HYFTOR

5 WARNINGS AND 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.

6 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.

<table width="60%"><caption>Table 1: Adverse Reactions in &#x2265;1% of Subjects Aged 6 Years and Older with Facial Angiofibroma Associated with Tuberous Sclerosis Through Week 12</caption><col width="50%" align="left" valign="middle"/><col width="25%" align="center" valign="middle"/><col width="25%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule">Preferred Term</th><th styleCode="Rrule">HYFTOR N = 30 </th><th styleCode="Rrule">Vehicle N = 32 </th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dry skin <footnote ID="K774">Dry skin includes dry skin and asteatosis</footnote></td><td styleCode="Rrule">12 (40%)</td><td styleCode="Rrule">4 (13%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Application site irritation</td><td styleCode="Rrule">11 (37%)</td><td styleCode="Rrule">9 (28%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pruritus</td><td styleCode="Rrule">5 (17%)</td><td styleCode="Rrule">4 (13%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Acne</td><td styleCode="Rrule">2 (7%)</td><td styleCode="Rrule">0 (0%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Acneiform dermatitis</td><td styleCode="Rrule">1 (3%)</td><td styleCode="Rrule">0 (0%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Ocular hyperemia</td><td styleCode="Rrule">1 (3%)</td><td styleCode="Rrule">0 (0%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Skin hemorrhage</td><td styleCode="Rrule">1 (3%)</td><td styleCode="Rrule">0 (0%)</td></tr><tr><td styleCode="Lrule Rrule">Skin irritation</td><td styleCode="Rrule">1 (3%)</td><td styleCode="Rrule">0 (0%)</td></tr></tbody></table>