Hyftor Drug Information

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.

Complete all age-appropriate vaccinations as recommended by current immunization guidelines prior to HYFTOR initiation . 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. Apply to the skin of the face affected with angiofibroma twice daily.

The maximum daily dosage is: 600 mg (2 cm) for patients 6 to 11 years of age. 800 mg (2.5 cm) for patients 12 years of age and older. Do not use with occlusive dressings. For topical use only.

Not for oral, ophthalmic, or intravaginal use.

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.

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.

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.

Pregnancy 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.

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. The safety and effectiveness of HYFTOR for this indication have not been established in pediatric patients less than 6 years of age.

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 . History of hypersensitivity to sirolimus or any other component of HYFTOR.