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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 (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:
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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 C51H79NO13 and a molecular weight of 914.19.
HYFTOR is indicated for the treatment of facial angiofibroma associated with tuberous sclerosis in adults and pediatric patients 6 years of age and older.
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 (NDC 73683-101-10). Each gram contains 2 mg of sirolimus.
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.
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 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%) |
| a Dry 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.
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. |
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.
Included as part of the "PRECAUTIONS" Section
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.
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.
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.
Increased serum cholesterol and triglycerides requiring treatment have been observed with oral administration of sirolimus. Monitor for hyperlipidemia during treatment with HYFTOR.
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.
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.
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, CLINICAL PHARMACOLOGY].
Azoospermia or oligospermia has been observed after oral administration of sirolimus [see Use In Specific Populations, Nonclinical Toxicology]. Sirolimus is an anti-proliferative drug and affects rapidly dividing cells like the germ cells. Advise males that HYFTOR may impair fertility.
Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).
Inform 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 WARNINGS AND PRECAUTIONS].
Inform patients that oral sirolimus has been associated with increased susceptibility to infections, including opportunistic infections and latent viral infections, such as progressive multifocal leukoencephalopathy (PML). Advise patients to discontinue HYFTOR immediately and seek medical attention if symptoms occur [see WARNINGS AND PRECAUTIONS].
Inform patients that oral sirolimus has been associated with malignancy, including lymphoma and skin 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 WARNINGS AND PRECAUTIONS].
Inform patients that oral sirolimus has been associated with increased serum cholesterol and triglycerides requiring treatment and that periodic laboratory monitoring may be needed [see WARNINGS AND PRECAUTIONS].
Inform 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 WARNINGS AND PRECAUTIONS].
Inform patients that during treatment with HYFTOR, vaccinations may be less effective. Instruct patients that vaccination with 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 WARNINGS AND PRECAUTIONS].
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 WARNINGS AND PRECAUTIONS, Use In Specific Populations].
Advise lactating women that breastfeeding is not recommended during treatment with HYFTOR [see Use In Specific Populations].
Inform male and female patients that HYFTOR may impair fertility [see WARNINGS AND PRECAUTIONS, Use In Specific Populations, Nonclinical Toxicology].
Inform patients that the skin being treated with HYFTOR should not be covered with bandages, dressings or wraps [see DOSAGE AND ADMINISTRATION].
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 in malignant lymphoma at all dose levels compared with control animals. In a second oral mouse carcinogenicity study, sirolimus-related hepatocellular adenoma and carcinoma were induced in male mice. In an oral carcinogenicity study conducted in rats with sirolimus there were no significant findings.
Sirolimus was not genotoxic in the in vitro bacterial reverse mutation assay, the Chinese hamster ovary cell chromosomal aberration assay, the mouse lymphoma cell forward mutation assay, or the in vivo mouse 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, atrophy of testes, epididymides, prostate, seminiferous tubules and/or reduced sperm counts were observed. In female rats, decreased ovarian and uterine weights and decreased implantation were observed. Testicular tubular degeneration was also seen in a 4-week intravenous study of sirolimus in monkeys at 0.1 mg/kg.
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.
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.
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.
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, Pregnancy].
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, Nonclinical Toxicology]. 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.
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 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.
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.
No Information Provided.
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 WARNINGS AND PRECAUTIONS].
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 tuberous sclerosis.
It is not known if HYFTOR is safe and effective in children under 6 years of age.
Do not use HYFTOR if you 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:
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?
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:
The most common side effects of HYFTOR include dry 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?
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?
Active ingredient: 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.
