Home / Resources / Disasters Averted / Preventing Potential Drug Interaction with a Drug With UNIQUE Directions 

Preventing Potential Drug Interaction with a Drug With UNIQUE Directions 

May 12, 2020
Editor: Steve Freed, R.PH., CDE

Author: Trang Pham, PharmD Candidate 2023 & Joshua J. Neumiller, PharmD, CDCES, FADCES, FASCP 

Rybelsus, oral semaglutide, requires very precise administration.

We were following up with a person with type 2 diabetes who was recently started on the new oral formulation of the GLP-1 receptor agonists semaglutide (Rybelsus®). This patient had a 12-year history of type 2 diabetes as well as several comorbidities that included hypertension, hyperlipidemia, obesity (BMI = 33 kg/m2), knee osteoarthritis, and hypothyroidism. The patient was previously resistant to initiating a GLP-1 receptor agonist due to his hesitancy toward self-injection. He agreed at his last primary care visit to start a trial of oral semaglutide to improve his glucose control and lose some weight. His medication regimen was as follows: 


  • Metformin 1,000mg twice daily 
  • Pioglitazone 30mg once daily 
  • Oral semaglutide 3mg once daily for 30 days 
  • Lisinopril 40mg once daily 
  • Amlodipine 10mg once daily 
  • Atorvastatin 40mg once daily 
  • Acetaminophen 1,000mg three times daily 
  • Levothyroxine 100mcg once daily in the AM 

Because oral semaglutide has a low oral bioavailability, there are precise instructions for administration recommended by the manufacturer.1 The product is recommended to be taken at least 30 minutes before the first food, beverage, or other oral medications of the day with no more than 4 ounces of plain water.  

When we called the patient one week after receiving his Rybelsus prescription, he reported that he had not yet initiated the medication. When asked why he reported confusion about how to take the semaglutide without interfering with his thyroid medication that he takes first thing in the morning before breakfast. After identifying this barrier, we were able to work with the patient and his primary care provider to switch the levothyroxine to bedtime2 so he could initiate the new oral semaglutide prescription in the morning as recommended. The appropriate administration of oral semaglutide was reinforced, and the patient was scheduled for appropriate follow-up to up-titrate the oral semaglutide and monitor his A1C and TSH. 

Lessons Learned: 

  1. Always consider potential administration interactions between new and existing medications. 
  2. Oral semaglutide ( Rybelsus ) has precise administration recommendations due to its low oral bioavailability. If patients are taking any other medications first thing in the morning on an empty stomach (e.g., levothyroxine, oral bisphosphonates), devise an appropriate strategy to minimize administration interactions.  


  1. Semaglutide tablets (Rybelsus®). Prescribing information. Novo Nordisk Inc., Plainsboro, NJ. January 2020. 
  2. Bolk N, Visser TJ, Nijman J, et al. Effects of evening vs. morning levothyroxine intake: a randomized, double-blind crossover trial. Arch Intern Med 2010;170(22):1996-2003. 


Trang Pham, PharmD Candidate 2023 

Joshua J. Neumiller, PharmD, CDCES, FADCES, FASCP 


See more about Rybelsus (oral semaglutide).