Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied HYFTOR ® (sirolimus topical gel) 0.2% is a colorless and transparent gel supplied as 10 g in aluminum tubes (NDC 73683-101-10). Each gram contains 2 mg of sirolimus. Storage and Handling Store refrigerated at 2° to 8°C (36° to 46°F). Protect from light.; PRINCIPAL DISPLAY PANEL - 10 g Tube Carton NDC 73683-101-10 HYFTOR ® (sirolimus topical gel) 0.2% Nobel pharma For topical use only | Keep refrigerated | 10 g tube | Rx Only Dispense enclosed Patient Information to patient. PRINCIPAL DISPLAY PANEL - 10 g Tube Carton
- 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied HYFTOR ® (sirolimus topical gel) 0.2% is a colorless and transparent gel supplied as 10 g in aluminum tubes (NDC 73683-101-10). Each gram contains 2 mg of sirolimus. Storage and Handling Store refrigerated at 2° to 8°C (36° to 46°F). Protect from light.
- PRINCIPAL DISPLAY PANEL - 10 g Tube Carton NDC 73683-101-10 HYFTOR ® (sirolimus topical gel) 0.2% Nobel pharma For topical use only | Keep refrigerated | 10 g tube | Rx Only Dispense enclosed Patient Information to patient. PRINCIPAL DISPLAY PANEL - 10 g Tube Carton
Overview
HYFTOR ® (sirolimus topical gel) 0.2% is an mTOR inhibitor immunosuppressant for topical use. Each gram contains 2 mg of sirolimus, which is solubilized in a gel consisting of alcohol 51%, Carbomer 940, purified water, and trolamine. Chemically, sirolimus is designated as (3 S ,6 R ,7 E ,9 R ,10 R ,12 R ,14 S ,15 E ,17 E ,19 E ,21 S ,23 S ,26 R ,27 R ,34a S )-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-[(1 R )-2-[(1 S ,3 R ,4 R )-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3 H -pyrido[2,1- c ][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4 H ,6 H ,31 H )-pentone. It has the following structural formula: Sirolimus is a white to off-white powder and is insoluble in water, but freely soluble in chloroform, acetone and acetonitrile. Sirolimus has a molecular formula of C 51 H 79 NO 13 and a molecular weight of 914.19. Chemical Structure
Indications & Usage
HYFTOR is indicated for the treatment of facial angiofibroma associated with tuberous sclerosis in adults and pediatric patients 6 years of age and older. HYFTOR is an mTOR inhibitor immunosuppressant indicated for the treatment of facial angiofibroma associated with tuberous sclerosis in adults and pediatric patients 6 years of age and older. ( 1 )
Dosage & Administration
Complete all age-appropriate vaccinations as recommended by current immunization guidelines prior to HYFTOR initiation [see Warning and Precautions (5.6) ] . Apply HYFTOR to the skin of the face affected with angiofibroma twice daily in the morning and at bedtime. The maximum recommended daily dosage is: 600 mg (2 cm) for pediatric patients 6 to 11 years of age 800 mg (2.5 cm) for adults and pediatric patients 12 years of age and older If symptoms do not improve within 12 weeks of treatment, reevaluate the need for continuing HYFTOR. Do not use HYFTOR with occlusive dressings. For topical use only. Not for oral, ophthalmic, or intravaginal use. Complete all age-appropriate vaccinations as recommended by current immunization guidelines prior to HYFTOR initiation. ( 2 ) Apply to the skin of the face affected with angiofibroma twice daily. ( 2 ) The maximum daily dosage is: 600 mg (2 cm) for patients 6 to 11 years of age. ( 2 ) 800 mg (2.5 cm) for patients 12 years of age and older. ( 2 ) Do not use with occlusive dressings. ( 2 ) For topical use only. Not for oral, ophthalmic, or intravaginal use. ( 2 )
Warnings & Precautions
Hypersensitivity Reactions : Oral sirolimus has been associated with hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis. Discontinue HYFTOR immediately if symptoms of hypersensitivity occur. ( 5.1 ) Serious Infection : Serious infections, including opportunistic infections and latent viral infections, such as progressive multifocal leukoencephalopathy, have been reported with oral sirolimus. Discontinue HYFTOR immediately if symptoms of infection occur. ( 5.2 ) Malignancy : Oral sirolimus has been associated with malignancy, including lymphoma and skin cancer. Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using HYFTOR. ( 5.3 ) Hyperlipidemia : Oral sirolimus has been associated with increased serum cholesterol and triglycerides requiring treatment. Monitor for hyperlipidemia during treatment. ( 5.4 ) Interstitial Lung Disease (ILD)/Non-infectious Pneumonitis : Oral sirolimus has been associated with ILD, sometimes fatal. Discontinue HYFTOR if ILD symptoms occur. ( 5.5 ) Immunizations: During treatment with HYFTOR, vaccinations may be less effective. Avoid use of live vaccines during treatment with HYFTOR. ( 5.6 ) Embryo-Fetal Toxicity : Based on animal studies, HYFTOR can cause fetal harm. Use of effective contraception is recommended for females of reproductive potential prior to and throughout treatment, and for 12 weeks after final dose of HYFTOR. ( 5.7 , 8.1 , 8.3 ) Male Infertility : Oral sirolimus has been associated with azoospermia and oligospermia. Advise males that HYFTOR may impair fertility. ( 5.8 , 8.3 , 13.1 ) 5.1 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 HYFTOR 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 HYFTOR immediately if symptoms of hypersensitivity occur. 5.2 Serious Infection 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 HYFTOR immediately if symptoms of infection occur. 5.3 Malignancy 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 HYFTOR. If patients need to be outdoors while using HYFTOR, they should wear protective clothing and discuss other sun protection measures with their physician. 5.4 Hyperlipidemia Increased serum cholesterol and triglycerides requiring treatment have been observed with oral administration of sirolimus. Monitor for hyperlipidemia during treatment with HYFTOR. 5.5 Interstitial Lung Disease/Non-Infectious Pneumonitis Cases of interstitial lung disease [ILD] (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 ILD has resolved upon discontinuation or dosage reduction of oral sirolimus. Discontinue HYFTOR immediately if symptoms of ILD occur. 5.6 Immunizations During treatment with HYFTOR, vaccinations may be less effective. Complete all age-appropriate vaccinations as recommended by current immunization guidelines prior to initiating treatment with HYFTOR. The use of live vaccines should be avoided during treatment with HYFTOR. 5.7 Embryo-Fetal Toxicity 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. HYFTOR 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 HYFTOR [see Use in Specific Populations (8.1 , 8.3) , Clinical Pharmacology (12.1 , 12.3) ]. 5.8 Male Infertility Azoospermia or oligospermia has been observed after oral administration of sirolimus [see Use in Specific Populations (8.3) , Nonclinical Toxicology (13.1) ]. Sirolimus is an anti-proliferative drug and affects rapidly dividing cells like the germ cells. Advise males that HYFTOR may impair fertility.
Contraindications
HYFTOR is contraindicated in patients with a history of hypersensitivity to sirolimus or any other component of HYFTOR. Reactions to sirolimus have included anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis [see Warning and Precautions (5.1) ] . History of hypersensitivity to sirolimus or any other component of HYFTOR. ( 4 )
Adverse Reactions
Most common adverse reactions (≥1%) are dry skin, application site irritation, pruritus, acne, acneiform dermatitis, ocular hyperemia, skin hemorrhage, and skin irritation. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Nobelpharma America, LLC at 1 (877) 375-0825 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In a randomized, double-blind, vehicle-controlled trial, subjects aged 6 years and older with facial angiofibroma associated with tuberous sclerosis applied HYFTOR twice daily for 12 weeks. A total of 30 subjects were treated with HYFTOR and 32 with the vehicle. The majority of the subjects were female (54.8%). A total of 40.3% were less than 18 years of age. The most common adverse reactions reported by ≥1% of subjects treated with HYFTOR and more frequently than in subjects treated with vehicle are presented in Table 1. Adverse reactions occurred with similar frequency in pediatric subjects 6 years of age and older. Table 1: Adverse Reactions in ≥1% of Subjects Aged 6 Years and Older with Facial Angiofibroma Associated with Tuberous Sclerosis Through Week 12 Preferred Term HYFTOR N = 30 Vehicle N = 32 Dry skin Dry skin includes dry skin and asteatosis 12 (40%) 4 (13%) Application site irritation 11 (37%) 9 (28%) Pruritus 5 (17%) 4 (13%) Acne 2 (7%) 0 (0%) Acneiform dermatitis 1 (3%) 0 (0%) Ocular hyperemia 1 (3%) 0 (0%) Skin hemorrhage 1 (3%) 0 (0%) Skin irritation 1 (3%) 0 (0%) In a 104-week, open-label safety trial, the most common adverse reactions associated with HYFTOR application were application site irritation (31%), dry skin (28%), acne (20%), pruritus (9%), eye irritation (9%), erythema (7%), acneiform dermatitis (6%), contact dermatitis (5%), solar dermatitis (1%), and photosensitivity reaction (1%). Adverse reactions occurred with similar frequency in adult and pediatric subjects 6 years of age and older.
Drug Interactions
CYP3A4 Inhibitors: During concomitant use of HYFTOR with CYP3A4 inhibitors, monitor for adverse reactions of HYFTOR. ( 7.1 ) Substrates and Inhibitors of CYP3A : During concomitant use of HYFTOR with drugs that are both substrates and inhibitors of CYP3A, monitor for adverse reactions of the CYP3A substrate and inhibitor. ( 7.2 ) 7.1 Effects of Other Drugs on HYFTOR Table 2 presents clinically significant drug interactions involving drugs that affect HYFTOR. Table 2: Effects of CYP3A4 Inhibitors on HYFTOR Clinical Impact Concomitant use of HYFTOR with inhibitors of CYP3A4 has the potential to increase the systemic exposure of sirolimus and increase the risk of HYFTOR adverse reactions. Intervention Monitor for adverse reactions of HYFTOR. 7.2 Effects of HYFTOR on Other Drugs Systemic exposure of drugs that are both substrates and inhibitors of CYP3A could be increased with coadministration with HYFTOR. Monitor for adverse reactions of such co-administered drugs.
Storage & Handling
Storage and Handling Store refrigerated at 2° to 8°C (36° to 46°F). Protect from light.
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