acknowledgements
This supplement has been sponsored by Merck.
Funding
Sponsorship for this manuscript, the Rapid Service Fees, and the Open Access fee were all funded by Merck.


Volledig artikel:
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2e artikel
Review
First Online: 04 September 2019

Levothyroxine Formulations: Pharmacological and Clinical Implications of Generic Substitution


Benvenga S1,2,3, Carlé A4.
Author information
1 Endocrinology Section, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy. s.benvenga@live.it.
2 Master Program on Childhood, Adolescent and Women's Endocrine Health, University of Messina, Messina, Italy. s.benvenga@live.it.
3 Interdepartmental Program of Molecular and Clinical Endocrinology and Women's Endocrine Health, University Hospital, AOU Policlinico G. Martino, Messina, Italy. s.benvenga@live.it.
4 Department of Endocrinology and Internal Medicine, Aalborg University Hospital, Aalborg, Denmark.


Abstract
Oral levothyroxine (LT4) is the standard therapy for patients with hypothyroidism. Oral LT4 is available in several formulations, including tablets, soft gel capsules and oral solution. Multiple brand-name and generic LT4 tablets are available.

In the US, the Food and Drug Administration (FDA) has developed a protocol for establishing bioequivalence of LT4 formulations based on serum thyroxine (T4) levels after a single oral dose administered to healthy volunteers.
This protocol has been criticized by professional endocrinology associations for using healthy individuals and ignoring serum thyroid-stimulating hormone (TSH) levels.
In addition, the protocol did not initially correct for baseline T4 levels, although this was changed in a later version.
There are concerns that the FDA's protocol could allow products with clinically significant differences in bioavailability to be declared therapeutically equivalent and interchangeable.

Once a generic LT4 has been shown to be bioequivalent to a brand-name LT4, it may be substituted for that brand-name LT4 with no need for dose adjustment or follow-up therapeutic monitoring.
Often, the substitution is made by the pharmacy without the physician's knowledge.
Even small differences between LT4 formulations can cause significant changes in TSH levels.
This may be a particular concern in vulnerable populations, including elderly, pregnant, and pediatric patients.
Problems that can be encountered when switching between formulations or when original products are reformulated are discussed in this review.
These problems include altered efficacy and adverse events, some of which can be caused by excipients. Patients should be maintained on the same LT4 preparation if possible. If the LT4 preparation is changed, TSH levels should be evaluated and, if necessary, the dose of LT4 adjusted.

Funding: Merck.


Table 1
Summary of practices for physicians and patients, with regard to switching levothyroxine formulations, that were proposed in international/national guidelines/statements [3, 13, 20, 21]
For physicians
. Patients should be maintained on the same brand name of levothyroxine product
If the brand of levothyroxine medication is changed from one brand to another brand, from a brand to a
generic product or from a generic product to another generic product:
. Patients should be re-evaluated and retested by measuring serum TSH in 6 weeks;
The drug should be retitrated as needed
For patients
. Use the same brand of thyroid medication throughout your treatment
. Thyroid disease often requires lifelong therapy and is best managed with consistent and precise
treatment with the same brand of thyroid hormone
. Your doctor may change your dose of thyroid hormone, but the brand of your thyroid hormone
medication should always stay the same
. When you go to the pharmacy, do not change the brand of your thyroid medication without checking
with your doctor
. You should not change your dose from one brand of thyroid medication to another, from your brand of
thyroid medication to a generic product, or from one generic product to another without first checking
with your doctor
. If your doctor changes the type of thyroid medication you are taking, you will need to have repeat blood
tests and visits to your doctor to make sure that you are on the correct dose. Your dose may need to be
readjusted if your thyroid medication is changed


Methods
In December 2018, the PubMed database was searched for articles of potential interest
using “levothyroxine” in combination with each of the following search terms; “interchangeability”, “bioequivalence”, “formulations” and “generic”.
These combinations returned 10, 120, 128 and 79 entries, respectively. The titles and abstracts of English-language articles identified through the search were then reviewed to determine relevance. Furthermore, > zie verder artikel


Bioequivalence and Interchangeability
Bioequivalence of LT4 formulations is defined as the absence of a significant difference in bioavailability, expressed in terms of the maximum concentration (Cmax) or area under the curve (AUC), of the active ingredient of a drug product when administered at the same molar dose in healthy volunteers [14, 18, 22].

A specific LT4 pharmacokinetic protocol for bioequivalence has been developed by the FDA [2, 23].
In this protocol, a single oral dose of 600 µg of LT4 is administered to healthy volunteers [12].
The 90% confidence interval (CI) for test/reference product geometric mean AUC and Cmax ratios of serum T4 must be in the 80–125% range [14].
Note that the 90% CI for narrow therapeutic index drugs is 90–111.1%, and LT4 is often considered a narrow therapeutic index drug [13, 14, 24].
The FDA assigns an AB + number TE code to LT4 tablets (Table 2) [25, 26, 27, 28, 29, 30, 31, 32, 33]. Products with the same TE code are considered therapeutically equivalent [32].


Table 2
FDA therapeutic equivalence ratings for currently available levothyroxine tablet products [25, 26, 27, 28, 29, 30, 31, 32, 33]
Levothyroxine tablet product Reference listed druga Therapeutic equivalence codeb Inactive ingredientsc
Brand name
Unithroid Yes AB1, AB2, AB3 Acacia, colloidal silicon dioxide, corn starch, lactose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate
Synthroid Yes AB1, AB2 Acacia, confectioner’s sugar (contains corn starch), lactose monohydrate, magnesium stearate, povidone, talc
Levoxyl Yes AB1, AB3 Calcium sulfate dehydrate, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, sodium bicarbonate
Levo-T No AB1, AB2, AB3 Magnesium stearate, microcrystalline cellulose, colloidal silicone dioxide, sodium starch glycolate
Euthyrox No AB2 Citric acid anhydrous, corn starch, gelatin, magnesium stearate, mannitol, sodium croscarmellose
Generic
Levothyroxine sodium (Mylan) No AB1, AB2, AB3, AB4 Butylated hydroxyanisole, colloidal silicon dioxide, crospovidone, ethyl alcohol, magnesium stearate, mannitol, microcrystalline cellulose, povidone, sodium lauryl sulfate, sucrose
aA drug identified by the FDA as a product on which an applicant relies in seeking approval of an abbreviated new drug application for a generic product
bIf bioequivalence to a reference listed drug product is demonstrated, the product will be given the same code as the reference listed drug it was compared against: AB1 vs. Unithroid, AB2 vs. Synthroid, AB3 vs. Levoxyl; AB4 vs. Levothroid/Thyro-Tabs (now discontinued). One common code indicates therapeutic equivalence between products
cAll formulations except Euthyrox also contain colorants that differ according to tablet dose



The LT4 bioequivalence protocol produced by the FDA has been criticized by professional endocrinology associations. In their joint letter, the ATA, the ES and the AACE pointed out that pharmacokinetic assessments are not suitable for biologics and that the protocol does not include TSH assessment [13]. Omitting TSH is illogical, considering that > zie verder artikel


There are no equivalent European guidelines for the demonstration of LT4 formulation bioequivalence, but the FDA bioequivalence guidelines for LT4 are referred to in European countries [37, 38].
Instead, the relevant European guideline is the 2010 European Medicines Agency Guideline on the Investigation of Bioequivalence [10]. This guideline is focused on > zie verder artikel


In order to assess bioequivalence after a single dose, the Guideline recommends analyzing AUC(0–t) or, when relevant, AUC(0–72h), and Cmax.
In order to assess bioequivalence of immediate release formulations at a steady state, analysis of AUC(0–τ) and Cmax,SS is recommended.
Bioequivalence is established when the 90% CI for the ratio of the test and reference products is ≥ 80.00% and ≤ 125.00% when rounded to two decimal places.
The acceptance interval may need to be narrowed to 90.00–111.11% for products with narrow therapeutic range [10].
In Europe, medicinal products are considered to be therapeutically equivalent if they contain the same active substance or therapeutic moiety and have the same > zie verder artikel


Tablet Formulations
In the US, physicians currently have a choice of several LT4 sodium tablet preparations, five branded products and one generic formulation (Table 2) [31].
According to the US FDA system of evaluation for therapeutic equivalence, preparations with the same TE code are considered to be interchangeable (Table 2) [31, 32].
Although several LT4 products do have similar pharmacokinetic performance, this is not assured for each of the AB-rated pairs because not all have been directly compared in pharmacokinetic studies [2].
A range of LT4 tablet brand-name and generic formulations are also available in Europe and used interchangeably (brand-name products include Eltroxin, Euthyrox/Levothyrox, Thyrax, Tirosint, Eutirox, Letrox and Levaxin) [21, 38, 40, 41].


Soft Gel and Liquid Formulations
Soft gel and liquid LT4 formulations are alternative dosage forms of LT4 [2, 22, 37]. Lower doses of LT4 are generally required with these formulations compared with traditional tablets, because dissolution of tablet excipients does not need to occur before LT4 is > zie verder artikel


Reformulation
To minimize the variability of LT4 products, the FDA now requires LT4 products to retain 95–105% of labeled LT4 content over the expected shelf life of the product instead of the previously accepted range of 90–110% [60].
The US Pharmacopeia revised their monograph for levothyroxine sodium tablets to support this change. These revisions went into effect in October 2009 [61].
The French Agence Nationale de Sécurité des Médicaments (ANSM) also requires that LT4 products retain 95–105% of LT4 content, whereas 90–105% is acceptable in the UK [24, 38].
Several branded products have been reformulated to meet the new standards, including Euthyrox/Levothyrox and Levoxyl tablets and Tirosint soft-gel capsules [2, 62, 63, 64]. Using the FDA criteria, the new formulations have been shown to > zie verder artikel


Table 3
Geometric mean ratios of pharmacokinetic parameters for baseline-adjusted total plasma thyroxine after administration of new versus old formulations of levothyroxine (600 µg) in healthy volunteers [70, 71, 72]
Parameter Euthyrox Levoxyl Tirosint
C max 101.7 (98.8–104.6) 92.5 (87.1–98.2) 103.1 (93.5–113.6)
AUC(0–48h) NA 96.9 (90.5–103.8) NA
AUC(0–72h) 99.3 (95.6–103.2) NA 109.8 (100.3–120.3)
AUC(0–48h) area under the concentration–time curve from 0 to 48 h, AUC(0–72h) area under the concentration–time curve from 0 to 72 h, Cmax maximum concentration, NA not assessed



TSH Levels After Generic Substitution
The TSH reference range for the general population is 0.4–4.5 mIU/L [1, 3], but may increase with age (depending on dietary iodine intake), so that the upper limit is ~ 5–6 mIU/L in patients aged > 70–90 years [65]. For example, in Denmark, where the populations in > zie verder artikel


Problems Encountered After Forced Switching on a National Level
Problems have been encountered in several countries when patients have been forced to switch LT4 products because of supply problems or mandated transition to a reformulated product that contained different excipients [21, 43, 74].


Generic or Brand Substitution
In the Netherlands, there was a recent shortage of the most commonly used LT4 brand (Thyrax), resulting in a forced brand switch (mainly to LT4 Teva or Euthyrox) and an increase in the reported number of adverse events [21]. Although Thyrax and Euthyrox share some excipients in common (corn starch, gelatin, lactose monohydrate), most excipients are different.

Thyrax Duotab
0.025-, 0.100- and 0.150-mg tablets contain talc, sodium citrate dihydrate (E 331), gelatin, glycerol (E 422), colloidal anhydrous silica (E 551), magnesium stearate (E572), as well as colorants (E132 in the 0.025-mg tablet and E127 in the 0.150-mg tablet) [75].
Teva levothyroxine tablets contain maize starch, mannitol (E421), microcrystalline cellulose, sodium citrate, acacia and magnesium stearate [76].
Euthyrox tablets contain magnesium stearate (E 572) and croscarmellose sodium (E 468) [77]. Overall, 53% of patients using > 100 µg/day showed biochemical signs of over-supplementation [21].
In response, general advice was issued to check serum TSH 6 weeks after any brand change, and to consider dose reduction for patients receiving > 100 µg/day [21].


In February 2012, the UK Medicines and Healthcare products Regulatory Agency suspended the license for Teva levothyroxine 100-µg tablets following reports from prescribers and patients describing reduced efficacy when switching from other levothyroxine products [78]. In October 2016, the suspension was lifted after Teva reformulated the tablets by making them lactose-free and changing the manufacturing process [79].


Reformulation
In 2017, a switch was made to the new formulation of Levothyrox (Euthyrox in other EU countries) in France to comply with the requirement for 95–105% potency specification, and, by 2018,  there had been > 17,000 reports of advers e events [21, 43].
As previously mentioned, the new formulation (lactose removed and mannitol and citric acid added) had been shown to be bioequivalent to the previous formulation, and complied with the relatively stringent bioequivalence criteria for narrow therapeutic index drugs [21, 43, 63].
For adverse events with reported TSH levels, approximately 60% occurred in patients with normal TSH levels (suggesting that patients were receiving the right dose), and 15–20% in patients with TSH levels indicative of hypothyroidism or hyperthyroidism [21].
These numbers are not unusual > zie verder artikel


Similar problems occurred in New Zealand and Denmark a decade ago in relation to reformulated Eltroxin [21, 43, 74, 81]. A major review of the New Zealand situation also found > zie verder artikel


Conclusions
Physicians should alert patients that their LT4 prescription may be switched at the pharmacy, encourage patients to ask to remain on the same preparation at every refill, and make sure that patients understand that they need to have their TSH retested every time their LT4 product is switched [13, 19].
In some countries, such as the USA and Denmark, physicians can state on the prescription that switching is not allowed [2].

Great care must be taken to keep clinicians and patients fully informed when a reformulated branded product is introduced, and pharmacovigilance plans should be in place to monitor adverse events [21, 24, 81].
Patients need to understand that the recommendation to stay on the same LT4 formulation is based on the concern that switching products could lead to changes in TSH that require TSH testing and dose adjustment [3].


Acknowledgements
This supplement has been sponsored by Merck



Volledig artikel:
https://rd.springer.com/content/pdf/10. ... 1079-1.pdf


Nog een paar andere volledige artikelen:
Hypothyroidism in Context: Where We’ve Been and Where We’re Going
L. Chiovato (&) _ F. Magri
Istituti Clinici Scientifici Maugeri IRCCS, Unit of Internal Medicine and Endocrinology and Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
e-mail: luca.chiovato@icsmaugeri.it
A. Carle´ Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark

https://rd.springer.com/content/pdf/10. ... 1080-8.pdf



Seven Decades of Levothyroxine: A Comprehensive Profile
Evgenideion Hospital, Unit of Endocrinology, Diabetes and MetabolismUniversity of AthensAthensGreece
Leonidas H. Duntas

“…the past is useful if it points to the present and the present is beneficial if it looks forward to the future.” *
* Zirogiannis PN. A Medical Vade Mecum. Motivating insights to new doctors. Ed. Athens Medical Association, pp 194–195, 2017

The prevalence of hypothyroidism varies depending on geography (e.g., it is somewhat higher in Europe than in the USA), populations studied, and definition [1]. Age is also a crucial factor, since, worldwide, its prevalence is greater among the elderly, standing, for example, at about 7% in individuals aged between 85 and 89 years [2]. Among all age groups, however, the actual percentages are most likely to be substantially higher, given that no age-specific reference range for TSH is currently applied, while the disease often remains undiagnosed.

https://rd.springer.com/content/pdf/10. ... 1081-7.pdf

.

Kiek
Berichten: 4322
Lid geworden op: 12 sep 2013, 11:36

Re: Nieuwe artikelen over levothyroxine

Bericht door Kiek » 06 sep 2019, 14:29

Fijne info, Ineke!
Nuchter lab 8.00 uur - dosis pas slikken na het prikken - lees over schildklieren en ervaringen, want deze kennis geeft inzicht. Door Hashimoto een ervaren schildklierhormoongebruikster (geen arts).

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laura
Berichten: 3159
Lid geworden op: 11 sep 2013, 22:42
Contacteer:

Re: Nieuwe artikelen over levothyroxine

Bericht door laura » 06 sep 2019, 15:28

Op Schildkliertje zorg ik voor een verwijzing, Ineke.

En leuk dit stukje: Thyroxine was isolated on Christmas Day 1914 by Kendall. Its chemical structure was determined in 1926 by Harington, and it was synthesised in 1927 by Harington and Barger [1, 2]. The acidity of the thyroxine molecule, which caused diminished absorption resulting in low bioavailability, was an unresolved problem for more than 20 years following its discovery [3]. In 1949, a commercial product containing synthesised sodium thyroxine was launched in the USA and some years later in Europe, signalling a new era in the treatment of hypothyroidism, which had advanced from partially purified extracts of bovine thyroid gland and desiccated thyroid extracts from sheep and pigs to fully synthesised thyroxine [4, 5]. The manufacture of sodium thyroxine (levothyroxine) thus resulted in a major pharmacological achievement in endocrinology, giving a more stable and effective thyroid hormone compound that, over the last few decades, has considerably improved the lives of millions of patients with various forms of hypothyroidism.
laura

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ineke
Berichten: 426
Lid geworden op: 08 nov 2014, 17:53

Re: Nieuwe artikelen over levothyroxine

Bericht door ineke » 06 sep 2019, 18:47

laura schreef:
06 sep 2019, 15:28
Op Schildkliertje zorg ik voor een verwijzing, Ineke.
Ik zag het staan.


Off topic
Maar ook dit:
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laura
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Lid geworden op: 11 sep 2013, 22:42
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Re: Nieuwe artikelen over levothyroxine

Bericht door laura » 09 sep 2019, 15:54

:D
laura

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