Practical Application of Levothyroxine-Based Therapy

The intention of this chapter is to complete this book on the role of levothyroxine (LT4) in the management of thyroid dysfunction, with a summary of the practical application of this treatment. The focus of the chapter will be on the management of hypothyroidism; for information relating to the implications of TSHsuppressive doses of LT4, the reader should consult chapter “Levothyroxine and Bone” and chapter “Levothyroxine and Cancer”. I will consider how to dose LT4, how patients should take it and the tolerability and safety implications long-term LT4based therapy. This approach will involve reviewing important information from prescribing documentation for preparations of LT4 from Europe [1] and the USA [2], as these impact on clinical practice across a large area of the world beyond the borders of those regions. For example, physicians in Middle-Eastern countries are influenced by, but not bound by, labelling from both of these regions. Physicians should always consult their local labelling, where available, before prescribing LT4, however. Finally, the chapter will provide a resource of guidelines for the management of hypothyroidism around the world.


Introduction
The intention of this chapter is to complete this book on the role of levothyroxine (LT4) in the management of thyroid dysfunction, with a summary of the practical application of this treatment. The focus of the chapter will be on the management of hypothyroidism; for information relating to the implications of TSH-suppressive doses of LT4, the reader should consult chapter "Levothyroxine and Bone" and chapter "Levothyroxine and Cancer". I will consider how to dose LT4, how patients should take it and the tolerability and safety implications long-term LT4-based therapy. This approach will involve reviewing important information from prescribing documentation for preparations of LT4 from Europe [1] and the USA [2], as these impact on clinical practice across a large area of the world beyond the borders of those regions. For example, physicians in Middle-Eastern countries are influenced by, but not bound by, labelling from both of these regions. Physicians should always consult their local labelling, where available, before prescribing LT4, however. Finally, the chapter will provide a resource of guidelines for the management of hypothyroidism around the world.

Avoiding Symptoms of Thyroid Dysfunction
The prescribing documentation for levothyroxine (LT4) products for use in patients with hypothyroidism notes that the adverse events associated with this treatment generally refer to over-treatment with LT4, which induces a state of thyrotoxicosis. Alternatively, inadequate correction of TSH leaves the hypothyroid patient at risk of a range of adverse outcomes, including major adverse cardiovascular events and premature death (see chapter "Levothyroxine and the Heart" for more details) [3,4]. Accordingly, both over-treatment and under-treatment with LT4 leave the patient with hypothyroidism at increased risk of adverse long-term clinical outcomes, as well as troublesome symptoms of thyroid dysfunction (summarised in Fig. 1). The goal of LT4 management is thus to optimise the LT4 dosage [1][2][3][4][5]. It is important to note that symptoms of thyroid dysfunction are often non-specific in nature, and in some cases similar symptoms are identified for both under-and over-treatment with LT4. Increased actions of catecholamines are a feature of thyrotoxicosis, including following an overdose of LT4 [6]. Accordingly, a number of adverse consequences of thyrotoxicosis following over-treatment with LT4 are mediated via over-stimulation of β-adrenoceptors, such as tachycardia, anxiety, agitation and hyperkinesia. Treatment with a β-blocker may be helpful here. The European prescribing documentation also warns that over dosage of LT4 may increase the risk of acute psychosis (especially in patients at risk of this condition), and that long-term abuse of LT4 has been associated with cardiovascular death. Seizures are another rare complication of LT4 therapy [2].
The possibility of increased risk of cardiovascular events (see chapter "Levothyroxine and the Heart"), or of osteoporotic fractures (see chapter "Levothyroxine and Bone"), are among the more serious long-term consequences of thyrotoxicosis. This is a particular concern where TSH-suppressive doses of LT4 are administered. Long-term treatment with high doses of LT4 may be administered after total thyroidectomy for well-differentiated thyroid carcinoma in order to suppress secretion of TSH from the pituitary (e.g. see chapter "Levothyroxine and Cancer"), which induces a thyrotoxic status similar to a chronic form of subclinical hyperthyroidism [7][8][9]. These patients are likely to be at elevated risk of long-term adverse effects, such as those in the cardiovascular system (possible increased risk of adverse cardiovascular events, see chapter "Levothyroxine and the Heart") or the skeleton (possible increased risk of osteoporosis and fractures, especially in those at increased risk, such as postmenopausal women-see chapter "Levothyroxine and Bone").

Adverse Reactions to the LT4 Tablet Itself
Additionally, as with any medicinal product, hypersensitivity reactions in the skin or respiratory system may occur rarely in response to components of the LT4 tablet, possibly including LT4 itself [1,2]. Such reactions tend to manifest with symptoms, such as urticaria, eczema-like rashes, fever and disturbances of liver function tests, and may persist when different LT4 products are prescribed [10][11][12][13]. Excipients vary somewhat between LT4 preparations, and so changes the brand of LT4 may help to resolve the issue; however, hypersensitivity to LT4 itself may effectively prevent the effective management of hypothyroidism [14]. Procedures for oral desensitisation have been described, where administration of successively increasing LT4 dosages (e.g. at 30-min intervals, from an initial dose as low as 0.01 μg) enable subsequent chronic therapy with doses of LT4 that are clinically effective [10][11][12][13].

How to Prescribe and Take Levothyroxine
Hypothyroidism usually requires patients to take LT4 for life. Accordingly, patients must be educated on how to take their LT4 tablets correctly, to have any chance of achieving stable, euthyroid-like thyroid hormone function over the long term (Table 1). Food has a markedly inhibitory effect on the absorption and bioavailability of LT4 (see chapter "Administration and Pharmacokinetics of Levothyroxine"). Accordingly, it is important that LT4 is taken on an empty stomach, and that no food, coffee, etc. is consumed for at least 30 min (according to European guidance, and up to 1 h, according to guidance from the USA) after taking the LT4 tablet (half a glass of water or so is permitted to allow the tablet to be taken). The usual recommendation is to take LT4 first thing in the morning, so that the 30 min before needing to eat is occupied by the usual morning rituals of bathing, etc. In principle, LT4 can be taken at bedtime although the need to wait for 3 h after the evening meal before taking the tablet [15,16] may be difficult to maintain consistently, with a consequent reduction in the stability of LT4's biological actions. The administration of LT4 in the management of hypothyroidism is tailored to the individual needs of the patient, according to an individually determined target for thyrotropin (thyroid-stimulating hormone, TSH) [17,18]. Starting and maintenance doses (Table 1) vary according to a number of factors, including the therapeutic indication for LT4, age and comorbidity (especially where there is concomitant cardiovascular disease). Starting doses of LT4 for the management of hypothyroidism, and perhaps long-term targets for the TSH level, are likely to be lower in patients with certain comorbidities. US labelling for LT4 permits initiating treatment at the estimated full LT4 dose for T4 replacement in a patient with recent onset hypothyroidism uncomplicated by comorbidities, however. The speed at which the LT4 dose is titrated to achieve control of TSH also varies with the characteristics of the individual patient.
Contraindications and warnings associated with LT4 usually relate to use in patients with comorbidities where the potential harm of accidental over-treatment with LT4 is highest. These relate especially to comorbidities in the cardiovascular and adrenal systems and the risk of osteoporosis (Table 1).

Overview of Guidelines on the Management of Hypothyroidism
This book has drawn on major guidelines from Europe and the USA to summarise the current role of LT4 in the management of hypothyroidism, as described in its individual chapters. Many other sources of guidance are available; however, we have listed some of these in Table 2, alongside those from Europe and the USA, as a resource our readers in these areas [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32]. For clarity and brevity, we have restricted this slit to guidelines that impact on the management of hypothyroidism: please consult chapter "Levothyroxine and Cancer" for detailed information on the use of LT4 in the management of differentiated thyroid cancer. Guidelines from the American Thyroid Association tend to be comprehensive and cover multiple aspects of thyroid dysfunction, while those from the European Thyroid Association tend to focus on specific aspects, such as subclinical hypothyroidism in special patient populations. Hypothyroidism is especially difficult to manage in the setting of pregnancy and breastfeeding, and guidelines from these expert societies address this need. Regional guidelines are available from Latin America, also, as well as individual countries including the UK and Japan.

Conclusions
The LT4 molecule is identical chemically with the endogenous thyroid hormone, T4. Accordingly, other than rare hypersensitivity reactions to excipients or other pharmaceutical components of the LT4 tablet, symptoms reported by people with hypothyroidism receiving LT4 treatment will relate to the dosage of LT4 they receive, and the severity of their thyroid dysfunction. Novel, re-engineered formulations of LT4 have the potential to increase the reproducibility and constancy of exposure to LT4 during long-term management, which may help to achieve optimal dose titration of LT4 (see chapter "Administration and Pharmacokinetics of Levothyroxine" for an example). Some patients are given supra-physiologic doses of LT4 as a deliberate part of their management, such as those undergoing LT4-based suppression of TSH levels to reduce the risk of disease recurrence after thyroidectomy for thyroid cancer, or to reduce the growth and potential for malignancy of thyroid nodules. Research is continuing to determine the most appropriate LT4-based management algorithms for these patients, to optimise their long-term clinical outcomes.
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