A 43-year-old female has arrived at your pharmacy with a new prescription for Rybelsus. She has a PMH of T2DM, hypertension, and hypothyroidism. She also has drug allergies to sulfa-containing drugs and lisinopril. Her current medication list includes: Metformin 1000 mg PO BID, Losartan 50 mg PO QD, and Levothyroxine 125 mcg PO QAM 30 minutes to 1 hour before meals. The patient would like to have counseling on this new medication. What details are appropriate to discuss with the patient prior to dispensing? 

A. The starting dose is not the effective dose, the dose is slowly increased in most circumstances to tolerable levels due to the side effects of nausea, abdominal pain, and constipation. 

B. Since the patient has a drug allergy to sulfa-containing drugs, do not fill the prescription until further clarification of patient allergy. 

C. Take Rybelsus at least 30 minutes before first food, beverage, or other oral medications with plain water only. 

D. Proper administration of Rybelsus is to inject under the skin of the patient’s abdomen, upper arms, or thigh, also to rotate injection sites to prevent irritation of skin tissue. 

E. Rybelsus should be discontinued approximately 2 months prior to planned pregnancy to effectively washout the medication to limit potential harm to the fetus. 

Answers with Rationale: A, C, E 

Rybelsus is the first oral glucagon-like-peptide-1 (GLP-1) agonist for the treatment of T2DM. The generic name for Rybelsus is semaglutide, with the brand name subcutaneous injection form being Ozempic. Rybelsus is an option for patients who are not willing to inject themselves weekly. There are several key counseling points further discussed in the rationale. 

Answer choice A is correct as the main side effects related to GLP-1 agonists are gastrointestinal side effects such as nausea, vomiting, constipation, and diarrhea. The way to alleviate or prevent these side effects is to titrate the dose slowly from 3 mg once daily to the therapeutic dose of 7 mg once daily after a period of 1 month. The dose can be further increase to 14 mg once daily if further glycemic control is necessary. 

Answer choice B is incorrect as Rybelsus does not contain any sulfa group within its chemical structure. Rybelsus is a recombinant DNA-produced polypeptide analogue to mimic the human GLP-1. The class of diabetic medication with sulfa groups is sulfonylureas, consisting of glipizide, glimepiride, and glyburide. Most patients with "sulfa" allergies can take medications like sulfonylureas or many diuretics that contain a sulfa group as the allergy is relevant more to sulfonamides like sulfamethoxazole. 

Answer choice C is correct as Rybelsus causes gastroparesis or delays gastric emptying. This means that food in the stomach takes longer than normal to empty its contents into the small intestine, which the cause of Rybelsus gastroparesis is due to the medication being mainly absorbed in the stomach. This is important as the impact of Rybelsus on the absorption of oral medications is significant. Since the patient is on levothyroxine, the administration of both medications should be separated by at least 30 minutes as a drug interaction study found that levothyroxine exposure was increased by 33% when co-administered with Rybelsus. Even though gastroparesis is a side effect, the mechanism also has the therapeutic effect of delaying the absorption of post-prandial glucose absorption, thus reducing the rate of glucose circulation. 

Answer choice D is incorrect as Rybelsus is administered orally on a once daily basis. This is contrast to the alternative formulation of Ozempic, a version of semaglutide that is injected subcutaneously in the abdomen, upper arms, and thighs on a once weekly basis. Both drugs share the need for dose titrations to a therapeutic dose. Another key note is Rybelsus should remain in its original blister packaging and only opened when ready for administration. 

Answer choice E is correct as GLP-1 agonists are not recommended as per American Diabetes Association 2022 on the Standards of Medical Care in Diabetes. Another recommendation is patients who can become pregnant should be on effect contraception during therapy. For Rybelsus, studies on the effects on the fetus were insufficient and animal studies showed potential harm in fetuses exposed to Rybelsus. Due to a long wash out period with Rybelsus, women planning pregnancy should discontinue Rybelsus at least 2 months in advance to prevent complication with gestation. In contrast, poorly controlled diabetes poses are at an increased risk for complications with both the fetus and mother, however other options such as insulin may be a better option for glycemic control with gestation. The labeling per the manufacturer of Rybelsus states that ultimately a risk benefit assessment should be made before using this product in pregnancy. 

 An important note not discussed is that Rybelsus along with other GLP-1 agonists are contraindicated with medullary thyroid carcinoma and endocrine neoplasia syndrome type 2. Animal studies showed correlation between Rybelsus administration and formation of thyroid C-Cell tumors. Also, a serious adverse event not discussed is pancreatitis which is another class effect shared with GLP-1 agonists. Rybelsus should be discontinued at first signs of pancreatitis (severe abdominal pain, radiating pain to the back, vomiting), and if confirmed, should not be restarted. More information about Rybelsus can be found here.

2.4 – Pregnancy or lactation 

3.4 – Drug dosing or dosing adjustments; duration of therapy 

3.5 – Drug route of administration, dosage forms, or delivery systems 

3.6 – Drug contraindications, allergies, or precautions