Sirolimus (Topical) (Monograph)

Brand name: Hyftor
Drug class: Immunomodulatory Agents

Medically reviewed by Drugs.com on Nov 10, 2024. Written by ASHP.

Introduction

Mammalian target of rapamycin (mTOR) inhibitor immunosuppressive agent.

Uses for Sirolimus (Topical)

Facial Angiofibroma

Treatment of facial angiofibroma associated with tuberous sclerosis in adults and pediatric patients ≥6 years of age.

Designated an orphan drug by FDA for this use.

Sirolimus (Topical) Dosage and Administration

General

Pretreatment Screening

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

Patient Monitoring

• Monitor for serious infections, including opportunistic infections.

• Examine patients for skin changes periodically.

• Perform routine laboratory monitoring of lipids.

• Monitor for signs and symptoms of interstitial lung disease (ILD).

• Monitor for serious hypersensitivity reactions.

Administration

Topical Administration

Apply gel topically to the skin. For external use only and not for oral, ophthalmic, or intravaginal use.

Apply to affected areas of the skin twice daily in the morning and at bedtime.

Do not use with occlusive dressings.

Wash hands prior to and following application of the cream.

Dosage

Pediatric Patients

Facial Angiofibroma

Topical

Apply to the skin of the face affected with angiofibroma twice daily, in the morning and at bedtime. Maximum 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.

Adults

Facial Angiofibroma

Topical

Apply up to 800 mg (2.5 cm) to the skin of the face affected with angiofibroma twice daily, in the morning and at bedtime.

Prescribing Limits

Pediatric Patients

Facial Angiofibroma

Topical

Maximum 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.

Adults

Facial Angiofibroma

Topical

Maximum daily dosage is 800 mg (2.5 cm).

Special Populations

Manufacturer makes no special population dosage recommendations for sirolimus gel.

Cautions for Sirolimus (Topical)

Contraindications

• Hypersensitivity to sirolimus or any ingredient in the formulation.

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

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

Infectious Complications

Serious infections, including opportunistic infections, reported after administration of oral sirolimus.

Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal, reported in patients treated with oral sirolimus. Discontinue immediately if symptoms of infection occur.

Carcinogenicity

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

Hyperlipidemia

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

Interstitial Lung Disease/Noninfectious Pneumonitis

Cases of interstitial lung disease (including pneumonitis, bronchiolitis obliterans organizing pneumonia, and pulmonary fibrosis), some fatal, reported with oral sirolimus. In some cases, the condition resolved upon discontinuation or dosage reduction.

Discontinue sirolimus topical gel immediately if symptoms of interstitial lung disease occur.

Immunizations

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. Avoid use of live vaccines during treatment.

Fetal/Neonatal Morbidity and Mortality

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. (See Pregnancy under Cautions.)

Impairment of Male Fertility

Sirolimus gel may impair fertility in men. Azoospermia or oligospermia observed after oral sirolimus administration.

Specific Populations

Pregnancy

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.

Lactation

No available data exist on presence of sirolimus in human milk, effects on the breast-fed infant, or 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 gel.

Females and Males of Reproductive Potential

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.

Based on clinical findings and findings in animal studies, male and female fertility may be compromised by sirolimus.

Pediatric Use

Safety and efficacy not established in pediatric patients <6 years of age.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients.

Common Adverse Effects

Adverse reactions ≥1% in adult and pediatric patients ≥6 years of age: dry skin, application site irritation, pruritus, acne, acneiform dermatitis, ocular hyperemia, skin hemorrhage, and skin irritation.

Drug Interactions

Drug interaction studies not conducted.

Inhibitors of CYP3A4 or P-gp

Sirolimus is a known substrate for CYP3A4 and P-gp. Inhibitors of CYP3A4 and P-gp may increase sirolimus concentrations. During concomitant use of sirolimus topical gel with CYP3A4 inhibitors, monitor for adverse reactions of sirolimus topical gel.

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

Sirolimus (Topical) Pharmacokinetics

Absorption

Bioavailability

Following 12 weeks of treatment, blood concentrations ranged from undetectable to 0.50 ng/mL after multiple doses in adult and pediatric patients ≥6 years of age.

Distribution

Extent

No evidence of systemic accumulation following topical application for periods of up to 1 year.

Elimination

Metabolism

Substrate for CYP3A4 and P-glycoprotein and is extensively metabolized in the liver by O-demethylation and/or hydroxylation.

Stability

Storage

Topical

Gel

2–8°C. Refrigerate immediately after application. Protect from light.

Actions

• Precise mechanism of action uncertain.

• Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder caused by TSC1 or TSC2 mutations that lead 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.

• Sirolimus may increase risk of skin cancer. 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.

• 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 to 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.

• Advise patients to inform their clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Inform patients of other important precautionary information.

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.

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.

Sirolimus topical gel is available through a specialty pharmacy network. Clinicians may consult the Hyftor website at [Web] or call Nobelpharma Connect at 1-877-649-3867 for specific availability information.

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