Drugs That Interact With Levothyroxine

An Observational Study From the Thyroid Epidemiology, Audit and Research Study (TEARS)

Savannah A. Irving; Thenmalar Vadiveloo; Graham P. Leese


Clin Endocrinol. 2015;82(1):136-141. 

In This Article

Materials and Methods

The study was carried out using databases available at the Health Informatics Centre (HIC) of the University of Dundee. All the data sets are held by HIC under the Data Protection Act for the purposes of research and audit and anonymized after linkage using Standard Operating Procedures (SOP) (http://medicine.dundee.ac.uk/standard-operating-procedures-sops). The study was approved by the Tayside Research Ethics Committee, and permission for the case record validation audit was obtained from Tayside Caldicott Guardians. Cross-sectional data linkage was facilitated by the use of the Community Health Index (CHI) number. This is a unique 10-digit health index assigned to every person registered with a General Practice in Scotland. The CHI is used as a patient identifier for all contact within NHS health care.

Study Population

The study population consisted of Tayside residents who were 18 years and above and who were alive between 1 January 1993 and 31 December 2012. Patients were included in the study if they had at least three thyroxine prescriptions before the start of the study drug. There was a substudy looking at patients who were on an unchanged dosage of thyroxine for 18 months. Patients were excluded from the study if:

  • They were on carbimazole, propylthiouracil or amiodarone within 6 months of the last thyroxine prescription.

  • They had a pituitary disorder (on local database).

  • They were on a study drug prior to baseline.

  • Any TSH measurements were taken in the hospital setting.

  • More than one study drug was initiated during the study period.


Three principal databases were used in the study population. These databases cover primary, secondary and private health care.

Tayside population demographic database: This served as a master index to provide information on gender, date of birth, date of death and dates registered with general practitioner. It was used to define the study population from which cases were identified.

Biochemistry database: This contained all thyroid function tests. TSH was measured in all patients. Free thyroxine (fT4) (10–25 pmol/l), total thyroxine (T4) (65–155 nmol/l) and total triiodothyronine (T3) (0·9–2·6 nmol/l) measurements were triggered if the TSH concentration was outside the range of 0·1–4·0 mU/l. Each entry comprised the patient's anonymized CHI, the test performed, date and the results. All biochemistry tests were carried out in a centralized laboratory for the region. Three TSH assays were used throughout the time frame of the study period; ACS:180 from 1993 till July 1998, ACS: Centaur from August 1998 till June 2003 and Roche Modular E170 from July 2003 onwards. The reference range for TSH concentration was quoted as 0·4–4·0 mU/l for the entire study period. During the study period, there was a primary care regional call–recall thyroid register, replaced later by a national payment system for primary care recall of all patients taking thyroxine (Quality and Outcomes Framework).

Tayside prescription database: This contained all prescriptions dispensed from all community pharmacies in Tayside. Each entry comprised the patient's anonymized CHI, prescription date, drug name, formulation, dosage, frequency and duration. This data set was used to identify patients who were on thyroxine and study drugs. Iron and calcium were studied because of previous reports,[6,9–11,13] although these were small case series. PPIs and H2 antagonists were chosen because of their impact on stomach pH affecting absorption and also due to conflicting reports regarding interaction.[14–17] Oestrogens were chosen because of their impact on binding proteins.[12] Corticosteroids and DMARDS were chosen to see whether any potential impact was due to immunosuppressive activity or another mechanism of action. Statins were chosen because they are very commonly co-prescribed in this patient population and they are not known to effect thyroxine absorption.[19]

British National Formulary codes (listed in Table 1) were used to reference the prescriptions for drugs.

Data Analysis

TSH measurements were analysed for 1 year prior to the introduction of any study drug. This acted as a control period to identify any changes in TSH concentration during the baseline time, before study drugs were initiated.

TSH measurements after 6 months of starting the study drugs were compared with TSH measurements before the start of the study drugs. Wilcoxon signed rank test was used to test the changes in the TSH measurements as data were not normally distributed. All analyses were carried out using spss (v19.0) and sas 9.2. The proportion of patients with a TSH change of more than 5 mU/l was analysed. A change in serum TSH concentration of this magnitude was recognized as being more likely to be of clinical significance than smaller changes.