, Volume 59, Issue 3, pp 585–592 | Cite as

Drug interactions in users of tablet vs. oral liquid levothyroxine formulations: a real-world evidence study in primary care

  • Valeria Guglielmi
  • Alfonso Bellia
  • Elisa Bianchini
  • Gerardo Medea
  • Iacopo Cricelli
  • Paolo Sbraccia
  • Davide Lauro
  • Claudio Cricelli
  • Francesco LapiEmail author
Original Article



Several medications may interact with levothyroxine (LT4) intestinal absorption or metabolism, thus reducing its bioavailability. We investigated the variability of thyroid stimulating hormone (TSH) levels and prescribed daily dosages (PDDs) of LT4 before and during potential drug–drug interactions (DDIs) in users of tablets vs. oral liquid LT4 formulations.


By using the Italian general practice Health Search Database (HSD), we retrospectively selected adult patients with at least one LT4 prescription from 2012 to 2015 and at least 1 year of clinical history recorded. The incident prescription of interacting medications (e.g., proton pump inhibitors, calcium or iron salts) was the index date. Analysis was carried out using a self-controlled study design.


Overall, 3965 users of LT4 formed the study cohort (84.1% women, mean age 56 ± 16.5 years). TSH variability on the entry date was greater among liquid LT4 users than in those prescribed with tablets as shown by the difference between 75th and 25th centile, which were 3.01 and 3.8, respectively. The incidence rate ratio (IRR) for TSH variability did not differ between groups, before and during exposure to DDIs. In contrast, PDDs less likely increased during the exposure to DDI with oral liquid LT4 compared with tablets (IRR = 0.84; 95% CI: 0.77–0.92), especially in patients with post-surgical hypothyroidism (IRR = 0.75; 95% CI: 0.64–0.85).


In clinical practice, the use of oral liquid LT4 is not associated with increased PDDs, compared with tablets formulation, during exposure to DDIs. These results support the need for individualizing LT4 formulation to prescribe, especially in patients with various comorbidities and complex therapeutic regimens.


Tablet levothyroxine Oral liquid levothyroxine Drug–drug interactions Gastrointestinal absorption Primary care Prescribed daily dosages 



This study was supported by IBSA. The funding institution had no role in the design and conduct of the study, the collection, management, analysis, and interpretation of the data, the preparation, review, or approval of the manuscript, or the decision to submit the manuscript for publication.

Compliance with ethical standards

Conflict of interest

Dr. I. Cricelli and Dr. F. Lapi provided consultancies in protocol preparation for epidemiological studies and data analyses for Angelini, Alfa Wassermann, Bayer, and IBSA. Dr. C. Cricelli, and Dr. G. Medea provided clinical consultancies for Angelini, Alfa Wassermann, Bayer, and IBSA. Dr. V. Guglielmi, Dr. A. Bellia, Dr. E. Bianchini, Prof. P. Sbraccia, and Prof. D. Lauro, have no conflict of interest to disclose.

Ethical approval

This is an observational, retrospective, non-interventional study. According to a by-law on the classification and implementation of observational drug-related research, as issued by the Italian National Drug Agency (an entity belonging to the Italian Ministry of Health), the present study does not require approval by an Ethics Committee in Italy (Italian Drug Agency note of 3rd August 2007).


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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Valeria Guglielmi
    • 1
  • Alfonso Bellia
    • 1
  • Elisa Bianchini
    • 2
  • Gerardo Medea
    • 3
  • Iacopo Cricelli
    • 2
  • Paolo Sbraccia
    • 1
  • Davide Lauro
    • 1
  • Claudio Cricelli
    • 3
  • Francesco Lapi
    • 2
    Email author
  1. 1.Department of Systems MedicineUniversity of Rome “Tor Vergata”RomeItaly
  2. 2.Health SearchItalian College of General Practitioners and Primary CareFlorenceItaly
  3. 3.Italian College of General Practitioners and Primary CareFlorenceItaly

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