Levothyroxine for Hypothyroidism: Can Bedtime Administration Be a Viable Option?

Hypothyroidism is estimated to occur in up to 2% of the US population and is most commonly treated with thyroid-replacement medications such as levothyroxine or liothyronine.¹ Due to its lack of immunogenicity, clinical history, tolerability, and affordability, levothyroxine is the first-line treatment option.¹

While levothyroxine is taken once daily, there are significant administration requirements in order to obtain consistent benefits from the medication: It must be taken on an empty stomach; it must be taken with only water; and other medications must be withheld for at least 30 minutes and up to 60 minutes after taking levothyroxine. For patients with busy lifestyles or those taking multiple medications that require morning administration, these requirements for levothyroxine can make appropriate dosing difficult. Such barriers can lead to potentially labile thyroid levels and suboptimal hypothyroidism control.

Is there another administration option that minimizes the administration burden for these patients while still maximizing control of the disease?

Case Report

MH is a 65-year-old woman with a history of hypothyroidism, hypertension, and osteoporosis. She takes levothyroxine 100 µg daily, amlodipine 5 mg daily, alendronate 70 mg once weekly, and calcium 500 mg/vitamin D 400 IU twice daily. MH has a 35-minute commute to work each morning and is often rushed when leaving the house. Accordingly, she tends to take all of her medications at the same time while driving to work and eating a light breakfast of coffee and a bagel or fruit. She knows that her levothyroxine should be taken 30 to 60 minutes before her other medications and before food, but she has difficulty consistently adhering to this requirement. This is especially problematic on the day she has to take her alendronate.

Her thyroid function—thyrotropin, free triiodothyronine (FT₃), and free thyroxine (FT₄)—exhibits various levels of control, often requiring small adjustments in her levothyroxine dose. Fortunately, during the periods outside of her goal thyrotropin range, she infrequently exhibits mild symptoms.

Does she have any dosing options other than morning dosing for the levothyroxine?

The Evidence

Given the well-known kinetics of levothyroxine, morning dosing before food or medication has long been the standard, and only scarce evidence exists on alternative strategies. Recently, Geer and colleagues² conducted a literature search to determine whether any evidence supports bedtime administration of levothyroxine. Of the 4 studies identified, 2 showed a significant reduction in thyrotropin levels, while 1 showed an increase in thyrotropin levels; the final study did not find a difference between the treatment strategies. Despite potential limitations and inconsistencies between the studies, it is important to note that patient-reported quality of life scores and symptoms did not correlate with either dosing strategy. Finally, 2 of the studies showed that more patients preferred bedtime administration of levothyroxine to morning administration.

Although the available body of evidence is small and limited, the literature does not seem to suggest that bedtime dosing negatively impacts the overall efficacy of therapy; instead, there is potential suggestion for improvement in markers of thyroid function (thyrotropin). Patient-reported quality of life scores and symptom severity are not improved, but they are not worsened, either. Taken together, the net-neutral patient reports of symptoms and quality of life combined with the potentially improved thyrotropin values seem to suggest that, for patients experiencing difficulties with morning dosing, either in lack of control of thyrotropin or intolerable symptoms, the “neutral” impact of bedtime dosing may actually represent an improvement over the patient’s current situation. At the very least, it does not appear that patient outcomes will be worsened with bedtime administration, again further lowering the potential risks, creating a positive benefit-to-risk ratio even with marginal benefits.

Clinical Application

Because MH is having trouble adhering to morning dosing with her levothyroxine, she could be considered for a bedtime dosing regimen of the medication. If her thyrotropin, FT₃, or FT₄ values were in range, and she was asymptomatic, her current morning dosing regimen could likely be continued; however, because she is experiencing difficulties, alternative dosing strategies should be investigated.

Prior to pursuing such an approach, patients should be educated on the importance of adherence with bedtime dosing and strategies such as alarms, calendars, pill bottles, or tying medication administration to a consistent nighttime activity so that the medication is taken reliably. Close monitoring of thyroid panel results is also indicated, since the new regimen with improved administration will likely boost bioavailability of the levothyroxine, potentially leading to a different (and often) lower dose of levothyroxine being needed.

After discussion with MH about continued morning dosing vs bedtime dosing and the potential adherence strategies that go with the bedtime regimen, she notes that she has a consistent nighttime routine that will allow for proper adherence. Therefore, she will be counseled to start taking her levothyroxine at 10 pm (or at least 4 hours after dinner) before going to bed. Her thyroid function should be rechecked in 4 to 6 weeks to ensure the new dosing regimen has not overcorrected her thyroid panel results, and she will be counseled to monitor for symptoms of hyperthyroidism and to alert you should any symptoms develop.

Eric A. Dietrich, PharmD, BCPS, is a graduate of the University of Florida College of Pharmacy and completed a 2-year fellowship in family medicine where he was in charge of an anticoagulation clinic. He works for the College of Pharmacy and the College of Medicine at the University of Florida in Gainesville.

Kyle Davis, PharmD, BCPS, is a graduate of the University of Florida College of Pharmacy in Gainesville and completed a 2-year residency in internal medicine at Indiana University in Indianapolis. He is an internal medicine specialist at Ochsner Medical Center in Jefferson, Louisiana.

References:

1. Garber JR, Cobin RH, Gharib H, et al; American Association of Clinical Endocrinologists and American Thyroid Association Taskforce on Hypothyroidism in Adults. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract. 2012;18(6):988-1028.
2. Geer M, Potter DM, Ulrich H. Alternative schedules of levothyroxine administration. Am J Health Syst Pharm. 2015;72(5):373-377.