AHFS Class:

• Immunomodulatory Agents 84:06.28

Generic Name(s):

• Sirolimus

Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, is an immunosuppressive agent.1

Facial Angiofibroma

Sirolimus 0.2% gel is used topically for the treatment of facial angiofibroma associated with tuberous sclerosis in adults and pediatric patients ≥6 years of age.1 Sirolimus has been designated an orphan drug by FDA for this use.4

Clinical Experience

Safety and efficacy of sirolimus gel for the treatment of facial angiofibroma associated with tuberous sclerosis were established in a single, randomized, double-blind, vehicle-controlled, multi-center, phase 3 trial conducted in Japan.1,2 The study included 62 adults and pediatric patients ≥6 years of age with 3 or more angiofibromas (≥2 mm in diameter with redness) on the face; 40% of the patients were between 6 and <18 years of age.1,2 Patients applied either sirolimus topical gel or placebo vehicle twice daily for 12 weeks to the skin of their face affected with angiofibroma.1,2

The efficacy was assessed by the investigator based on the composite improvement from baseline in size and color (redness) of facial angiofibroma, using baseline photographs as reference.1,2 An assessment of “improved” was defined as at least a 50% reduction in the size and a 2-level reduction in redness, and an assessment of “markedly improved” was defined as at least a 75% reduction in the size and a 3-level reduction in redness.1,2

At 12 weeks, the proportion of patients assessed by the investigator as improved or markedly improved in facial angiofibroma was 23% in patients treated with sirolimus compared with 6% of those treated with vehicle; although this difference was not statistically significant, the result was considered to be clinically meaningful.1,7

A long-term, uncontrolled, open label extension study was conducted to further evaluate safety and efficacy of sirolimus gel for the treatment of adults and pediatric patients ≥3 years of age† with a skin lesion associated with tuberous sclerosis, including angiofibromas; 62 patients had completed treatment in the previous phase 3 randomized trial.3 Patients applied sirolimus gel twice daily to the skin of the affected area of their face.3 The primary objective of the study was to evaluate safety up to 136 weeks and secondarily to evaluate efficacy over 52 weeks.3 Sirolimus gel, when applied topically for ≥104 weeks, was well tolerated by patients with tuberous sclerosis complex, including those with severe facial skin lesions.3 The response to sirolimus continued to increase over the 52-week evaluation period, improving the size and color of severe facial angiofibromas.3

General

Pretreatment Screening

• Complete any necessary age-appropriate immunizations in accordance with current immunization guidelines prior to initiation of therapy.1

Patient Monitoring

• Monitor for serious infections, including opportunistic infections.1
• Examine patients for skin changes periodically.1
• Perform routine laboratory monitoring of lipids.1
• Monitor for signs and symptoms of interstitial lung disease (ILD).1
• Monitor for serious hypersensitivity reactions.1

Administration

Sirolimus is applied topically to the skin as a gel.1 The topical gel is for external use only and not for oral, ophthalmic, or intravaginal use. 1

The safety of sirolimus topical gel under occlusion, which may promote systemic exposure, has not been evaluated.1 Do not use sirolimus gel with occlusive dressings.1

Hands should be washed prior to and following application of the cream.1

Sirolimus topical gel should be refrigerated at 2-8°C.1 Refrigerate immediately after application.6 Protect from light.1

Dosage

Adult Dosage

Facial Angiofibroma

Apply sirolimus topical gel to the skin of the face affected with angiofibroma twice daily, in the morning and at bedtime.1 The maximum recommended daily dosage in adults is 800 mg (2.5 cm).1

Pediatric Dosage

Pediatric Patients (6 Years of Age)

Apply sirolimus topical gel to the skin of the face affected with angiofibroma twice daily, in the morning and at bedtime.1 The maximum recommended daily dosage is 600 mg (2 cm) for pediatric patients 6-11 years of age and 800 mg (2.5 cm) for pediatric patients ≥12 years of age.1

Special Populations

The manufacturer makes no special population dosage recommendations for sirolimus gel.1

Contraindications

• History of hypersensitivity to sirolimus or any ingredient in the formulation.1

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis have been associated with oral administration of sirolimus.1 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.1 Elevated sirolimus levels (with or without concomitant ACE inhibitors) may also potentiate angioedema.1 Discontinue sirolimus gel immediately if symptoms of hypersensitivity occur.1

Infectious Complications

Serious infections, including opportunistic infections, have been reported after oral administration of sirolimus.1 Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal have been reported in patients treated with oral sirolimus.1 Discontinue sirolimus gel immediately if symptoms of infection occur.1

Carcinogenicity

Lymphoma and other malignancies, particularly of the skin, have been observed after oral administration of sirolimus.1 Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using sirolimus topical gel.1 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.1

Hyperlipidemia

Increased serum cholesterol and triglycerides requiring treatment have been observed with oral administration of sirolimus.1 Monitor for hyperlipidemia during treatment with sirolimus topical gel.1

Interstitial Lung Disease/Noninfectious Pneumonitis

Cases of interstitial lung disease (including pneumonitis, bronchiolitis obliterans organizing pneumonia, and pulmonary fibrosis), some fatal, with no identified infectious etiology have occurred in patients receiving oral sirolimus.1 In some cases, the interstitial lung disease has resolved upon discontinuation or dosage reduction.1 Discontinue sirolimus topical gel immediately if symptoms of interstitial lung disease occur.1

Immunizations

During treatment with sirolimus topical gel, vaccinations may be less effective.1 Complete all age-appropriate vaccinations as recommended by current immunization guidelines prior to initiating treatment.1 Avoid use of live vaccines during treatment.1

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.1 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.1 Sirolimus topical gel is systemically absorbed after topical administration and may result in fetal exposure.1

Impairment of Male Fertility

Azoospermia or oligospermia has been observed after oral administration of sirolimus.1 Sirolimus is an anti-proliferative drug and affects rapidly dividing cells like germ cells.1 Advise males that sirolimus topical gel may impair fertility. 1

Specific Populations

Pregnancy

Based on animal studies and mechanism of action, oral sirolimus can cause fetal harm when administered to a pregnant woman.1 Sirolimus topical gel is systemically absorbed after topical administration and may result in fetal exposure.1 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.1

Animal reproduction studies have not been conducted with sirolimus topical gel.1 In an animal reproduction study with oral sirolimus, embryolethality occurred when sirolimus was administered orally to pregnant rats during the period of organogenesis.1 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 gel.1

Lactation

There are no available data on the presence of sirolimus in human milk; it is not known whether the drug has any effects on the breast-fed infant or on milk production.1 After oral administration, sirolimus was present in the milk of lactating rats.1 Because of the potential for serious adverse reactions in the breast-fed infant, the manufacturer states that breast-feeding is not recommended during treatment with sirolimus gel.1

Females and Males of Reproductive Potential

Females of reproductive potential should avoid becoming pregnant and should use an effective contraceptive method during treatment with sirolimus gel.1 Effective contraception should be initiated before sirolimus therapy and used throughout treatment and for 12 weeks after the final dose.1

Based on clinical findings and findings in animal studies, male and female fertility may be compromised by sirolimus.1 Ovarian cysts and menstrual disorders (including amenorrhea and menorrhagia) have been reported in females receiving oral sirolimus.1 Azoospermia has been reported in males receiving oral sirolimus and has been reversible upon discontinuance of the drug in most cases.1

Pediatric Use

The safety and effectiveness of sirolimus topical gel have been established in pediatric patients ≥6 years of age for the treatment of facial angiofibroma associated with tuberous sclerosis.1 Use of sirolimus 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.1,3 A total of 13 pediatric patients 6 to 17 years of age received sirolimus gel in the phase 3 clinical trial along with 48 pediatric patients 3 to 17 years of age in the 104-week open label safety trial.1,3 Adverse reactions occurred with similar frequency in adult and pediatric subjects.1

The safety and effectiveness of sirolimus topical gel for the topical treatment of facial angiofibroma associated with tuberous sclerosis have not been established in pediatric patients <6 years of age.1

Geriatric Use

Clinical studies of sirolimus topical gel did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently from younger patients.1 Other reported clinical experience has not identified differences in responses between the elderly and younger patients.1

Common Adverse Effects

Most common adverse reactions (≥1%) with sirolimus gel in adults and pediatric patients ≥6 years of age are dry skin, application site irritation, pruritus, acne, acneiform dermatitis, ocular hyperemia, skin hemorrhage, and skin irritation.1

Drug interaction studies with sirolimus gel have not been conducted.1 Sirolimus is a known substrate for cytochrome P-450 (CYP) isoenzyme 3A4 (CYP3A4) and P-glycoprotein (P-gp).1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Inhibitors of CYP3A4 and P-gp may increase sirolimus concentrations.1 During concomitant use of sirolimus gel with CYP3A4 inhibitors, monitor patients for adverse reactions of sirolimus.1

Systemic exposure of drugs that are both substrates and inhibitors of CYP3A could be increased with concomitant administration with sirolimus topical gel.1 Monitor for adverse reactions of such coadministered drugs.1

Description

The precise mechanism of action of sirolimus in the treatment of angiofibroma associated with tuberous sclerosis is uncertain.1 Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder caused by TSC1 or TSC2 mutations, which lead to the constitutive activation of mammalian target of rapamycin (mTOR).1,2 Sirolimus inhibits mTOR activation.1

Following 12 weeks of treatment with sirolimus topical gel in adult and pediatric subjects ≥6 years of age, sirolimus blood concentrations ranged from undetectable to 0.50 ng/mL after multiple doses.1 There was 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. 1

Sirolimus is a substrate for cytochrome P-450 (CYP) isoenzyme 3A4 and P-glycoprotein and is extensively metabolized in the liver by O -demethylation and/or hydroxylation.1 While 7 major metabolites of sirolimus have been identified, sirolimus is the principal species in whole blood and is responsible for greater than 90% of immunosuppressive activity.1

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.1
• 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).1 Advise patients to discontinue sirolimus topical gel immediately and seek medical attention if symptoms occur.1
• Sirolimus may increase risk of skin cancer.1 Advise patients of the importance of avoiding sunlight or other UV light by wearing protective clothing and sunglasses and using broad spectrum sunscreen with a high protection factor.1
• Inform patients that oral sirolimus has been associated with increased serum cholesterol and triglycerides requiring treatment and that periodic laboratory monitoring may be needed.1
• Inform patients that oral sirolimus has been associated with interstitial lung disease (ILD), sometimes fatal, with no identified infectious etiology.1 Advise patients to discontinue sirolimus topical gel immediately and to seek medical attention if symptoms (e.g., shortness of breath) occur.1
• Inform patients that during treatment with sirolimus topical gel, vaccinations may be less effective.1 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.1
• Sirolimus topical gel may cause fetal harm if used during pregnancy.1 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.1 Advise pregnant females of the potential risk to a fetus.1
• Advise lactating females that breast-feeding is not recommended during treatment with sirolimus topical gel.1
• Inform male and female patients that sirolimus topical gel may impair fertility.1
• Advise patients to inform their clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1
• Inform patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Nobelpharma America, LLC. HYFTOR^® (sirolimus) TOPICAL prescribing information. 2022 Mar. [Web]

2. Wataya-Kaneda M, Ohno Y, Fujita Y, et al.. Sirolimus Gel Treatment vs Placebo for Facial Angiofibromas in Patients With Tuberous Sclerosis Complex: A Randomized Clinical Trial.. JAMA Dermatol. . 2018; 154:781-88.

3. Wataya-Kaneda M, Nagai H, Ohno Y, et al. Safety and Efficacy of the Sirolimus Gel for TSC Patients With Facial Skin Lesions in a Long-Term, Open-Label, Extension, Uncontrolled Clinical Trial. Dermatol Ther. 2020; 10: 635-50.

4. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Rockville, MD. From FDA website. Accessed 2023 Jan 20.

5. Nobelpharma. Nobelpharma connect^®. From Hyfta^® website. Accessed 2023 Jan 25. [Web]

6. Nobelpharma. Personal communication. February 1, 2023.

7. Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 213478Orig1s000: Multi-discipline review. From FDA website. [Web]