Hyftor

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)

5.1Hypersensitivity 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.

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.

Lactation: Breastfeeding not recommended. (8.2)

8.1Pregnancy Risk Summary

Based on animal studies and mechanism of action, oral sirolimus can cause fetal harm when administered to a pregnant woman. HYFTOR is systemically absorbed after topical administration and may result in fetal exposure. The available data from case reports on HYFTOR use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with HYFTOR. In an animal reproduction study, oral administration of 0.5 mg/kg/day sirolimus caused embryo-fetal lethality in pregnant rats when administered during the period of organogenesis (see Data). 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 HYFTOR. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In embryo-fetal development studies in rats, oral administration of sirolimus to pregnant rats during the period of organogenesis (gestation days 6 -15) induced embryo-fetal lethality at 0.5 mg/kg/day, reduced fetal body weight at 1.0 mg/kg/day and caused maternal toxicity at 2.0 mg/kg/day. No treatment related embryo-fetal developmental effects were observed at 0.1 mg/kg/day. In embryo-fetal development studies in rabbits, oral administration of sirolimus to pregnant rabbits during the period of organogenesis (gestation days 6 -18) induced maternal toxicity (decreased body weight) at 0.05 mg/kg/day, which was associated with embryo-fetal loss or early resorption. No treatment related developmental effects were observed at 0.025 mg/kg/day. In a pre- and postnatal development toxicity study, oral administration of sirolimus to pregnant rats during gestation and lactation (gestation day 6 through lactation day 20) increased the incidence of dead pups, resulting in reduced live litter size at 0.5 mg/kg/day. No treatment related developmental effects were observed at 0.1 mg/kg/day. Sirolimus did not cause maternal toxicity or affect developmental parameters in the surviving offspring (morphological development, motor activity, learning, or fertility assessment) at 0.5 mg/kg/day, the highest dose tested. 8.2 Lactation Risk Summary There are no available data on the presence of sirolimus in human milk, the effects on the breastfed infant, or the 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 breastfed infant, breastfeeding is not recommended during treatment with HYFTOR. 8.3 Females and Males of Reproductive Potential Contraception Based on animal studies with oral sirolimus, HYFTOR may cause fetal harm when administered to pregnant women. Females of reproductive potential are recommended to avoid becoming pregnant and to use an effective contraceptive method. Effective contraception should be initiated before HYFTOR therapy and used throughout treatment and for 12 weeks after the final dose of HYFTOR [see Warnings and Precautions (5.7), Use in Specific Populations (8.1)]. Infertility Based on clinical findings and findings in animal studies, male and female fertility may be compromised by the treatment with sirolimus [see Warnings and Precautions (5.8), Nonclinical Toxicology (13.1)]. Ovarian cysts and menstrual disorders (including amenorrhea and menorrhagia) have been reported in females with the use of oral sirolimus. Azoospermia has been reported in males with the use of oral sirolimus and have been reversible upon discontinuation of sirolimus in most cases. 8.4 Pediatric Use The safety and effectiveness of HYFTOR have been established in pediatric patients aged 6 years and older for the topical treatment of facial angiofibroma associated with tuberous sclerosis. Use of HYFTOR 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. A total of 13 pediatric subjects aged 6 years to 17 years received HYFTOR in the Phase 3 clinical trial along with 48 pediatric subjects aged 3 years to 17 years in the 104-week open label safety trial. Adverse reactions occurred with similar frequency in adult and pediatric subjects [see Adverse Reaction (6.1), Clinical Studies (14)]. The safety and effectiveness of HYFTOR for this indication have not been established in pediatric patients less than 6 years of age. 8.5 Geriatric Use Clinical studies of HYFTOR did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Risk Summary Based on animal studies and mechanism of action, oral sirolimus can cause fetal harm when administered to a pregnant woman. HYFTOR is systemically absorbed after topical administration and may result in fetal exposure. The available data from case reports on HYFTOR use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with HYFTOR. In an animal reproduction study, oral administration of 0.5 mg/kg/day sirolimus caused embryo-fetal lethality in pregnant rats when administered during the period of organogenesis (see Data). 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 HYFTOR. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In embryo-fetal development studies in rats, oral administration of sirolimus to pregnant rats during the period of organogenesis (gestation days 6 -15) induced embryo-fetal lethality at 0.5 mg/kg/day, reduced fetal body weight at 1.0 mg/kg/day and caused maternal toxicity at 2.0 mg/kg/day. No treatment related embryo-fetal developmental effects were observed at 0.1 mg/kg/day. In embryo-fetal development studies in rabbits, oral administration of sirolimus to pregnant rabbits during the period of organogenesis (gestation days 6 -18) induced maternal toxicity (decreased body weight) at 0.05 mg/kg/day, which was associated with embryo-fetal loss or early resorption. No treatment related developmental effects were observed at 0.025 mg/kg/day. In a pre- and postnatal development toxicity study, oral administration of sirolimus to pregnant rats during gestation and lactation (gestation day 6 through lactation day 20) increased the incidence of dead pups, resulting in reduced live litter size at 0.5 mg/kg/day. No treatment related developmental effects were observed at 0.1 mg/kg/day. Sirolimus did not cause maternal toxicity or affect developmental parameters in the surviving offspring (morphological development, motor activity, learning, or fertility assessment) at 0.5 mg/kg/day, the highest dose tested.