Rapamycin (Sirolimus) Side Effects: Severity Distribution by Patient Phenotype

What does the label report?

The Rapamune label covers sirolimus tablets and oral solution. In renal transplant patients, the reactions reported at 30% or more include peripheral edema, hypertriglyceridemia, hypertension, hypercholesterolemia, increased creatinine, constipation, abdominal pain, diarrhea, headache, fever, urinary tract infection, anemia, nausea, arthralgia, pain, and thrombocytopenia [1]. In the LAM study, the list at 20% or more starts with stomatitis and diarrhea and also includes abdominal pain, nausea, nasopharyngitis, acne, chest pain, peripheral edema, upper respiratory tract infection, headache, dizziness, myalgia, and hypercholesterolemia [1]. In the LAM study, 11% of subjects stopped because of adverse reactions, and no single reaction led to stopping in more than one patient [1]. In renal transplant trials, increased creatinine, hypertriglyceridemia and thrombotic thrombocytopenic purpura each led to discontinuation in more than 5% of patients [1]. These are transplant and LAM doses, not the low intermittent doses used in longevity trials [1].

The label says reactions related to Rapamune were generally dependent on dose or concentration, and that patients given 2 mg per day had an overall better safety profile than those given 5 mg per day, and that no efficacy advantage over the 2 mg dose could be established in renal transplant patients [1]. This table shows selected reactions from the placebo-controlled renal transplant trial (Study 2), in which patients also took cyclosporine and corticosteroids [1]:

Which labeled risks are serious?

The boxed warning covers increased susceptibility to infection and possible lymphoma and other malignancies, particularly of the skin, from immunosuppression; it also says Rapamune is not recommended in liver or lung transplant patients [1]. Other labeled risks include hypersensitivity and angioedema, impaired wound healing, hyperlipidemia, proteinuria, interstitial lung disease, renal function decline with long-term cyclosporine, HUS/TTP/TMA, male infertility, and avoidance of live vaccines [1]. Patients with a body mass index >30 kg/m2 may be at increased risk of abnormal wound healing based on medical literature [1].

Do patient differences change exposure or risk?

Hepatic impairment raises sirolimus AUC by 43% in mild, 94% in moderate, and 189% in severe impairment; the maintenance dose is reduced by about one third in mild-to-moderate and one half in severe impairment [1]. Sirolimus can cause fetal harm, and the label recommends highly effective contraception during treatment and for 12 weeks after the last dose [1]. The label also lists male infertility with azoospermia or oligospermia [1].

What did low-dose weekly trials find?

The PEARL trial was a 48-week double-blind, placebo-controlled trial in healthy, normative-aging adults. Participants received placebo or 5 mg or 10 mg compounded rapamycin once weekly. Adverse and serious adverse events were similar across groups, and blood biomarkers remained within normal ranges. The authors concluded that low-dose intermittent rapamycin was relatively safe over 48 weeks and that efficacy was not established; there was no lifespan outcome [2]. Compounded rapamycin is not FDA-approved [3]. Sirolimus use for longevity is off-label; Rapamune is approved for renal transplant rejection prophylaxis and LAM [1].

A pilot trial enrolled 25 adults aged 70 to 95 and randomized them to 1 mg of rapamycin daily or placebo; 11 rapamycin participants and 14 placebo participants completed at least 8 weeks. Reported side effects in the rapamycin group were facial rash in 1 participant, stomatitis in 1 and gastrointestinal issues in 2, and the rapamycin group had statistically significant decreases in hemoglobin, hematocrit, red cell count, RDW, MCV and MCH [4].

What about proteinuria after a switch?

A retrospective study followed 68 renal transplant recipients switched from calcineurin inhibitors to sirolimus. Mean proteinuria was 0.39 g/day at baseline, rose to 1.44 g/day at 3 months (P<0.001), and remained elevated at 6, 12, and 24 months. When sirolimus was withdrawn in 19 patients, proteinuria fell from 1.95 g/day to 0.9 g/day (P<0.05). Proteinuria above 0.3 g/day before the switch correlated with later decline in renal function [5]. The authors concluded that kidney transplant recipients treated with calcineurin inhibitors may develop reversible proteinuria when switched to sirolimus [5].