Rapamycin (Sirolimus) Side Effects: Rare but Serious Adverse Events

What does the boxed warning actually cover?

Rapamune (sirolimus) is approved to prevent organ rejection in patients aged 13 and older receiving a kidney transplant, and to treat lymphangioleiomyomatosis [1]. It carries a single boxed warning, headed 'Immunosuppression, use is not recommended in liver or lung transplant patients' [1].

The label warns that immunosuppression can increase susceptibility to infection and may lead to lymphoma or other malignancies, particularly of the skin [1]. In the label's renal transplant studies, lymphoma and lymphoproliferative disease occurred in 0.7% to 3.2% of Rapamune-treated patients versus 0.6% to 0.8% of azathioprine and placebo controls [1].

The boxed warning also covers transplant types other than kidney. In de novo liver transplant patients, Rapamune combined with tacrolimus was associated with excess mortality and graft loss (22% versus 9% on tacrolimus alone) [1]. Use with cyclosporine or tacrolimus was associated with hepatic artery thrombosis (7% versus 2% in the control arm), most cases within 30 days of transplantation and most leading to graft loss or death [1]. In de novo lung transplant patients, bronchial anastomotic dehiscence, most of it fatal, has been reported [1].

Interstitial lung disease and non-infectious pneumonitis

Interstitial lung disease and non-infectious pneumonitis are listed among the label's warnings and precautions [1].

One series followed 8 renal transplant recipients who developed unexplained interstitial pneumonitis during sirolimus therapy [2]. All had bilateral interstitial infiltrates on chest X-ray and CT, and all but one had marked general symptoms. Bronchoalveolar lavage showed lymphocytic alveolitis, mainly of the CD4 type, in 7 patients and alveolar hemorrhage in 1. Transbronchial biopsies in 2 patients showed bronchiolitis obliterans with organizing pneumonia combined with lymphocytic interstitial pneumonitis, and pulmonary infection was excluded by stains and cultures [2]. Sirolimus was stopped in 7 patients and the dose reduced in 1; clinical and radiological status improved within a few weeks and resolved completely within 3 months [2].

Serious and opportunistic infections

The label warns that oversuppression of the immune system can increase susceptibility to infection, including opportunistic infections such as tuberculosis, fatal infections and sepsis [1]. Latent viral infections are listed separately among the warnings and precautions [1].

In the 48-week PEARL trial of healthy adults taking rapamycin weekly, overall adverse and serious adverse events were similar across the rapamycin and placebo groups [3].

Impaired wound healing and fluid accumulation

The label reports impaired or delayed wound healing in patients receiving Rapamune, including lymphocele and wound dehiscence [1]. It notes that mTOR inhibitors such as sirolimus have been shown in vitro to inhibit production of certain growth factors that may affect angiogenesis, fibroblast proliferation and vascular permeability, that lymphocele occurred significantly more often in a dose-related fashion in Rapamune-treated patients, and that patients with a body mass index greater than 30 kg/m2 may be at increased risk of abnormal wound healing based on data from the medical literature [1].

In a retrospective comparison of kidney transplant recipients, perinephric fluid collections occurred in 135 of 354 patients (38.1%) on sirolimus plus cyclosporine and prednisone versus 24 of 136 (17.6%) on cyclosporine and prednisone with or without azathioprine [4]. Treatment for lymphoceles was needed in 56 of 354 (15.8%) versus 6 of 136 (4.4%) [4].

Fluid can accumulate in other compartments too. The label lists peripheral edema, lymphedema, pleural effusion, ascites and pericardial effusions, including hemodynamically significant effusions and tamponade requiring intervention [1].

Hypersensitivity and angioedema

Rapamune is contraindicated in patients with a hypersensitivity to Rapamune [1]. Hypersensitivity reactions including anaphylactic and anaphylactoid reactions, angioedema, exfoliative dermatitis and hypersensitivity vasculitis have been associated with its administration [1].

On angioedema specifically, the label says that concomitant use with other drugs known to cause angioedema, such as ACE inhibitors, may increase the risk, and that elevated sirolimus levels with or without concomitant ACE inhibitors may also potentiate it [1]. In some cases the angioedema resolved when Rapamune was discontinued or the dose reduced [1].

Kidney effects: proteinuria, function decline and TMA

Three kidney-related risks appear in the label: a decline in renal function with long-term combination of cyclosporine and Rapamune, proteinuria, and an increased risk of calcineurin-inhibitor-induced hemolytic uremic syndrome, thrombotic thrombocytopenic purpura and thrombotic microangiopathy [1]. TTP/HUS also appears in the adverse reaction list for events reported in 3% to under 20% of renal transplant patients [1].

A report of four cases described significant thrombotic microangiopathy in the setting of contemporaneous or contiguous calcineurin inhibitor and sirolimus use [5]. The authors suggested that intrarenal cyclosporine concentration is thought to be significantly elevated when cyclosporine and sirolimus are used together, and called for caution in co-administration [5].

Metabolic events: lipids and new-onset diabetes

Lipid changes are common rather than rare, and the label quantifies them. In the placebo-controlled renal transplant study, hypercholesterolemia occurred in 43% to 46% of Rapamune-treated patients and hypertriglyceridemia in 45% to 57%, versus 23% for each in placebo controls [1]. In trials of Rapamune plus cyclosporine or Rapamune after cyclosporine withdrawal, up to 90% of patients required lipid-lowering treatment, and despite that up to 50% had fasting serum cholesterol above 240 mg/dL [1].

Diabetes mellitus appears among the labeled adverse reactions reported in 3% to under 20% of renal transplant patients [1]. In a U.S. registry analysis of 20,124 adults without diabetes who received a first kidney transplant, sirolimus-treated patients had a higher risk of new-onset diabetes than patients treated with cyclosporine and mycophenolate mofetil or azathioprine: adjusted hazard ratios were 1.61 with sirolimus plus cyclosporine, 1.66 with sirolimus plus tacrolimus and 1.36 with sirolimus plus an antimetabolite. The study was observational and does not establish causation [6].

Malignancy risk

Melanoma, squamous cell carcinoma and basal cell carcinoma appear in the label's list of adverse reactions reported in 3% to under 20% of renal transplant patients [1].

A prospective randomized trial examined switching long-term renal transplant recipients to sirolimus for skin-cancer outcomes. In this single-center trial, 44 long-term renal transplant recipients with skin lesions were assigned either to switch to sirolimus or to continue their original immunosuppression [7]. At 12 months, 1 patient in the sirolimus group had developed a histologically confirmed non-melanoma skin cancer versus 8 in the control group (p = 0.0176), and progression of pre-existing premalignancies stopped or regressed [7].

Interactions that can raise or lower sirolimus levels

Sirolimus is a substrate of both CYP3A4 and P-glycoprotein, and the label says to avoid concomitant use with strong inducers (rifampin, rifabutin) and strong inhibitors (ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, clarithromycin) of these pathways [1].

With weaker modulators the label advises caution and possible dose adjustment. Drugs that could increase sirolimus concentrations include bromocriptine, cimetidine, cisapride, clotrimazole, danazol, diltiazem, fluconazole, letermovir, HIV and hepatitis C protease inhibitors, metoclopramide, nicardipine, troleandomycin and verapamil; drugs that could decrease them include carbamazepine, phenobarbital, phenytoin, rifapentine and St. John's wort [1]. Cannabidiol may raise sirolimus blood levels, and a dose reduction of Rapamune should be considered when the two are used together [1]. The label says cyclosporine increases sirolimus concentrations and recommends taking Rapamune 4 hours after cyclosporine. It also says grapefruit juice must not be taken with Rapamune or used to dilute it [1].

What about low-dose rapamycin for longevity?

Rapamycin has no FDA-approved indication for aging, longevity or healthspan; the labeled uses are renal transplant rejection prophylaxis and lymphangioleiomyomatosis [1]. Use for longevity is off-label, and the PEARL trial used compounded rapamycin, which is not FDA-approved and whose safety, effectiveness and quality FDA does not verify before marketing [8][3].

The PEARL trial was a 48-week, double-blind, placebo-controlled randomized trial in healthy, normative-aging adults given placebo or 5 mg or 10 mg compounded rapamycin once weekly [3]. Adverse and serious adverse events were similar across all groups, and changes in blood biomarkers stayed within normal ranges; visceral adiposity, the primary outcome, did not change [3]. The authors concluded that low-dose intermittent rapamycin was relatively safe over 48 weeks and that efficacy was not established, with no lifespan outcome reported [3].

An earlier pilot randomized 25 generally healthy adults aged 70 to 95 to rapamycin 1 mg daily or placebo; 11 rapamycin and 14 placebo participants completed at least 8 weeks [9]. Reported side effects in the rapamycin group were facial rash in 1, 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 [9].