Hyftor

DESCRIPTION

HYFTOR™ (sirolimustopical gel) 0.2% is an mTOR inhibitorimmunosuppressantfor topical use. Eachgramcontains 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 (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-4hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-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 C₅₁H₇₉NO₁₃and a molecular weight of 914.19.

INDICATIONS

HYFTOR is indicated for the treatment of facial angiofibroma associated with tuberous sclerosis in adults and pediatric patients 6 years of age and older.

DOSAGE AND ADMINISTRATION

• Complete all age-appropriate vaccinations as recommended by current immunization guidelines prior to HYFTOR initiation [see警告AND PRECAUTIONS].
• 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.

HOW SUPPLIED

Dosage Forms And Strengths

Topical Gel, 0.2%

Each gram contains 2 mg of sirolimus in a colorless and transparent gel in 10-gram tubes.

HYFTOR™ (sirolimus topical gel) 0.2%is a colorless and transparent gel supplied as 10 g in aluminum tubes (NDC73683-101-10). Each gram contains 2 mg of sirolimus.

Storage And Handling

Store refrigerated at 2° to 8°C (36° to 46°F). Protect from light.

Distributed by: Nobelpharma America, LLC 4520 East-West Highway, Suite 400, Bethesda, MD 20814. Revised Mar 2022.

副作用

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.

在一个随机、双盲、vehicle-controlledtrial, 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 skina	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%)
aDry skin includes dry skin and asteatosis

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

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.

警告

Included as part of the"PRECAUTIONS"Section

PRECAUTIONS

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions,angioedema, exfoliativedermatitis, and hypersensitivityvasculitishave been associated with the oral administration of sirolimus. The concomitant use of HYFTOR with other drugs known to cause angioedema, such asangiotensin-converting enzyme (ACE) inhibitors, may increase the risk of developing angioedema. Elevated sirolimus levels (with or without concomitantACE inhibitors) may also potentiate angioedema. Discontinue HYFTOR immediately if symptoms of hypersensitivity occur.

Serious Infection

Serious infections, including opportunistic infections, have been reported after oral administration of sirolimus. Cases of渐进多焦点的脑白质病(PML), sometimes fatal have been reported in patients treated with oral sirolimus. Discontinue HYFTOR immediately if symptoms of infection occur.

Malignancy

Lymphomaand 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.

Hyperlipidemia

Increased serumcholesterolandtriglyceridesrequiring treatment have been observed with oral administration of sirolimus. Monitor forhyperlipidemiaduring treatment with HYFTOR.

Interstitial Lung Disease/Non-Infectious Pneumonitis

Cases ofinterstitiallung disease [ILD] (including pneumonitis,bronchiolitisobliterans organizingpneumonia[BOOP], andpulmonary fibrosis), some fatal, with no identified infectiousetiologyhave 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.

Immunizations

During treatment with HYFTOR, vaccinations may be less effective. Complete all age-appropriate vaccinations as recommended by currentimmunizationguidelines prior to initiating treatment with HYFTOR. The use of livevaccinesshould be avoided during treatment with HYFTOR.

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 [seeUse In Specific Populations,CLINICAL PHARMACOLOGY].

Male Infertility

Azoospermiaoroligospermiahas been observed after oral administration of sirolimus [seeUse In Specific Populations,Nonclinical Toxicology]. Sirolimus is an anti-proliferativedrug and affects rapidly dividing cells like thegermcells. Advise males that HYFTOR may impair fertility.

Patient Counseling Information

建议病人阅读FDA-approved patient labeling (PATIENT INFORMATION).

Hypersensitivity

通知patients that oral sirolimus has been associated with hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis. Advise patients to discontinue HYFTOR immediately and seek medical attention if symptoms occur [see警告AND PRECAUTIONS].

Serious Infections

通知patients that oral sirolimus has been associated with increased susceptibility to infections, including opportunistic infections andlatentviral infections, such as progressivemultifocalleukoencephalopathy (PML). Advise patients to discontinue HYFTOR immediately and seek medical attention if symptoms occur [see警告AND PRECAUTIONS].

Malignancy

通知patients that oral sirolimus has been associated withmalignancy, including lymphoma andskin cancer. Advise patients to minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment), and to use protective measures if exposure cannot be avoided, while using HYFTOR [see警告AND PRECAUTIONS].

Hyperlipidemia

通知patients that oral sirolimus has been associated with increased serum cholesterol and triglycerides requiring treatment and that periodic laboratory monitoring may be needed [see警告AND PRECAUTIONS].

Interstitial Lung Disease

通知patients that oral sirolimus has been associated with interstitial lung disease [ILD] sometimes fatal, with no identified infectious etiology. Advise patients to discontinue HYFTOR immediately and seek medical attention if symptoms (e.g. shortness of breath) occur [see警告AND PRECAUTIONS].

Immunization

通知patients that during treatment with HYFTOR, vaccinations may be less effective. Instruct patients thatvaccinationwith live vaccines should be avoided during treatment with HYFTOR and to inform the healthcare practitioner that they are using HYFTOR prior to a potential vaccination [see警告AND PRECAUTIONS].

Pregnancy

HYFTOR may cause fetal harm if used during pregnancy. Advise female patients of reproductive potential to avoid becoming pregnant and to use effective contraception prior to, throughout treatment, and for 12 weeks after the final dose of HYFTOR. Advise pregnant women of the potential risk to a fetus [see警告AND PRECAUTIONS,Use In Specific Populations].

Lactation

Advise lactating women that breastfeeding is not recommended during treatment with HYFTOR [seeUse In Specific Populations].

Infertility

通知male and female patients that HYFTOR may impair fertility [see警告AND PRECAUTIONS,Use In Specific Populations,Nonclinical Toxicology].

Administration Information

通知patients that the skin being treated with HYFTOR should not be covered with bandages, dressings or wraps [seeDOSAGE AND ADMINISTRATION].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Oral carcinogenicity studies were conducted in mice and rats. In an oral carcinogenicity study conducted in female mice, sirolimus administered once daily for 86 weeks was associated with a statistically significant increase inmalignantlymphoma at all dose levels compared with control animals. In a second oral mouse carcinogenicity study, sirolimus-related hepatocellularadenomaandcarcinomawere induced in male mice. In an oral carcinogenicity study conducted in rats with sirolimus there were no significant findings.

Sirolimus was not genotoxic in thein vitrobacterial reverse mutation assay, the Chinese hamster ovary cell chromosomal aberration assay, the mouse lymphoma cell forward mutation assay, or thein vivomouse micronucleus assay.

Fertility was decreased in both male and female rats following oral administration of sirolimus 2.0 and 0.5 mg/kg, respectively. In male rats,atrophyof testes, epididymides,prostate, seminiferous tubules and/or reducedspermcounts were observed. In female rats, decreasedovarianand uterine weights and decreasedimplantationwere observed. Testicular tubular degeneration was also seen in a 4-week intravenous study of sirolimus in monkeys at 0.1 mg/kg.

Use In Specific Populations

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 (seeData). 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 ofbirth 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

在大鼠胚胎-胎仔发育的研究中,口服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 earlyresorption. 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.

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.

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警告AND PRECAUTIONS,Pregnancy].

Infertility

Based on clinical findings and findings in animal studies, male and female fertility may be compromised by the treatment with sirolimus [see警告AND PRECAUTIONS,Nonclinical Toxicology]. Ovariancystsand menstrual disorders (includingamenorrheaandmenorrhagia) 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.

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 withtuberous 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 [seeADVERSE REACTIONS,Clinical Studies].

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

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.

OVERDOSE

No Information Provided.

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警告AND PRECAUTIONS].

PATIENT INFORMATION

HYFTOR™
(hyfe tore)
(sirolimus topical gel)

Important: HYFTOR is for use on the skin only (topical use). Do not use HYFTOR in your mouth, eyes, or vagina.

What is HYFTOR?

HYFTOR is a prescription medicine that is used on the skin (topical) to treat adults and children 6 years of age and older with a type of noncancerous tumor called angiofibroma on your face caused by the genetic condition tuberoussclerosis.

It is not known if HYFTOR is safe and effective in children under 6 years of age.

Do not use HYFTOR ifyou are allergic to sirolimus or any of the other ingredients in HYFTOR. See the end of this leaflet for a complete list of ingredients in HYFTOR.

Before using HYFTOR, tell your healthcare provider about all of your medical conditions, including if you:

• have a skin infection at the treatment site
• have high cholesterol or high triglycerides (fat orlipids) in your blood
• are scheduled to receive an immunization (vaccine). You should avoid receiving live vaccines during treatment with HYFTOR. Vaccines may be less effective during treatment with HYFTOR.
• are pregnant or plan to become pregnant. HYFTOR may harm your unborn baby. You should not become pregnant during treatment with HYFTOR.
  • Females who are able to become pregnant should use effective birth control (contraception) before starting treatment with HYFTOR, during treatment, and for 12 weeks after your final dose of HYFTOR. Talk to your healthcare provider about types of birth control that you can use during this time.
• are breastfeeding or plan to breastfeed. It is not known if HYFTOR passes into your breast milk. You should not breastfeed during treatment with HYFTOR.

Tell your healthcare provider about all the medicines you take,including prescription and over-the-counter medicines, vitamins, and herbal supplements. Using HYFTOR with certain medicines may affect each other causing side effects.

How should I use HYFTOR?

• Use HYFTOR exactly as your healthcare provider tells you to use it.
• Before you use HYFTOR, your healthcare provider or pharmacist should show you how to correctly measure your dose.
• 之前洗手and after applying HYFTOR.
• Apply HYFTOR to the skin of the face affected with angiofibroma 2 times a day, in the morning and at bedtime.
• Do notcover, wrap, apply dressings, or bandage the skin area treated with HYFTOR.
• Tell your healthcare provider if the treated skin area does not improve within 12 weeks of treatment.

What should I avoid while using HYFTOR?

Limit your exposure to sunlight and ultraviolet light, such as tanning beds and ultraviolet light therapy, during treatment with HYFTOR. Wear clothing that covers your skin if you need to go outside. Talk with your healthcare provider about other ways you can protect your skin from the sun.

What are the possible side effects of HYFTOR?

HYFTOR may cause serious side effects, including:

• Allergic reactions.Serious allergic reactions have happened in people who have taken sirolimus by mouth. Stop using HYFTOR and get medical help right away if you get any of these symptoms of a serious allergic reaction:
  • swelling of your face, eyes, or mouth
  • chest pain or tightness
  • trouble breathing orwheezing
  • feeling dizzy or faint
  • throat tightness
  • rash or peeling of your skin
• Infections.Serious infections, including infections that can happen when yourimmune systemis weak, have happened in people who have taken sirolimus by mouth. Some people have developed a rare, serious brain infection called progressive multifocal leukoencephalopathy (PML) which can sometimes cause death. Stop using HYFTOR and call your healthcare provider right away if you get symptoms of an infection including fever or chills.
• Risk of cancer.Lymphoma and other cancers, especially skin cancer, have happened in people who have taken sirolimus by mouth. Talk with your healthcare provider about your risk for cancer if you use HYFTOR.
• Increased levels of cholesterol and triglycerides (fat or lipids) in the bloodhave happened in people who have taken sirolimus by mouth. Your healthcare provider may do blood tests to check you for highlipidlevels during treatment with HYFTOR and treat you, if needed.
• Lung or breathing problems.Lung or breathing problems, including problems that have sometimes caused death, have happened in people who have taken sirolimus by mouth. Stop using HYFTOR and get medical help right away if you get symptoms such as shortness of breath, new or worsening cough, or chest pain.

The most common side effects of HYFTOR includedry skin, application site irritation, itching, acne, acne-like rash, eye redness, skin bleeding, and skin irritation.

HYFTOR may cause fertility problems in males and females, which may affect your ability to have children. Talk to your healthcare provider if this is a concern for you.

These are not all the possible side effects of HYFTOR.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store HYFTOR?

• Store HYFTOR in the refrigerator between at 36°F to 46°F (2°C to 8°C).
• Keep HYFTOR out of light. Keep HYFTOR and all medicines out of the reach of children.

General information about the safe and effective use of HYFTOR.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use HYFTOR for a condition for which it was not prescribed. Do not give HYFTOR to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about HYFTOR that is written for health professionals.

What are the ingredients in HYFTOR?

活性成分:sirolimus

Inactive ingredients:alcohol 51%, Carbomer 940, purified water, and trolamine.

This Patient Information has been approved by the U.S. Food and Drug Administration.