Oral Micronized Progesterone: Traveling While on This Drug

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What the label says about taking a dose on the road

The labeled regimen for endometrial protection is 200 mg orally as a single dose at bedtime for 12 days sequentially per 28-day cycle, in a postmenopausal woman with a uterus who is taking daily conjugated estrogens tablets [1]. For secondary amenorrhea the label's dose is 400 mg at bedtime for 10 days [1]. The patient leaflet gives the reason for the bedtime timing: some women become very drowsy or dizzy [2]. Women who have trouble swallowing the capsule are told to take it with a glass of water while standing [2].

Two details matter on a trip. Food increased the bioavailability of a 200 mg dose compared with fasting in postmenopausal women [2], so taking a capsule with or without a meal may change exposure. And absorption is fast: maximum serum concentration is reached within about 3 hours of a dose [2]. After five daily doses in postmenopausal women, mean Cmax was 17.3 ng/mL at 100 mg and 38.1 ng/mL at 200 mg, with high between-woman variability (SD often exceeding the mean) [2].

The label says pharmacokinetics in hepatic or renal impairment and in obesity have not been studied [2].

Crossing time zones when the label only says bedtime

The label ties the dose to bedtime, not to a clock time [1]. With a five-hour time difference, a capsule taken at 10 p.m. New York time would fall at 3 a.m. in London. Taken at local bedtime instead, the gap since the previous dose is no longer 24 hours, and the label's dosing section does not address a shortened or lengthened interval between doses [1].

The schedule is also a variable. The endometrial-protection regimen is 12 dosing days out of every 28 [1], so a two-week trip may fall entirely inside the dosing window or entirely outside it. The amenorrhea regimen is a 10-day course [1].

Drowsiness, dizziness and driving

The label says Prometrium may cause transient dizziness and drowsiness and should be used with caution when driving a motor vehicle or operating machinery [1]. During initial therapy, the label adds, a few women have had a cluster of symptoms including extreme dizziness or drowsiness, blurred vision, slurred speech, difficulty walking, loss of consciousness, vertigo, confusion, disorientation, feeling drunk, and shortness of breath [2].

Dizziness also shows up in the trial tables. In the label's secondary amenorrhea study, dizziness was reported by 24% of women on 400 mg/day (n=25) versus 4% on placebo (n=24) [2]. In the larger 3-year trial, dizziness was 15% with cyclic 200 mg plus conjugated estrogens (n=178) versus 9% with placebo (n=174), but the active arm took estrogen as well, so that figure cannot be assigned to progesterone alone [2].

A cross-over study comparing oral and vaginal progesterone found that, at similar progesterone levels, the ratio of 5-alpha- and 5-beta-pregnanolone to progesterone in plasma was dramatically higher after oral dosing; the authors note these metabolites have known psychotropic effects [3].

Long flights and clot risk

Active DVT or PE, or a history of either, is a labeled contraindication, as is active arterial thromboembolic disease such as stroke or myocardial infarction, or a history of these [1]. The label also says to discontinue Prometrium immediately if a PE, DVT, stroke or MI occurs or is suspected, and, if feasible, to discontinue it at least 4 to 6 weeks before surgery of the type associated with increased thromboembolic risk, or during periods of prolonged immobilization [1][2].

Travel itself carries a measurable venous thromboembolism risk. A meta-analysis of 14 studies covering 4,055 VTE cases found a pooled relative risk of 2.0 (95% CI 1.5 to 2.7) for travelers versus nontravelers, 2.8 (2.2 to 3.7) when studies using referred controls were excluded, and a dose response of 18% higher risk for every 2 hours of travel by any mode and 26% for every 2 hours of air travel [4].

The label does not give a VTE rate for oral micronized progesterone on its own. Its Women's Health Initiative numbers (DVT relative risk 1.87, PE 1.98, stroke 1.37) come from conjugated estrogens 0.625 mg plus medroxyprogesterone 2.5 mg, a different progestin, in 16,608 women [1][5].

Peanut oil and substitutions

The capsules contain peanut oil, and peanut allergy is a labeled contraindication rather than a caution [1]. Compounded progesterone is not FDA-approved, and FDA does not verify the safety, effectiveness or quality of compounded drugs before they are marketed [6].