Prometrium Plateau & Non-Response Troubleshooting

What the Label Does and Does Not Define

The Prometrium label does not define a plateau or provide a regimen for a perceived return of symptoms, a changed bleeding pattern, or reduced bedtime drowsiness [1]. The label reports a 36-month endometrial trial, a separate withdrawal-bleeding study after 10 days of treatment, and adverse-reaction data from clinical trials [1].

The Doses the Label Defines

For prevention of endometrial hyperplasia in a postmenopausal woman with a uterus, Prometrium is 200 mg at bedtime for 12 days sequentially per 28-day cycle, with daily conjugated estrogens tablets. For secondary amenorrhea the label gives 400 mg at bedtime for 10 days [1]. The endometrial dosing and the label's endometrial studies used conjugated estrogens, not estradiol [1].

Blood Levels Vary Widely, and Food Matters

After five daily oral doses in postmenopausal women, mean peak serum progesterone was 17.3 ± 21.9 ng/mL at 100 mg, 38.1 ± 37.8 ng/mL at 200 mg and 60.6 ± 72.5 ng/mL at 300 mg, with concentrations linear and dose proportional from 100 to 300 mg [2]. The standard deviations equal or exceed the means, so two women on the same dose can sit far apart.

Food is the one variable the label names: concomitant food increased bioavailability versus fasting at 200 mg in postmenopausal women [2]. In a crossover study of 15 postmenopausal women using a different micronized progesterone product (Utrogestan), food increased the area under the curve and peak concentration without changing the time to peak, enhancing absorption about twofold, and oral bioavailability was about 10% relative to intramuscular progesterone [3]. The Prometrium label states that the absolute bioavailability is not known [2].

What the Trials Measured

In the label's 36-month trial of 358 women with a uterus, hyperplasia occurred in 6% taking cyclical Prometrium 200 mg plus conjugated estrogens 0.625 mg, 64% taking conjugated estrogens alone and 3% taking placebo; atypical hyperplasia occurred in 1%, 12% and 0% [1].

In a labeled single-center secondary-amenorrhea study of premenopausal women, 10 days of 300 mg daily produced withdrawal bleeding within 7 days in 80% of women (n=20) versus 10% on placebo (n=21) [1].

What the Label Reports and Leaves Open

The label reports an in-vitro finding that ketoconazole inhibited progesterone metabolism by human liver microsomes, and says the clinical relevance is unknown; it names no CYP3A4 inducers [2]. It also reports that when 29 postmenopausal women took conjugated estrogens 0.625 mg with Prometrium 200 mg for 12 days, total estrone rose from 3.68 to 4.93 ng/mL and total equilin from 2.27 to 3.22 ng/mL [2].

The label says Prometrium may cause transient dizziness and drowsiness and should be taken as a single daily dose at bedtime, and it lists six contraindications, including peanut allergy because the capsules contain peanut oil [1]. Pharmacokinetics have not been studied in hepatic or renal impairment, and have not been assessed in low body weight or obese patients [2].