sirolimus topical (Rx)

Brand and Other Names:Hyftor
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

topical gel

  • 0.2%

Facial Angiofibroma

Indicated for treatment of facial angiofibroma associated with tuberous sclerosis

Apply thin layer to affected skin BID (morning and bedtime)

Not to exceed 800 mg/day (2.5 cm/day)

If symptoms do not improve within 12 weeks, reevaluate need for continued treatment

Dosing Considerations

Complete all age-appropriate vaccinations as recommended by current immunization guidelines before initiating

Females of reproductive potential should avoid pregnancy; initiate effective contraceptive before starting treatment, during therapy, and for 12 weeks after the final dose

Dosage Forms & Strengths

topical gel

  • 0.2%

Facial Angiofibroma

Indicated for treatment of facial angiofibroma associated with tuberous sclerosis in children aged ≥6 years

<6 years: Safety and efficacy not established

≥6 years

  • Apply thin layer to affected skin BID (morning and bedtime)
  • 6-11 years: Not to exceed 600 mg/day (2 cm/day)
  • ≥12 years: Not to exceed 800 mg/day (2.5 cm/day)
  • If symptoms do not improve within 12 weeks, reevaluate need for continued treatment

Dosing Considerations

Complete all age-appropriate vaccinations as recommended by current immunization guidelines before initiating

Females of reproductive potential should avoid pregnancy; initiate effective contraceptive before starting treatment, during therapy, and for 12 weeks after the final dose

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Interactions

Interaction Checker

and sirolimus topical

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      Serious - Use Alternative

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                    Adverse Effects

                    >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%)

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                    Warnings

                    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
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                    Pregnancy & Lactation

                    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.

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                    Pharmacology

                    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%)
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                    Administration

                    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

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                    Patient Handout

                    A Patient Handout is not currently available for this monograph.
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                    Formulary

                    FormularyPatient Discounts

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                    The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

                    Tier Description
                    1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
                    2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
                    3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
                    4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                    5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                    6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                    NC NOT COVERED – Drugs that are not covered by the plan.
                    Code Definition
                    PA Prior Authorization
                    Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
                    QL Quantity Limits
                    Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
                    ST Step Therapy
                    Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
                    OR Other Restrictions
                    Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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                    Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.