Rapamycin (Sirolimus) Side Effects: Potentially Permanent Adverse Events Explained

What happens to rapamycin side effects after the drug is stopped?

The Rapamune label covers sirolimus tablets and oral solution, with a boxed warning, a long warnings and precautions section, and adverse-reaction tables from transplant and LAM studies [1]. Its rates come from daily transplant and LAM doses, not the low weekly doses used off-label for longevity [1].

Where follow-up after the drug was stopped is reported, the picture is mixed. Sirolimus-associated pneumonitis resolved in every patient in one case series, while sperm parameters improved significantly in only three of the six men who interrupted treatment [3][2]. The lipid, wound-healing and kidney data below describe what happened during treatment [1][4][7].

Interstitial pneumonitis: what the follow-up shows

The label lists interstitial lung disease and non-infectious pneumonitis among sirolimus warnings [1]. In a 2001 case series in Transplantation, Morelon and colleagues described eight kidney transplant recipients who developed unexplained pneumonitis while taking sirolimus: bilateral interstitial infiltrates on chest X-ray and CT, lymphocytic alveolitis (mostly CD4 cells) on bronchoalveolar lavage in seven, and alveolar hemorrhage in one. Lung biopsies in two patients showed bronchiolitis obliterans with organizing pneumonia combined with lymphocytic interstitial pneumonitis. Sirolimus was stopped in seven patients and the dose reduced in one; symptoms and imaging improved within weeks and resolved completely within 3 months, which the authors called complete and lasting [3].

That record covers eight patients [3].

Lymphoma and skin cancer

The boxed warning states that increased susceptibility to infection and the possible development of lymphoma and other malignancies may result from immunosuppression [1]. In the label's 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]. Melanoma, squamous cell carcinoma and basal cell carcinoma appear in the label's list of reactions reported in 3% to under 20% of patients [1].

The label also records serious outcomes in liver and lung transplants. In de novo liver transplant patients, Rapamune with tacrolimus was associated with excess mortality and graft loss (22% versus 9% on tacrolimus alone), and hepatic artery thrombosis occurred in 7% versus 2%, mostly within 30 days and mostly leading to graft loss or death. In de novo lung transplant patients, bronchial anastomotic dehiscence, most cases fatal, has been reported. The boxed warning states that use is not recommended in liver or lung transplant patients [1].

Male fertility: what happened when sirolimus was stopped

The label states that azoospermia or oligospermia may occur [1]. The human data come from an observational study of men aged 20 to 40 who received a kidney transplant between 1995 and 2005; of 116 contacted, 95 provided complete information. Men treated with sirolimus throughout had a total sperm count of 28.6 million versus 292.2 million in men not given sirolimus (p=0.006) and a lower proportion of motile spermatozoa, 22.2% versus 41.0% (p=0.01). The fathered pregnancy rate was 5.9 per 1,000 patient-years on sirolimus-based regimens versus 92.9 per 1,000 patient-years on sirolimus-free regimens (p=0.007). Six men interrupted sirolimus and only three showed a significant improvement in sperm parameters [2].

Wound healing, lymphocele and fluid collections

The label's warning on fluid accumulation and wound healing reports impaired or delayed healing including lymphocele and wound dehiscence. It notes that mTOR inhibitors such as sirolimus have been shown in vitro to inhibit production of growth factors that may affect angiogenesis, fibroblast proliferation and vascular permeability, that lymphocele occurred significantly more often in a dose-related fashion, and that patients with a body mass index above 30 may be at increased risk of abnormal wound healing. Reported fluid accumulation includes peripheral edema, lymphedema, pleural effusion, ascites and pericardial effusions, including hemodynamically significant effusions and tamponade requiring intervention [1].

A retrospective single-center study of 235 adult kidney transplants compared 158 recipients on tacrolimus and prednisone: 84 also took mycophenolate mofetil and 74 took sirolimus. The overall complication rate was 21.5%, and it was 2.4% in the mycophenolate group versus 43.2% in the sirolimus group (p<0.0001). Regression analysis identified sirolimus (p<0.001) and low albumin (p=0.006) as the factors independently correlated with complications, and lymphoceles correlated only with sirolimus (p=0.003) [4].

Lipids: high rates during transplant treatment

In the label's renal transplant studies, hypertriglyceridemia occurred in 45% of patients taking sirolimus 2 mg/day and 57% of those taking 5 mg/day, versus 23% on placebo; hypercholesterolemia occurred in 43% and 46% versus 23% [1]. Up to 90% of patients receiving Rapamune plus cyclosporine, or Rapamune after cyclosporine withdrawal, required lipid-lowering treatment, and despite that up to 50% had fasting serum cholesterol above 240 mg/dL [1].

Kidney risk: thrombotic microangiopathy

The label lists proteinuria, a decline in renal function with long-term cyclosporine-plus-sirolimus use, and an increased risk of calcineurin-inhibitor-induced hemolytic uremic syndrome, thrombotic thrombocytopenic purpura and thrombotic microangiopathy [1]. A US Renal Data System cohort of 15,870 kidney transplant recipients from 1998 to 2000 found TMA at 5.6 episodes per 1,000 person-years, 4.9 per 1,000 for de novo cases, with the highest risk in the first 3 months after transplant. Initial use of sirolimus was one of the risk factors for de novo TMA, and patient survival after TMA was about 50% at 3 years [6].

Not every kidney signal points the same way. In the Spare-the-Nephron trial, 299 kidney recipients were randomized to mycophenolate mofetil with a calcineurin inhibitor or to mycophenolate mofetil with sirolimus; the measured GFR change favored the sirolimus arm at 1 year and was indistinguishable at 2 years, and no patients on the sirolimus arm died versus five on the calcineurin-inhibitor arm [7].

Pregnancy exposure

The label states that sirolimus can cause fetal harm and recommends highly effective contraception for females of reproductive potential during treatment and for 12 weeks after the final dose, started before therapy [1]. Animal data in the label show embryo-fetal lethality in rats at 0.5 mg/kg, 2.5-fold the clinical dose of 2 mg on a body surface area basis, and reduced fetal weight at 1 mg/kg, 5-fold that dose [1].

Low-dose weekly rapamycin for longevity

Sirolimus has no FDA-approved indication for aging, longevity or healthspan; the labeled uses are kidney transplant rejection prophylaxis in patients aged 13 and older and lymphangioleiomyomatosis [1]. Compounded rapamycin is not FDA-approved, and FDA does not verify the safety, effectiveness or quality of compounded drugs before they are marketed [8].

The PEARL trial randomized healthy adults with normative aging to placebo, 5 mg or 10 mg of compounded rapamycin once weekly for 48 weeks, double-blind and placebo-controlled. Adverse and serious adverse events were similar across all groups and blood biomarkers stayed within normal ranges. Visceral adiposity, the primary outcome, did not change (p=0.942). Lean tissue mass and self-reported pain improved in women taking 10 mg, and emotional well-being and general health improved in those taking 5 mg. The authors concluded that low-dose intermittent rapamycin was relatively safe over 48 weeks and that efficacy was not established [5].

An earlier pilot randomized 25 generally healthy adults aged 70 to 95 to rapamycin 1 mg daily or placebo, with 11 and 14 completing at least 8 weeks. Reported side effects in the rapamycin group were facial rash in one, stomatitis in one and gastrointestinal issues in two, and the rapamycin group had statistically significant decreases in hemoglobin, hematocrit, red cell count, RDW, MCV and MCH [9].