Ruxolitinib

OPZELURA is a Janus kinase (JAK) inhibitor indicated for: the topical short-term and non-continuous chronic treatment of mild to moderate atopic dermatitis in non-immunocompromised adult and pediatric patients 2 years of age and older whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. ( 1.1 ) the topical treatment of nonsegmental vitiligo in adult and pediatric patients 12 years of age and older. ( 1.2 ) Limitations of Use Use of OPZELURA in combination with therapeutic biologics, other JAK inhibitors or potent immunosuppressants such as azathioprine or cyclosporine is not recommended. ( 1.3 )

1.1 Atopic Dermatitis OPZELURA is indicated for the topical short-term and non-continuous chronic treatment of mild to moderate atopic dermatitis in non-immunocompromised adult and pediatric patients 2 years of age and older whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.

1.2 Nonsegmental Vitiligo OPZELURA is indicated for the topical treatment of nonsegmental vitiligo in adult and pediatric patients 12 years of age and older.

1.3 Limitations of Use Use of OPZELURA in combination with therapeutic biologics, other Janus kinase (JAK) inhibitors, or potent immunosuppressants such as azathioprine or cyclosporine is not recommended.

Atopic Dermatitis Apply a thin layer of OPZELURA topically twice daily to affected areas of up to 20% body surface area. ( 2.1 ) Do not use OPZELURA with occlusive dressings. ( 2.1 ) Adult and Pediatric Patients 12 Years of Age and Older Do not use more than one 60 gram tube of OPZELURA per week or one 100 gram tube per 2 weeks. ( 2.1 ) Pediatric Patients 2 to 11 Years of Age Do not use more than one 60 gram tube of OPZELURA per 2 weeks. ( 2.1 ) Nonsegmental Vitiligo Apply a thin layer of OPZELURA topically twice daily to affected areas of up to 10% body surface area. ( 2.2 ) Do not use more than one 60 gram tube of OPZELURA per week or one 100 gram tube per 2 weeks. ( 2.2 )

2.1 Recommended Dosage and Administration for Atopic Dermatitis OPZELURA is for topical use only. OPZELURA is not for ophthalmic, oral, or intravaginal use. Instruct patients to apply a thin layer of OPZELURA twice daily to affected areas of up to 20% body surface area. Do not use OPZELURA with occlusive dressings. Stop using when signs and symptoms (e.g., itch, rash, and redness) of atopic dermatitis resolve. If signs and symptoms do not improve within 8 weeks, patients should be re-examined by their healthcare provider [see Clinical Studies ( 14.1 )] . Adult and Pediatric Patients 12 Years of Age and Older Do not use more than one 60 gram tube of OPZELURA per week or one 100 gram tube per 2 weeks. Pediatric Patients 2 to 11 Years of Age Do not use more than one 60 gram tube of OPZELURA per 2 weeks.

2.2 Recommended Dosage and Administration for Nonsegmental Vitiligo OPZELURA is for topical use only. OPZELURA is not for ophthalmic, oral, or intravaginal use. Instruct patients to apply a thin layer of OPZELURA twice daily to affected areas of up to 10% body surface area. Do not use more than one 60 gram tube of OPZELURA per week or one 100 gram tube per 2 weeks. Satisfactory patient response may require treatment with OPZELURA for more than 24 weeks. If the patient does not find the repigmentation meaningful by 24 weeks, the patient should be re‑evaluated by the healthcare provider [see Clinical Studies ( 14.2 )] .

Cream: 15 mg of ruxolitinib per gram (1.5%) of white to off-white cream supplied in 60 g and 100 g tubes Cream: 1.5% ruxolitinib supplied in 60 g and 100 g tubes ( 3 )

None. None. ( 4 )

Drug interaction studies with OPZELURA have not been conducted. Ruxolitinib is known to be a substrate for cytochrome P450 3A4 (CYP3A4). Inhibitors of CYP3A4 may increase ruxolitinib systemic concentrations whereas inducers of CYP3A4 may decrease ruxolitinib systemic concentrations [see Clinical Pharmacology ( 12.3 )] . Strong Inhibitors of CYP3A4 Avoid concomitant use of OPZELURA with strong inhibitors of CYP3A4 as there is a potential to increase the systemic exposure of ruxolitinib and could increase the risk of OPZELURA adverse reactions [see Clinical Pharmacology ( 12.3 )] .

Pregnancy Exposure Registry There is a pregnancy registry that monitors pregnancy outcomes in pregnant persons exposed to OPZELURA during pregnancy. Pregnant persons exposed to OPZELURA and healthcare providers should report OPZELURA exposure by calling 1-855-463-3463 or visiting www.opzelura.pregnancy.incyte.com. Risk Summary Available data from pregnancies reported in clinical trials with OPZELURA are not sufficient to evaluate a drug-associated risk for major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of ruxolitinib to pregnant rats and rabbits during the period of organogenesis resulted in adverse developmental outcomes at doses associated with maternal toxicity (see Data) . The background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies carry some risk of birth defects, loss, or other adverse outcomes. The background risk in the U.S. general population of major birth defects and miscarriage is 2-4% and 15-20%, respectively. Data Animal Data Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses of 15, 30, or 60 mg/kg/day in rats and 10, 30, or 60 mg/kg/day in rabbits. There were no treatment-related malformations at any dose. A decrease in fetal weight of approximately 9% was noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose resulted in systemic exposure approximately 22 times the clinical systemic exposure at the maximum recommended human dose (MRHD; the clinical systemic exposure from ruxolitinib cream, 1.5% applied twice daily to 25-40% atopic dermatitis-affected body surface area is used for calculation of multiples of human exposure). In rabbits, lower fetal weights of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of 60 mg/kg/day. This dose resulted in systemic exposure approximately 70% the MRHD clinical systemic exposure. In a pre-and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implantation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse effects on embryofetal survival, postnatal growth, development parameters or offspring reproductive function at the highest dose evaluated (3.1 times the MRHD clinical systemic exposure).

Atopic Dermatitis The safety and effectiveness of OPZELURA for the topical short-term and non-continuous chronic treatment of mild to moderate atopic dermatitis have been established in non-immunocompromised pediatric patients ages 2 years and older whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. Use of OPZELURA in this age group is supported by evidence from adequate and well-controlled trials in adults and pediatric subjects ages 2 years and older with mild to moderate atopic dermatitis [see Clinical Studies ( 14.1 )]. Trials included 92 subjects 12 to 17 years of age and 130 subjects 2 to 11 years of age treated with OPZELURA. Application site reactions, pyrexia, and decreased white blood cell were reported more frequently in pediatric subjects ages 2 to 11 years compared to adults and pediatric subjects ages 12 years and older [see Adverse Reactions ( 6.1 )] . The safety and effectiveness of OPZELURA have not been established in pediatric patients younger than 2 years of age with atopic dermatitis. Nonsegmental Vitiligo The safety and effectiveness of OPZELURA for the topical treatment of nonsegmental vitiligo have been established in pediatric patients ages 12 years and older. Use of OPZELURA in this age group is supported by evidence from TRuE-V1 and TRuE-V2, which included 55 subjects ages 12 to 17 years with nonsegmental vitiligo [see Clinical Studies ( 14.2 ) ] . The safety and effectiveness of OPZELURA have not been established in pediatric patients younger than 12 years of age with nonsegmental vitiligo. Juvenile Animal Toxicity Data Oral administration of ruxolitinib to juvenile rats resulted in effects on growth and bone measures. When administered starting at postnatal day 7 (the equivalent of a human newborn) at doses of 1.5 to 75 mg/kg/day, evidence of fractures occurred at doses ≥ 30 mg/kg/day, and effects on body weight and other bone measures [e.g., bone mineral content, peripheral quantitative computed tomography, and x-ray analysis] occurred at doses ≥ 5 mg/kg/day. When administered starting at postnatal day 21 (the equivalent of a human 2-3 years of age) at doses of 5 to 60 mg/kg/day, effects on body weight and bone occurred at doses ≥ 15 mg/kg/day, which were considered adverse at 60 mg/kg/day. Males were more severely affected than females in all age groups, and effects were generally more severe when administration was initiated earlier in the postnatal period. These findings were observed at systemic exposures that are at least 45% the MRHD in pediatric subjects 2 to 11 years of age (the clinical systemic exposure from ruxolitinib cream, 1.5% applied twice daily to 35-50% atopic dermatitis-affected body surface area in pediatric subjects 2 to 11 years of age is used for the calculation of multiples of human exposure in this subsection).

Of the 1249 total subjects with atopic dermatitis in clinical trials with OPZELURA, 115 (9%) were 65 years of age and older [see Clinical Studies ( 14.1 ) ] . No clinically meaningful differences in safety or effectiveness were observed between subjects less than 65 years and subjects 65 years and older. Of the 831 total subjects enrolled with nonsegmental vitiligo in clinical trials with OPZELURA, 65 (8%) were 65 years of age and older [see Clinical Studies ( 14.2 )] . Clinical trials of OPZELURA in subjects with nonsegmental vitiligo did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger adult subjects.

Ruxolitinib phosphate is a Janus kinase inhibitor with the chemical name ( R )-3-(4-(7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)-1 H -pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate and a molecular weight of 404.36 g/mol. Ruxolitinib phosphate has the following structural formula: Ruxolitinib phosphate is a white to off-white to light yellow to light pink powder. OPZELURA (ruxolitinib) cream is a white to off-white oil-in-water, solubilized emulsion cream for topical use. Each gram of OPZELURA contains 15 mg of ruxolitinib (equivalent to 19.8 mg of ruxolitinib phosphate) in a cream containing cetyl alcohol, dimethicone 350, edetate disodium, glyceryl stearate SE, light mineral oil, medium chain triglycerides, methylparaben, phenoxyethanol, phosphoric acid, polyethylene glycol 200, polysorbate 20, propylene glycol, propylparaben, stearyl alcohol, purified water, white petrolatum, and xanthan gum. structural formula

12.1 Mechanism of Action Ruxolitinib, a Janus kinase (JAK) inhibitor, inhibits JAK1 and JAK2 which mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, activation and subsequent localization of STATs to the nucleus leading to modulation of gene expression. The relevance of inhibition of specific JAK enzymes to therapeutic effectiveness is not currently known.

12.2 Pharmacodynamics The pharmacodynamics of OPZELURA is unknown. Cardiac Electrophysiology Under the conditions of clinical use, OPZELURA is not expected to prolong the QT interval.

12.3 Pharmacokinetics In Trial INCB18424-103, the pharmacokinetics of ruxolitinib were evaluated in 20 adult subjects and 21 pediatric subjects 13 years of age and older with atopic dermatitis with a mean ± SD BSA involvement of 37.5 ± 16.1% (range 25% to 90%). Subjects applied approximately 1.5 mg/cm 2 of OPZELURA (dose range was approximately 1.2 grams to 37.6 grams per application) twice daily for 28 days. Absorption Plasma concentrations of ruxolitinib were quantifiable in all subjects. In adult subjects, the mean ± SD maximum plasma concentration (C max ) and area under the concentration time curve from 0 to 12 hours post dose (AUC 0–12 ) for ruxolitinib on Day 1 were 449 ± 883 nM and 3215 ± 6184 h*nM, respectively. There is no evidence of ruxolitinib accumulation after daily application of OPZELURA for 28 days in subjects with atopic dermatitis. Distribution Plasma protein binding is approximately 97%. Elimination The mean terminal half-life of ruxolitinib following topical application of OPZELURA was estimated in 9 subjects and is approximately 116 hours. Metabolism Ruxolitinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C9 in vitro. Excretion Ruxolitinib and its metabolites are primarily excreted by urine (74%) and feces (22%). Less than 1% is excreted as unchanged drug. Specific Populations Pediatric Patients In Trial INCB18424-103, in subjects 13 to 17 years of age with atopic dermatitis, the mean ± SD C max and AUC 0–12 for ruxolitinib on Day 1 were 110 ± 255 nM and 801 ± 2019 h*nM, respectively. In Trial INCB18424-109, the pharmacokinetics of ruxolitinib was evaluated in 27 subjects 2 to 11 years of age with atopic dermatitis with a mean ± SD BSA involvement of 58.9 ± 20.6% (range 35% to 92%). The mean ± SD daily dose of the cream was 8.5 ± 6.3 g. Plasma concentrations of ruxolitinib were quantifiable in all subjects. The mean ± SD steady state plasma concentration (C ss ) and projected area under the concentration time curve from 0 to 12 hours post dose (AUC 0-12h ) for ruxolitinib were 84.1 ± 183 nM and 1009.2 ± 2196 h*nM, respectively in subjects 7 to less than 12 years of age (n = 12) and 109 ± 122 nM and 1308 ± 1464 h*nM, respectively in subjects 2 to less than 7 years of age (n = 15). There is no evidence of ruxolitinib accumulation after twice daily application of OPZELURA for 28 days in subjects 2 years to 17 years of age with atopic dermatitis. Drug Interactions Clinical Studies Drug interaction studies with OPZELURA have not been conducted. Strong CYP3A4 inhibitors : The C max and AUC of ruxolitinib increased 33% and 91%, respectively, with administration of 10 mg single dose orally following ketoconazole 200 mg twice daily for four days, compared to receiving the oral ruxolitinib dose alone in healthy subjects. Mild or moderate CYP3A4 inhibitors : There was an 8% and 27% increase in the C max and AUC of ruxolitinib, respectively, with the administration of 10 mg single dose orally following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, compared to receiving the oral ruxolitinib dose alone in healthy subjects. There are no clinical studies conducted with mild CYP3A4 inhibitor. CYP3A4 inducers: The C max and AUC of ruxolitinib decreased 32% and 61%, respectively, with the oral administration of 50 mg single dose of ruxolitinib following rifampin 600 mg once daily for 10 days, compared to receiving the oral ruxolitinib dose alone in healthy subjects. In Vitro Studies Cytochrome P450 (CYP) Enzymes: Ruxolitinib is not expected to inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and CYP3A4 or induce CYP1A2, 2B6 and 3A4 following topical application. Transporter Systems: Ruxolitinib is not expected to inhibit P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, or OAT3 transporter systems following topical application. Ruxolitinib is not a substrate for the P-gp transporter.

Ruxolitinib, a Janus kinase (JAK) inhibitor, inhibits JAK1 and JAK2 which mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, activation and subsequent localization of STATs to the nucleus leading to modulation of gene expression. The relevance of inhibition of specific JAK enzymes to therapeutic effectiveness is not currently known.

The pharmacodynamics of OPZELURA is unknown. Cardiac Electrophysiology Under the conditions of clinical use, OPZELURA is not expected to prolong the QT interval.

In Trial INCB18424-103, the pharmacokinetics of ruxolitinib were evaluated in 20 adult subjects and 21 pediatric subjects 13 years of age and older with atopic dermatitis with a mean ± SD BSA involvement of 37.5 ± 16.1% (range 25% to 90%). Subjects applied approximately 1.5 mg/cm 2 of OPZELURA (dose range was approximately 1.2 grams to 37.6 grams per application) twice daily for 28 days. Absorption Plasma concentrations of ruxolitinib were quantifiable in all subjects. In adult subjects, the mean ± SD maximum plasma concentration (C max ) and area under the concentration time curve from 0 to 12 hours post dose (AUC 0–12 ) for ruxolitinib on Day 1 were 449 ± 883 nM and 3215 ± 6184 h*nM, respectively. There is no evidence of ruxolitinib accumulation after daily application of OPZELURA for 28 days in subjects with atopic dermatitis. Distribution Plasma protein binding is approximately 97%. Elimination The mean terminal half-life of ruxolitinib following topical application of OPZELURA was estimated in 9 subjects and is approximately 116 hours. Metabolism Ruxolitinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C9 in vitro. Excretion Ruxolitinib and its metabolites are primarily excreted by urine (74%) and feces (22%). Less than 1% is excreted as unchanged drug. Specific Populations Pediatric Patients In Trial INCB18424-103, in subjects 13 to 17 years of age with atopic dermatitis, the mean ± SD C max and AUC 0–12 for ruxolitinib on Day 1 were 110 ± 255 nM and 801 ± 2019 h*nM, respectively. In Trial INCB18424-109, the pharmacokinetics of ruxolitinib was evaluated in 27 subjects 2 to 11 years of age with atopic dermatitis with a mean ± SD BSA involvement of 58.9 ± 20.6% (range 35% to 92%). The mean ± SD daily dose of the cream was 8.5 ± 6.3 g. Plasma concentrations of ruxolitinib were quantifiable in all subjects. The mean ± SD steady state plasma concentration (C ss ) and projected area under the concentration time curve from 0 to 12 hours post dose (AUC 0-12h ) for ruxolitinib were 84.1 ± 183 nM and 1009.2 ± 2196 h*nM, respectively in subjects 7 to less than 12 years of age (n = 12) and 109 ± 122 nM and 1308 ± 1464 h*nM, respectively in subjects 2 to less than 7 years of age (n = 15). There is no evidence of ruxolitinib accumulation after twice daily application of OPZELURA for 28 days in subjects 2 years to 17 years of age with atopic dermatitis. Drug Interactions Clinical Studies Drug interaction studies with OPZELURA have not been conducted. Strong CYP3A4 inhibitors : The C max and AUC of ruxolitinib increased 33% and 91%, respectively, with administration of 10 mg single dose orally following ketoconazole 200 mg twice daily for four days, compared to receiving the oral ruxolitinib dose alone in healthy subjects. Mild or moderate CYP3A4 inhibitors : There was an 8% and 27% increase in the C max and AUC of ruxolitinib, respectively, with the administration of 10 mg single dose orally following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, compared to receiving the oral ruxolitinib dose alone in healthy subjects. There are no clinical studies conducted with mild CYP3A4 inhibitor. CYP3A4 inducers: The C max and AUC of ruxolitinib decreased 32% and 61%, respectively, with the oral administration of 50 mg single dose of ruxolitinib following rifampin 600 mg once daily for 10 days, compared to receiving the oral ruxolitinib dose alone in healthy subjects. In Vitro Studies Cytochrome P450 (CYP) Enzymes: Ruxolitinib is not expected to inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and CYP3A4 or induce CYP1A2, 2B6 and 3A4 following topical application. Transporter Systems: Ruxolitinib is not expected to inhibit P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, or OAT3 transporter systems following topical application. Ruxolitinib is not a substrate for the P-gp transporter.

, Mutagenesis, Impairment of Fertility Ruxolitinib was not carcinogenic when administered orally in the 6-month Tg.rasH2 transgenic mouse model. In a 2-year oral rat carcinogenicity study, no drug-related tumors were observed at oral doses of ruxolitinib up to 60 mg/kg/day (3.5 times the MRHD clinical systemic exposure). In a 2-year dermal mouse carcinogenicity study, no drug-related tumors were observed at topical doses of ruxolitinib cream up to 1.5% applied at 100 μl/day (2.8 times the MRHD clinical systemic exposure). Ruxolitinib was not mutagenic in a bacterial mutagenicity assay (Ames test) or clastogenic in an in vitro chromosomal aberration assay (cultured human peripheral blood lymphocytes) or an in vivo rat bone marrow micronucleus assay. In a fertility study, ruxolitinib was administered orally to male rats prior to and throughout mating and to female rats prior to mating and up to the implantation day (gestation day 7). Ruxolitinib had no effect on fertility or reproductive function in male or female rats at doses up to 60 mg/kg/day (22 times the MRHD clinical systemic exposure). However, in female rats, doses of greater than or equal to 30 mg/kg/day (3.5 times the MRHD clinical systemic exposure) resulted in increased post-implantation loss.

17 PATIENT COUNSELING INFORMATION Advise the patient or caregivers to read the FDA-approved patient labeling (Medication Guide). Infections Inform patients that they may be at increased risk for developing infections, including serious infections, when taking Janus kinase inhibitors. Instruct patients to tell their healthcare provider if they develop any signs or symptoms of an infection [see Warnings and Precautions ( 5.1 )] . Advise patients that Janus kinase inhibitors increase the risk of herpes zoster, and some cases can be serious [see Warnings and Precautions ( 5.1 )] . Malignancies and Lymphoproliferative Disorders Inform patients that Janus kinase inhibitors may increase the risk for developing lymphomas and other malignancies including skin cancer [see Warnings and Precautions ( 5.3 ) ]. Instruct patients to inform their health care provider if they have ever had any type of cancer. Inform patients that periodic skin examinations should be performed while using OPZELURA. Advise patients that exposure to sunlight, and UV light should be limited by wearing protective clothing and using a broad-spectrum sunscreen [see Warnings and Precautions ( 5.3 )] . Major Adverse Cardiovascular Events Advise patients that events of major adverse cardiovascular events (MACE) including non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death, have been reported in clinical studies with Janus kinase inhibitors used to treat inflammatory conditions. Instruct all patients, especially current or past smokers or patients with other cardiovascular risk factors, to be alert for the development of signs and symptoms of cardiovascular events [see Warnings and Precautions ( 5.4 )] . Thrombosis Advise patients that events of DVT and PE have been reported in clinical studies with Janus kinase inhibitors used to treat inflammatory conditions. Instruct patients to tell their healthcare provider if they develop any signs or symptoms of a DVT or PE [see Warnings and Precautions ( 5.5 )] . Cytopenias Advise patients of the risk of thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia with OPZELURA. Instruct patients to tell their healthcare provider if they develop any signs or symptoms of thrombocytopenia, anemia, neutropenia, lymphopenia, or leukopenia [see Warnings and Precautions ( 5.6 )] . Administration Instructions Advise patients or caregivers that OPZELURA is for topical use only [see Dosage and Administration ( 2.1 , 2.2 )]. Atopic Dermatitis Adult and Pediatric Patients 12 Years of Age and Older : Advise patients or caregivers to limit treatment to one 60 gram tube of OPZELURA per week or one 100 gram tube per 2 weeks [see Dosage and Administration ( 2.1 )] . Pediatric Patients 2 to 11 Years of Age: Advise patients or caregivers to limit treatment to one 60 gram tube of OPZELURA per 2 weeks [see Dosage and Administration ( 2.1 )] . Nonsegmental Vitiligo Advise patients or caregivers to limit treatment to one 60 gram tube of OPZELURA per week or one 100 gram tube per 2 weeks [see Dosage and Administration ( 2.2 ) ] . Pregnancy Registry Inform patients to report their pregnancy to Incyte Corporation at 1-855-463-3463 or by visiting www.opzelura.pregnancy.incyte.com [see Use in Specific Populations ( 8.1 )]. Lactation Advise a patient not to breastfeed during treatment with OPZELURA and for about four weeks after the last dose [see Use in Specific Populations ( 8.2 )]. Manufactured for: Incyte Corporation 1801 Augustine Cut-off Wilmington, DE 19803 OPZELURA is a registered trademark of Incyte. All rights reserved. Patent Information: www.incyte.com/patents © 2021-2026 Incyte Corporation. All rights reserved.