Ozempic and Progesterone HRT Interaction: What Patients and Clinicians Need to Know

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What the Ozempic label says about other oral drugs

The Ozempic prescribing information states that semaglutide 'causes a delay of gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications' [1]. The same section then says that in clinical pharmacology trials semaglutide 'did not affect the absorption of orally administered medications to any clinically relevant degree', and still advises caution when oral medicines are given with the injection [1].

The semaglutide interaction studies found no clinically significant effect on lisinopril, warfarin, metformin, digoxin, ethinyl estradiol, levonorgestrel, furosemide or rosuvastatin, and omeprazole did not change semaglutide levels [1][5]. Progesterone is not on that list. With the tablet forms (Rybelsus and Ozempic tablets), levothyroxine exposure rose 33% [5].

Semaglutide is a peptide. It is broken down by proteolytic cleavage of the peptide backbone and beta-oxidation of a fatty acid side chain, not by CYP enzymes, and the label describes a very low potential to inhibit or induce CYP enzymes [1].

What the Prometrium label says about progesterone absorption

Prometrium is oral micronized progesterone. Its two labeled indications are prevention of endometrial hyperplasia in postmenopausal women with a uterus who are taking conjugated estrogens tablets, and secondary amenorrhea [4]. The labeled endometrial-protection regimen and trial pair Prometrium with conjugated estrogens. The separate labeled regimen for secondary amenorrhea is 400 mg at bedtime for 10 days [4].

After an oral dose, maximum serum concentrations are reached within 3 hours. In postmenopausal women after five daily doses, mean time to peak was 1.5 hours at 100 mg and 2.3 hours at 200 mg, and food increased progesterone bioavailability compared with fasting [2]. Between-person variability is wide: in the label's pharmacokinetic table the standard deviations are often about as large as the means [2].

The label does not name the enzyme responsible for progesterone's main metabolism. It describes metabolism in the liver, largely to pregnanediols and pregnanolones [2]. CYP3A4 appears once, in an in-vitro note that ketoconazole inhibited progesterone metabolism in human liver microsomes, followed by the label's own caveat that 'the clinical relevance of the in vitro findings is unknown' [2].

Neither label describes a study of semaglutide given with progesterone, so whether the two interact has not been established either way [1][2].

Does the route of progesterone matter?

The Ozempic label's gastric-emptying caution concerns swallowed oral medicines. A vaginal progesterone product does not pass through the stomach, so that specific absorption concern would not apply to it; the labels do not test this combination [1].

For context on the vaginal route, a 1994 study of 20 functionally agonadal women and 4 normally ovulating women found endometrial progesterone of 11.50 ng/mg protein after vaginal micronized progesterone, versus 0.30 in women with the highest serum levels after intramuscular injection [3]. That study did not involve semaglutide, and it measured tissue levels, not symptom control or bleeding patterns.

What the Prometrium label flags

Prometrium's label warns that it may cause transient dizziness and drowsiness, says the daily dose is taken at bedtime, and notes that during initial therapy a few women had extreme dizziness or drowsiness, blurred vision, slurred speech, difficulty walking, loss of consciousness, vertigo, confusion or shortness of breath [4][2]. It also warns about fluid retention in women with cardiac or renal dysfunction, and the capsules contain peanut oil [4].

The labeled contraindications are hypersensitivity (including peanut allergy), abnormal genital bleeding of unknown cause, known or suspected breast cancer or a history of it, active or past deep vein thrombosis or pulmonary embolism, active or past arterial thromboembolic disease, and known liver disease [4]. The label says to stop immediately if a PE, DVT, stroke or MI occurs or is suspected [2].

In the label's 36-month trial of 358 postmenopausal women with a uterus, endometrial hyperplasia occurred in 6% of those taking conjugated estrogens plus Prometrium 200 mg for 12 days per cycle, 64% of those taking conjugated estrogens alone, and 3% of those on placebo [4].

Prometrium's current label, revised 02/2026, has no boxed warning; it was one of the first six menopausal hormone products whose updated labeling FDA approved on 2026-02-12 [6][7][2]. The WHI estrogen-plus-progestin data remain in the Warnings and Clinical Studies sections [2].

The bottom line

The Ozempic and Prometrium labels do not name each other and neither describes an interaction study of the pair, so an interaction is neither shown nor ruled out [1][2]. The one mechanism the Ozempic label raises is delayed gastric emptying affecting oral medicines [1].