Drug Interactions between amoxicillin / clarithromycin / vonoprazan and levothyroxine / liothyronine

ADJUST DOSING INTERVAL: Consumption of certain foods as well as the timing of meals relative to dosing may affect the oral absorption of T4 thyroid hormone (i.e., levothyroxine). T4 oral absorption is increased by fasting and decreased by foods such as soybean flour (e.g., infant formula), cotton seed meal, walnuts, dietary fiber, calcium, and calcium fortified juices. Grapefruit or grapefruit products may delay the absorption of T4 thyroid hormone and reduce its bioavailability. The mechanism of this interaction is not fully understood.

MANAGEMENT: Some manufacturers recommend administering oral T4 as a single daily dose, on an empty stomach, one-half to one hour before breakfast. In general, oral preparations containing T4 thyroid hormone should be administered on a consistent schedule with regard to time of day and relation to meals to avoid large fluctuations in serum levels. Foods that may affect T4 absorption should be avoided within several hours of dosing if possible. Consult local guidelines for the administration of T4 in patients receiving enteral feeding.

ADJUST DOSING INTERVAL: Concurrent administration of calcium-containing products may decrease the oral bioavailability of levothyroxine by one-third in some patients. Pharmacologic effects of levothyroxine may be reduced. The exact mechanism of interaction is unknown but may involve nonspecific adsorption of levothyroxine to calcium at acidic pH levels, resulting in an insoluble complex that is poorly absorbed from the gastrointestinal tract. In one study, 20 patients with hypothyroidism who were taking a stable long-term regimen of levothyroxine demonstrated modest but significant decreases in mean free and total thyroxine (T4) levels as well as a corresponding increase in mean thyrotropin (thyroid-stimulating hormone, or TSH) level following the addition of calcium carbonate (1200 mg/day of elemental calcium) for 3 months. Four patients had serum TSH levels that were higher than the normal range. Both T4 and TSH levels returned to near-baseline 2 months after discontinuation of calcium, which further supported the likelihood of an interaction. In addition, there have been case reports suggesting decreased efficacy of levothyroxine during calcium coadministration. It is not known whether this interaction occurs with other thyroid hormone preparations.

MANAGEMENT: Some experts recommend separating the times of administration of levothyroxine and calcium-containing preparations by at least 4 hours. Monitoring of serum TSH levels is recommended. Patients with gastrointestinal or malabsorption disorders may be at a greater risk of developing clinical or subclinical hypothyroidism due to this interaction.

Grapefruit juice may delay the gastrointestinal absorption of clarithromycin but does not appear to affect the overall extent of absorption or inhibit the metabolism of clarithromycin. The mechanism of interaction is unknown but may be related to competition for intestinal CYP450 3A4 and/or absorptive sites. In an open-label, randomized, crossover study consisting of 12 healthy subjects, coadministration with grapefruit juice increased the time to reach peak plasma concentration (Tmax) of both clarithromycin and 14-hydroxyclarithromycin (the active metabolite) by 80% and 104%, respectively, compared to water. Other pharmacokinetic parameters were not significantly altered. This interaction is unlikely to be of clinical significance.