sirolimus topical (Rx)

>10%

Dry skin (28-40%)

Skin irritation (31-37%)

Acne (7-20%)

Pruritus (9-17%)

1-10%

Eye irritation (9%)

Erythema (7%)

Acneiform dermatitis (3-6%)

Contact dermatitis (5%)

Ocular hyperemia (3%)

Skin hemorrhage (3%)

Skin irritation (3%)

Solar dermatitis (1%)

Photosensitivity (1%)

Contraindications

Hypersensitivity to sirolimus or any other component

Cautions

Lymphoma and other malignancies, particularly skin, observed after oral sirolimus; instruct patients to minimize or avoid exposure to natural or artificial sunlight, including wearing protective clothing and sunscreen

Cases of interstitial lung disease (ILD) including pneumonitis, bronchiolitis obliterans organizing pneumonia (BOOP), and pulmonary fibrosis, some fatal, with no identified infectious etiology, reported with oral sirolimus; in some cases, ILD resolved upon discontinuation or dosage reduction; discontinue therapy immediately if symptoms of ILD occur

Increased serum cholesterol and triglycerides, requiring treatment, observed with oral sirolimus; monitor for hyperlipidemia during treatment

Based on animal studies and mechanism of action, oral sirolimus can cause fetal harm when administered to pregnant females

May impair male fertility

Hypersensitivity reactions

• Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis have been associated with oral sirolimus
• Elevated sirolimus levels (with or without concomitant ACE inhibitors) may also potentiate angioedema
• Discontinue immediately if hypersensitivity symptoms occur

Serious infections

• Serious infections, including opportunistic infections, reported after oral sirolimus
• Progressive multifocal leukoencephalopathy (PML) reports, including cases of fatal PML
• Discontinue immediately if symptoms of infection occur

Drug interaction overview

• Drug interaction studies for sirolimus topical have not been conducted
• Sirolimus is a substrate of CYP3A4 and p-glycoprotine (P-gp)

• Immunizations

  • Complete all age-appropriate vaccinations as recommended by current immunization guidelines before initiating
  • Avoid use of live vaccines during treatment
  • Sirolimus may decrease vaccine efficacy

• CYP3A4 inhibitors

  • Monitor for sirolimus adverse effects
  • Coadministration of sirolimus with CYP3A4 inhibitors may increase sirolimus systemic exposure

• Drugs that are both substrates and inhibitors of CYP3A

  • Monitor
  • Systemic exposure of drugs that are both substrates and inhibitors of CYP3A may increase when coadministered with sirolimus

Pregnancy

Based on animal studies and mechanism of action, oral sirolimus can cause fetal harm when administered to pregnant females

Sirolimus topical is systemically absorbed and may result in fetal exposure

Available data from case reports on sirolimus topical use in pregnant females are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes

Animal studies

• Animal reproduction studies have not been conducted with sirolimus topical
• Oral sirolimus 0.5 mg/kg/day caused embryo-fetal lethality in pregnant rats when administered during organogenesis
• Available data do not allow calculation of relevant comparisons between systemic exposure of sirolimus observed in animal studies to systemic exposure that would be expected in humans after topical use

Contraception

• Based on animal studies with oral sirolimus, may cause fetal harm when administered to pregnant females
• Females of reproductive potential are recommended to avoid becoming pregnant
• Initiate effective contraceptive before starting therapy, during treatment, and for 12 weeks after the final dose

Infertility

• Based on clinical findings and findings in animal studies, male and female fertility may be compromised by sirolimus treatment
• Ovarian cysts and menstrual disorders (including amenorrhea and menorrhagia) reported in females with oral sirolimus
• Azoospermia reported in males with oral sirolimus; reversible upon discontinuation of sirolimus in most cases

Lactation

Data are not available on presence in human milk, effects on breastfed infants, or effects on milk production

After oral administration, sirolimus was present in the milk of lactating rats

Breastfeeding is not recommended during treatment

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Topical mammalian target of rapamycin (mTOR) inhibitor

A germline mutation of the TSC1 or TSC2 gene, leading to activation of mTOR pathway, accounts for the pathogenesis of TSC-associated angiofibroma

Sirolimus inhibits mTOR activation by inhibition of phosphatidylinositol-3-kinase (PI3K)-like serine/threonine protein kinase

Absorption

Blood concentrations

• Following 12 weeks of administration: Undetectable to 0.5 ng/mL
• Maximum concentration with period samples during 52-week trial: 3.27 ng/mL (adults); 1.8 ng/mL (pediatrics)

Distribution

No evidence based on blood concentrations that sirolimus accumulates systemically upon topical application in patients with tuberous sclerosis for periods of up to 1 year

Metabolism

Metabolism studies for sirolimus topical have not been conducted

Sirolimus is a substrate for both CYP3A4 and P-gp

Extensively metabolized after oral administration in intestinal wall and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen

Elimination

Excretion studies for sirolimus topical have not been conducted

Single oral dose

• Half-life: 62 hr (stable renal transplant recipients)
• Excretion: Feces (91%); urine (2.2%)

Topical Administration

For topical use only; not for oral, ophthalmic, or intravaginal use

Wash hands before and after application

Instruct patient on how to correctly measure dose

Apply thin layer to affected skin; gently and completely rub in minimum amount of gel

Limit application to areas of involvement with angiofibroma

Do not use with occlusive dressing; safety of gel under occlusion, which may promote systemic exposure, has not been evaluated

Storage

Refrigerate at 2-8ºC (36-46ºF)

Protect from light