Sirolimus (Monograph)

Brand name: Hyftor
Drug class: Skin and Mucous Membrane Agents, Miscellaneous
Chemical name: (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]propan-2-yl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone
Molecular formula: C₅₁H₇₉NO₁₃
CAS number: 53123-88-9

Medically reviewed by Drugs.com on May 5, 2022. Written by ASHP.

Introduction

Sirolimus topical gel is a skin or mucous membrane agent.

Uses for Sirolimus

Sirolimus topical gel has the following uses:

Sirolimus topical gel is indicated for the treatment of facial angiofibroma associated with tuberous sclerosis in adults and children 6 years of age and older.

Sirolimus Dosage and Administration

General

Sirolimus topical gel is available in the following dosage form(s) and strength(s):

• Topical: sirolimus topical gel 0.2% (2 mg of sirolimus per gram).

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Pediatric Patients

Dosage and Administration

• For topical use only in children ≥6 years of age. Not for oral, ophthalmic, or intravaginal use.

• Sirolimus topical gel should be applied as a thin layer to the skin of the face affected with angiofibroma twice daily, in the morning and at bedtime.

• The minimum amount should be rubbed in gently and completely to control signs and symptoms of angiofibroma.

• Maximum daily dosage in patients 6 to 11 years of age: 600 mg (2 cm).

• Maximum daily dosage in patients ≥12 years of age: 800 mg (2.5 cm).

• Application should be limited to areas of involvement with angiofibromas.

• The safety of sirolimus topical gel under occlusion, which may promote systemic exposure, has not been evaluated. Do not use with occlusive dressings.

Adults

Dosage and Administration

• Sirolimus topical gel should be applied as a thin layer to the affected skin with angiofibroma twice daily

• For topical use only. Not for oral, ophthalmic, or intravaginal use.

• Sirolimus topical gel should be applied as a thin layer to the skin of the face affected with angiofibroma twice daily, in the morning and at bedtime.

• The minimum amount should be rubbed in gently and completely to control signs and symptoms of angiofibroma.

• Maximum daily dosage in adults: 800 mg (2.5 cm).

• Application should be limited to areas of involvement with angiofibromas.

• The safety of sirolimus topical gel under occlusion, which may promote systemic exposure, has not been evaluated. Do not use with occlusive dressings.

Cautions for Sirolimus

Contraindications

• Patients with a history of hypersensitivity to sirolimus or any other component of the gel.

Warnings/Precautions

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis have been associated with the oral administration of sirolimus. The concomitant use of sirolimus topical gel with other drugs known to cause angioedema, such as angiotensin-converting enzyme (ACE) inhibitors, may increase the risk of developing angioedema. Elevated sirolimus levels (with or without concomitant ACE inhibitors) may also potentiate angioedema. Discontinue sirolimus topical gel immediately if symptoms of hypersensitivity occur.

Infectious Complications

Serious infections, including opportunistic infections, have been reported after oral administration of sirolimus. Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal have been reported in patients treated with oral sirolimus. Discontinue sirolimus topical gel immediately if symptoms of infection occur.

Carcinogenicity

Lymphoma and other malignancies, particularly of the skin, have been observed after oral administration of sirolimus. Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using sirolimus topical gel. If patients need to be outdoors while using sirolimus topical gel, they should wear protective clothing and discuss other sun protection measures with their physician.

Hyperlipidemia

Increased serum cholesterol and triglycerides requiring treatment have been observed with oral administration of sirolimus. Monitor for hyperlipidemia during treatment with sirolimus topical gel.

Interstitial Lung Disease/non-infectious Pneumonitis

Cases of interstitial lung disease (including pneumonitis, bronchiolitis obliterans organizing pneumonia [BOOP], and pulmonary fibrosis), some fatal, with no identified infectious etiology have occurred in patients receiving oral sirolimus. In some cases, the interstitial lung disease has resolved upon discontinuation or dosage reduction of oral sirolimus. Discontinue sirolimus topical gel immediately if symptoms of interstitial lung disease occur.

Immunocompromised Patients

During treatment with sirolimus topical gel, vaccinations may be less effective. Complete all age-appropriate vaccinations as recommended by current immunization guidelines prior to initiating treatment with sirolimus topical gel. The use of live vaccines should be avoided during treatment with sirolimus topical gel.

Fetal/Neonatal Morbidity and Mortality

Based on animal studies and the mechanism of action, oral sirolimus can cause fetal harm when administered to a pregnant woman. In animal studies, oral sirolimus caused embryo-fetal toxicity when administered during the period of organogenesis at maternal exposures that were equal to or less than human exposures at the recommended lowest starting dose. Sirolimus topical gel is systemically absorbed after topical administration and may result in fetal exposure. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to avoid becoming pregnant. They should use effective contraception prior to, throughout treatment and for 12 weeks after the final dose of sirolimus topical gel

Impairment of Fertility

Azoospermia or oligospermia has been observed after oral administration of sirolimus Sirolimus is an anti-proliferative drug and affects rapidly dividing cells like the germ cells. Advise males that sirolimus topical gel may impair fertility.

Specific Populations

Pregnancy

Sirolimus topical gel is not absorbed systemically following topical administration, and maternal use is not expected to result in fetal exposure of the drug.

Based on animal studies and mechanism of action, oral sirolimus can cause fetal harm when administered to a pregnant woman. Sirolimus topical gel is systemically absorbed after topical administration and may result in fetal exposure. The available data from case reports on sirolimus topical gel use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with sirolimus topical gel. In an animal reproduction study, oral administration of 0.5 mg/kg per day sirolimus caused embryo-fetal lethality in pregnant rats when administered during the period of organogenesis. The available data do not allow the calculation of relevant comparisons between the systemic exposure of sirolimus observed in animal studies to the systemic exposure that would be expected in humans after topical use of sirolimus topical gel.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the US general population, the estimate background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Lactation

There are no available data on the presence of sirolimus in human milk, the effects on the breast-fed infant, or the effects on milk production. After oral administration, sirolimus was present in the milk of lactating rats. Because of the potential for serious adverse reactions in the breast-fed infant, breast-feeding is not recommended during treatment with sirolimus topical gel.

Females and Males of Reproductive Potential

Based on animal studies with oral sirolimus, sirolimus topical gel may cause fetal harm when administered to pregnant women. Females of reproductive potential are recommended to avoid becoming pregnant and to use an effective contraceptive method. Effective contraception should be initiated before sirolimus topical gel therapy and used throughout treatment and for 12 weeks after the final dose of sirolimus topical gel.

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

Pediatric Use

The safety and effectiveness of sirolimus topical gel have been established in pediatric patients aged 6 years and older for the topical treatment of facial angiofibroma associated with tuberous sclerosis. Use of sirolimus topical gel in this age group is supported by data from a randomized, vehicle-controlled, double-blind 12-week trial along with additional efficacy and long-term safety data from a 104-week open label safety trial. A total of 13 pediatric subjects aged 6 years to 17 years received sirolimus topical gel in the phase 3 clinical trial along with 48 pediatric subjects aged 3 years to 17 years in the 104-week open label safety trial. Adverse reactions occurred with similar frequency in adult and pediatric subjects.

The safety and effectiveness of sirolimus topical gel for this indication have not been established in pediatric patients less than 6 years of age.

Geriatric Use

Clinical studies of sirolimus topical gel did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Common Adverse Effects

Most common adverse reactions (≥1%) are dry skin, application site irritation, pruritus, acne, acneiform dermatitis, ocular hyperemia, skin hemorrhage, and skin irritation.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• CYP3A4 Inhibitors: During concomitant use of sirolimus topical gel with CYP3A4 inhibitors, monitor for adverse reactions of sirolimus topical gel.

• Substrates and Inhibitors of CYP3A: During concomitant use of sirolimus topical gel with drugs that are both substrates and inhibitors of CYP3A, monitor for adverse reactions of the CYP3A substrate and inhibitor.

Actions

Mechanism of Action

The mechanism of action of sirolimus in the treatment of angiofibroma associated with tuberous sclerosis is unknown. Tuberous sclerosis is associated with genetic defects in TSC1 and TSC2 which leads to the constitutive activation of mammalian target of rapamycin (mTOR). Sirolimus inhibits mTOR activation.

Advice to Patients

• Inform patients that oral sirolimus has been associated with hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis. Advise patients to discontinue sirolimus topical gel immediately and seek medical attention if symptoms occur.

• Inform patients that oral sirolimus has been associated with increased susceptibility to infections, including opportunistic infections and latent viral infections, such as progressive multifocal leukoencephalopathy (PML). Advise patients to discontinue sirolimus topical gel immediately and seek medical attention if symptoms occur.

• Inform patients that oral sirolimus has been associated with malignancy, including lymphoma and skin cancer. Advise patients to minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment), and to use protective measures if exposure cannot be avoided, while using sirolimus topical gel.

• Inform patients that oral sirolimus has been associated with increased serum cholesterol and triglycerides requiring treatment and that periodic laboratory monitoring may be needed.

• Inform patients that oral sirolimus has been associated with interstitial lung disease [ILD] sometimes fatal, with no identified infectious etiology. Advise patients to discontinue sirolimus topical gel immediately and seek medical attention if symptoms (e.g. shortness of breath) occur.

• Inform patients that during treatment with sirolimus topical gel, vaccinations may be less effective. Instruct patients that vaccination with live vaccines should be avoided during treatment with sirolimus topical gel and to inform the healthcare practitioner that they are using sirolimus topical gel prior to a potential vaccination.

• Sirolimus topical gel may cause fetal harm if used during pregnancy. Advise female patients of reproductive potential to avoid becoming pregnant and to use effective contraception prior to, throughout treatment, and for 12 weeks after the final dose of sirolimus topical gel. Advise pregnant females of the potential risk to a fetus.

• Advise lactating females that breast-feeding is not recommended during treatment with sirolimus topical gel.

• Inform male and female patients that sirolimus topical gel may impair fertility.

• Inform patients that the skin being treated with sirolimus topical gel should not be covered with bandages, dressings or wraps.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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