Rapamycin (Sirolimus) and Progesterone HRT Interaction: What Patients and Clinicians Need to Know

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Is progesterone on the sirolimus interaction list?

Sirolimus is a substrate of both CYP3A4 and P-glycoprotein, and the Rapamune label names the strong inhibitors it says to avoid: ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin and clarithromycin, plus the strong inducers rifampin and rifabutin [1]. It then lists agents that could raise sirolimus blood levels (bromocriptine, cimetidine, cisapride, clotrimazole, danazol, diltiazem, fluconazole, letermovir, HIV and hepatitis C protease inhibitors, metoclopramide, nicardipine, troleandomycin, verapamil) and agents that could lower them (carbamazepine, phenobarbital, phenytoin, rifapentine, St. John's wort) [1]. The label says grapefruit juice must not be taken with or used to dilute Rapamune [1].

Progesterone appears on none of those lists. The only contraindication in the label is hypersensitivity to Rapamune [1].

The label's sex-hormone entry is a different progestin

In its Clinical Pharmacology section, the label reports that clinically significant pharmacokinetic drug-drug interactions were not observed in studies of acyclovir, atorvastatin, digoxin, glyburide, nifedipine, norgestrel with ethinyl estradiol (Lo/Ovral), prednisolone and sulfamethoxazole with trimethoprim, and that sirolimus and these drugs may be co-administered without dose adjustments [1].

Norgestrel is a synthetic progestin studied in a combined oral contraceptive pill. It is not progesterone, and the statement is about that one pill combination only; the label does not address other contraceptives [1]. It therefore does not settle whether progesterone HRT changes sirolimus levels.

What the progesterone label says about how it is broken down

Prometrium capsules are metabolized primarily by the liver, largely to pregnanediols and pregnanolones, which are conjugated and excreted in bile and urine; the label does not name the enzyme responsible for the main metabolism, and pharmacokinetics have not been studied in hepatic or renal impairment [2]. CYP3A4 appears once, in an in-vitro result: ketoconazole inhibited progesterone metabolism by human liver microsomes with an IC50 below 0.1 micromolar, which the label says suggests that ketoconazole or other inhibitors of this enzyme may increase progesterone bioavailability, adding that the clinical relevance of the in-vitro finding is unknown [2].

The label also reports that giving conjugated estrogens 0.625 mg with Prometrium 200 mg for 12 days changed circulating estrogen levels (total estrone and equilin rose, 17-beta estradiol fell) [2]. That is a finding about estrogens, not sirolimus.

Dizziness and drowsiness from each drug

The Prometrium label says the capsules may cause transient dizziness and drowsiness, should be used with caution when driving a motor vehicle or operating machinery, and are taken as a single daily dose at bedtime [2]. Reported nervous-system events include sedation, stupor, depressed consciousness and loss of consciousness, and during initial therapy some women have had extreme dizziness or drowsiness, blurred vision, slurred speech, difficulty walking, vertigo and confusion [2].

The Rapamune label lists dizziness among the reactions reported in 20% or more of patients treated for lymphangioleiomyomatosis [1]. Those rates come from transplant and LAM dosing, not the low intermittent doses used in longevity trials.

Pregnancy and contraception

Sirolimus can cause fetal harm, and the label recommends highly effective contraception during treatment and for 12 weeks after the last dose, started before therapy begins [1]. Prometrium capsules should not be used during pregnancy [2]. Prometrium's labeled indications are prevention of endometrial hyperplasia in postmenopausal women taking conjugated estrogens tablets and treatment of secondary amenorrhea; contraception is not an indication [2]. Pregnancy is still possible during perimenopause, the time before 12 consecutive months without a period [4].

If the sirolimus is being used off-label

Rapamune's approved uses are prevention of organ rejection in kidney transplant recipients aged 13 and older, and treatment of lymphangioleiomyomatosis; there is no FDA-approved indication for aging or longevity [1]. The 48-week PEARL trial gave healthy adults in a normative-aging cohort placebo, 5 mg or 10 mg of compounded rapamycin once weekly. Adverse and serious adverse events were similar across groups, and the primary outcome of visceral adiposity did not change significantly; lean tissue mass and self-reported pain improved in women taking 10 mg, and the authors concluded that efficacy was not established [5]. Compounded drugs are not FDA-approved.