Rapamycin (Sirolimus): Restarting After Acute Illness

What the label says about infection risk

The boxed warning states that increased susceptibility to infection, and the possible development of lymphoma and other malignancies, particularly of the skin, may result from immunosuppression [1]. The Warnings and Precautions section adds that oversuppression of the immune system can increase susceptibility to infection, including opportunistic infections such as tuberculosis, fatal infections and sepsis [1]. The label states that only physicians experienced in immunosuppressive therapy and management of renal transplant patients should use Rapamune for rejection prophylaxis [1].

How long sirolimus stays in the body

Mean terminal half-life is about 62 hours (SD 16) in stable renal transplant patients, and 91% of radioactivity is recovered in feces [1]. Sirolimus is a substrate of both CYP3A4 and P-glycoprotein and is metabolized in the intestinal wall and liver [1].

Medicines started during the illness

The label says to avoid concomitant use with strong CYP3A4 and P-gp inhibitors (ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, clarithromycin) and with the strong inducers rifampin and rifabutin [1]. It advises caution with weaker modulators: bromocriptine, cimetidine, cisapride, clotrimazole, danazol, diltiazem, fluconazole, letermovir, protease inhibitors including ritonavir, metoclopramide, nicardipine, troleandomycin and verapamil can raise sirolimus concentrations, while carbamazepine, phenobarbital, phenytoin, rifapentine and St. John's wort can lower them [1]. Cannabidiol may increase sirolimus blood levels, and the label advises close monitoring and consideration of a dose reduction [1]. The Rapamune label says grapefruit juice must not be taken with the drug or used to dilute its oral solution [1].

What the healthy-adult trials tested

The 48-week PEARL trial studied weekly 5 mg or 10 mg of compounded rapamycin in healthy, normative-aging adults [2]. Adverse and serious adverse events were similar across groups, visceral adiposity did not change significantly (p=0.942), and blood biomarkers stayed within normal ranges [2]. The authors called the drug relatively safe over 48 weeks and said efficacy was not established [2]. Compounded drugs are not FDA-approved, and FDA does not verify their safety, effectiveness or quality before marketing [4].

An earlier pilot randomized 25 generally healthy adults aged 70 to 95 to rapamycin 1 mg daily or placebo, with 11 rapamycin and 14 placebo participants completing at least 8 weeks [3]. In the rapamycin group, side effects included facial rash (1 participant), stomatitis (1) and gastrointestinal issues (2), along with statistically significant decreases in hemoglobin, hematocrit and red cell count [3].