Clinical Significance of Smaller Gaps Between Strengths of Levothyroxine Preparations in the Treatment of Hypothyroidism

Individual Levothyroxine Dose

Lifetime substitution of levothyroxine (LT4) is the cornerstone of treatment for individuals with hypothyroidism. The usual daily dose for substitution treatment ranges between 12.5 and 150 µg. Therapy for many patients starts with a lower dose (25–50 µg/day), particularly for older individuals, those with low body weight, or those with significant (mainly cardiological) comorbidities.

Nearly half of all treated patients experience insufficient or excessive supplementation. Some LT4 preparations have relatively large intervals between available strengths (tablets containing 25, 50, and 75 µg), which can be a barrier for some patients in achieving the optimal maintenance dose.

Frequent Use of Low LT4 Doses in Clinical Practice

The main factor determining the initial LT4 dose is the residual function of the thyroid gland. For individuals with subclinical hypothyroidism, if substitution is indicated, the starting dose usually is 25–50 µg/day, and the maintenance dose typically ranges between 50 and 100 µg/day. This is also true for patients with manifest hypothyroidism and slightly elevated thyroid-stimulating hormone (TSH) levels. The initial LT4 dose is also influenced by body weight, age, and the presence of certain diseases. Real-world data indicates that a significant number of patients use relatively low maintenance doses of LT4 around 100 µg/day.

In the UK, general practitioners prescribe LT4 in strengths of 12.5 µg, 25 µg, 50 µg, 75 µg, 100 µg, and 125 µg. In the EU, in addition to these doses, oral preparations with strengths of 150–200 µg are available, and in some countries, strengths of 63 µg, 88 µg, 112 µg, and 137 µg are also available. In the USA, the most prescribed tablet is 50 µg (19%), followed by 75 µg (16%), 100 µg (12%), and 25 µg (9%). Although it's not known whether these tablets are prescribed as monotherapy or in combination with another preparation strength, this data suggests that tablets with strengths < 100 µg are frequently used in clinical practice.

Benefits of Preparations with Smaller Dose Intervals

The availability of preparations with smaller intervals between strengths is beneficial for more flexible dose titration. Even small increases in daily dose can have a clinically significant impact on TSH levels. The relative interval between tablet strengths is smaller at higher doses. Titrating the dose from 25 to 50 µg/day means a relative 100% increase, while titration from 175 to 200 µg/day is a relative increase of 13%. More doses at the lower end of the LT4 dose spectrum facilitate careful titration from an initial dose of 25 µg to a final dose around 75 µg/day. Current stringent regulatory requirements regarding the composition and manufacture of LT4 tablets are based on information about the clinical significance of even slight dose fluctuations. Therefore, the actual doses administered must not differ significantly between individual batches or different preparations of the same strength.

Aside from initial dose titration, the maintenance dose may also fall between available preparation strengths. For the patient, this may mean taking more than one tablet daily (requiring tablet splitting and/or combining different strengths). The availability of more LT4 preparation strengths increases the likelihood that the patient will achieve a maintenance dose with a single daily tablet. Simplicity in dosing regimens is a documented factor that increases adherence to treatment for chronic non-infectious diseases. Low or medium adherence to treatment has been documented in two-thirds of patients with hypothyroidism. Non-adherence, of course, increases healthcare costs and is associated with worse clinical outcomes. Maintenance treatment with a single tablet is also less financially burdensome than prescribing multiple preparations of different strengths to achieve the needed dose.

Conclusion

Many patients with hypothyroidism, especially the elderly, individuals with residual thyroid function, or those with significant comorbidities, require a low initial LT4 dose with slow, gradual titration to a maintenance dose based on achieved TSH levels and symptom reduction. Since LT4 is a drug with a narrow therapeutic range, smaller gaps between preparation strengths can facilitate dose titration and the use of an optimal individual maintenance dose.

(zza)

Source: Gottwald-Hostalek U., Razvi S. Getting the levothyroxine (LT4) dose right for adults with hypothyroidism: opportunities and challenges in the use of modern LT4 preparations. Curr Med Res Opin 2022; 38 (11): 1865−1870, doi: 10.1080/03007995.2022.2071059.