Rapamycin (Sirolimus) Hair and Skin Changes: What Patients and Clinicians Need to Know

What skin reactions does the Rapamune label list?

Acne sits in the label's list of the most common adverse reactions from the lymphangioleiomyomatosis (LAM) study, where reactions occurring in 20% or more of patients include stomatitis, diarrhea, abdominal pain, nausea, nasopharyngitis, acne and others [1]. In the placebo-controlled kidney transplant study (Study 2), acne occurred in 22% of the 2 mg/day group, 22% of the 5 mg/day group and 19% of the placebo group; rash occurred in 10%, 20% and 6% [1]. Every patient in that study also received cyclosporine and corticosteroids [1].

A number like 22% describes one setting: kidney transplant recipients on cyclosporine and steroids at daily labeled doses. The label notes that reactions related to Rapamune were generally dependent on dose or concentration [1].

Acne-like eruptions, folliculitis and other skin findings

A systematic examination of skin, mucous membranes, nails and hair in 80 kidney transplant recipients on sirolimus-based therapy found at least one cutaneous adverse event in 79 of them (99%) [2]. Acne-like eruptions occurred in 46%, scalp folliculitis in 26%, hidradenitis suppurativa in 12%, chronic edema in 55%, angioedema in 15%, aphthous ulceration in 60% and chronic nail changes in 74% [2]. Twenty-five percent had a serious event, and six patients (7%) stopped sirolimus in the 3 months after the study because of skin events [2]. Seventy-four of the 80 were also taking mycophenolate mofetil and steroids, and mean sirolimus treatment duration was 18 months [2].

A 2005 case report described two kidney transplant recipients with severe follicular acneiform eruptions that resolved only after sirolimus was discontinued [3]. A case report shows an event is possible; it says nothing about how often it happens.

Does sirolimus cause hair loss?

Whether sirolimus causes hair loss is unclear. The 80-patient skin survey examined hair along with skin, mucosa and nails, but its abstract lists pilosebaceous, edematous, mucosal and nail findings without a hair-loss figure [2]. Alopecia does not appear among the reactions in the label's Study 2 table or its less-frequent lists for renal transplant, and it is not in the LAM list of reactions at 20% or more [1].

Most participants in the skin survey also took mycophenolate mofetil and steroids, making it difficult to isolate sirolimus's effects [2].

Wound healing and skin cancer risk

The label warns of impaired or delayed wound healing in patients receiving Rapamune, including lymphocele and wound dehiscence, and 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 [1]. It also states that patients with a body mass index greater than 30 kg/m2 may be at increased risk of abnormal wound healing based on published data [1].

Evidence from skin surgery is limited. A small retrospective review compared 26 transplant recipients taking sirolimus with 37 transplant recipients who were not: postoperative infection occurred in 19.2% versus 5.4% (p=0.11) and wound dehiscence in 7.7% versus 0% (p=0.17), neither difference statistically significant, and the authors noted the small sample and retrospective design [4].

The boxed warning says immunosuppression can increase susceptibility to infection and the possible development of lymphoma and other malignancies [1]. The label's warnings section adds that these malignancies occur particularly in the skin [1]. Among reactions reported in 3% to less than 20% of patients in the renal transplant study, the label lists melanoma, squamous cell carcinoma and basal cell carcinoma [1]. Hypersensitivity reactions including anaphylactic/anaphylactoid reactions, angioedema and exfoliative dermatitis have also been associated with Rapamune [1].

Mouth sores

Stomatitis is among the reactions reported in 20% or more of patients in the LAM study, and in 3% to less than 20% of kidney transplant patients [1]. In a small 2018 pilot of daily low-dose rapamycin in older adults, one participant in the rapamycin group reported stomatitis [5].

What do the low-dose weekly studies show for skin and hair?

The PEARL trial randomized healthy, normally aging adults to placebo, 5 mg or 10 mg of compounded rapamycin once weekly for 48 weeks; adverse and serious adverse events were similar across all groups [6]. The primary outcome, visceral adiposity, did not change (p=0.942) [6]. The abstract does not report hair or skin outcomes separately, so it cannot say whether weekly rapamycin thins hair, causes acne or changes skin aging [6]. The rapamycin in PEARL was compounded, and compounded drugs are not FDA-approved, with no FDA verification of safety, effectiveness or quality before marketing [7].

A 2018 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 [5]. Reported side effects in the rapamycin group were facial rash in one participant, stomatitis in one, and gastrointestinal issues in two [5]. Its endpoints were immunological, physical performance and cognitive measures, not skin or hair [5].

Is rapamycin approved for skin aging or hair growth?

No. The Rapamune label's approved uses are prevention of organ rejection in kidney transplant recipients aged 13 years and older and treatment of LAM [1]. There is no FDA-approved indication for aging, longevity or cosmetic skin improvement [1].

Which medicines matter for skin effects?

The label says angioedema has been associated with Rapamune, that other drugs known to cause angioedema, such as ACE inhibitors, may increase the risk, and that elevated sirolimus levels may also potentiate angioedema [1].

Sirolimus is a substrate of both CYP3A4 and P-glycoprotein, so its levels change with other drugs. The label says to avoid strong inhibitors such as ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin and clarithromycin, and strong inducers such as rifampin and rifabutin [1]. It says grapefruit juice must not be taken with Rapamune or used to dilute it [1]. Cannabidiol can raise sirolimus blood levels, and the label advises close monitoring and considering a dose reduction [1]. Cyclosporine increases sirolimus concentrations, and the label says to take Rapamune 4 hours after cyclosporine [1].