5.1 Serious Infections

Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving oral Janus kinase inhibitors.

Serious lower respiratory tract infections were reported in the clinical development program with topical ruxolitinib.

Avoid use of OPZELURA in patients with an active, serious infection, including localized infections. Consider the risks and benefits of treatment prior to initiating OPZELURA in patients:

• with chronic or recurrent infection
• with a history of a serious or an opportunistic infection
• who have been exposed to tuberculosis
• who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or
• with underlying conditions that may predispose them to infection.

Closely monitor patients for the development of signs and symptoms of infection during and after treatment with OPZELURA. Interrupt OPZELURA if a patient develops a serious infection, an opportunistic infection, or sepsis. Do not resume OPZELURA until the infection is controlled.

Tuberculosis

No cases of active tuberculosis (TB) were reported in clinical trials with OPZELURA. Cases of active TB were reported in clinical trials of oral Janus kinase inhibitors used to treat inflammatory conditions. Consider evaluating patients for latent and active TB infection prior administration of OPZELURA.

During OPZELURA use, monitor patients for the development of signs and symptoms of TB.

Viral Reactivation

Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were reported in clinical trials with Janus kinase inhibitors used to treat inflammatory conditions including OPZELURA. If a patient develops herpes zoster, consider interrupting OPZELURA treatment until the episode resolves.

Hepatitis B and C

The impact of Janus kinase inhibitors used to treat inflammatory conditions including OPZELURA on chronic viral hepatitis reactivation is unknown. Patients with a history of hepatitis B or C infection were excluded from clinical trials.

Hepatitis B viral load (HBV-DNA titer) increases, with or without associated elevations in alanine aminotransferase and aspartate aminotransferase, have been reported in patients with chronic HBV infections taking oral ruxolitinib.

OPZELURA initiation is not recommended in patients with active hepatitis B or hepatitis C.

5.2 Mortality

A higher rate of all-cause mortality, including sudden cardiovascular death was observed in clinical trials of oral Janus kinase inhibitors used to treat inflammatory conditions. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with OPZELURA.

5.3 Malignancy and Lymphoproliferative Disorders

Malignancies, including lymphomas, were observed in clinical trials of oral Janus kinase inhibitors used to treat inflammatory conditions. Patients who are current or past smokers are at additional increased risk.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with OPZELURA, particularly in patients with a known malignancy (other than successfully treated non-melanoma skin cancers), patients who develop a malignancy, and patients who are current or past smokers.

Non-melanoma Skin Cancers

Non-melanoma skin cancers including basal cell and squamous cell carcinoma have occurred in patients treated with OPZELURA. Perform periodic skin examinations during OPZELURA treatment and following treatment as appropriate.

5.4 Major Adverse Cardiovascular Events (MACE)

Major adverse cardiovascular events (MACE) defined as cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke were observed in clinical trials of Janus kinase inhibitors used to treat inflammatory conditions.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with OPZELURA particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if these symptoms occur.

5.5 Thrombosis

Thrombosis, including deep venous thrombosis (DVT), pulmonary embolism (PE) and arterial thrombosis, has been observed at an increased incidence in patients treated with oral Janus kinase inhibitors for inflammatory conditions compared to patients treated with placebo. Many of these adverse reactions were serious and some resulted in death.

Thromboembolic events were observed in clinical trials with OPZELURA. There was no clear relationship between platelet count elevations and thrombotic events. OPZELURA should be used with caution in patients who may be at increased risk of thrombosis.

5.6 Thrombocytopenia, Anemia and Neutropenia

Thrombocytopenia, anemia and neutropenia were reported in the clinical trials with OPZELURA. Consider the benefits and risks for individual patients who have a known history of these events prior to initiating therapy with OPZELURA. Perform CBC monitoring as clinically indicated. If signs and/or symptoms of clinically significant thrombocytopenia, anemia, and neutropenia occur, patients should discontinue OPZELURA.

5.7 Lipid Elevations

Treatment with oral ruxolitinib has been associated with increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides.

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 two double-blind, vehicle-controlled clinical trials (Trials 1 and 2), 499 subjects 12 years of age and older with atopic dermatitis were treated with OPZELURA twice daily for 8 weeks. In the OPZELURA group, 62% of subjects were females, and 71% of subjects were White, 23% were Black, and 4% were Asian. The adverse reactions reported by ≥ 1% of OPZELURA-treated subjects and at a greater incidence than in the vehicle arm are listed in Table 1.

Adverse reactions that occurred in Trials 1 and 2 in < 1% of subjects in the OPZELURA group and none in the vehicle group were: neutropenia, allergic conjunctivitis, pyrexia, seasonal allergy, herpes zoster, otitis externa, Staphylococcal infection, and acneiform dermatitis.

8.1 Pregnancy

Pregnancy Exposure Registry

There will be 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.

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% 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).

8.2 Lactation

Risk Summary

There are no data on the presence of ruxolitinib in human milk, the effects on the breastfed child, or the effects on milk production. Ruxolitinib was present in the milk of lactating rats (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the serious adverse findings in adults, including risks of serious infections, thrombocytopenia, anemia, and neutropenia, advise women not to breastfeed during treatment with OPZELURA and for approximately four weeks after the last dose (approximately 5 elimination half-lives).

Data

Lactating rats were administered a single dose of [14C]-labeled ruxolitinib (30 mg/kg) on postnatal Day 10, after which plasma and milk samples were collected for up to 24 hours. The AUC for total radioactivity in milk was approximately 13 times the maternal plasma AUC. Additional analysis showed the presence of ruxolitinib and several of its metabolites in milk, all at levels higher than those in maternal plasma.

8.4 Pediatric Use

The safety and effectiveness of OPZELURA for the topical treatment of atopic dermatitis have been established in pediatric patients aged 12 to 17 years of age with mild-to-moderate atopic dermatitis. Use of OPZELURA in this age group is supported by evidence from Trials 1 and 2 which included 92 subjects aged 12 to 17 years [see Clinical Pharmacology (12.3) and Clinical Studies (14)]. No clinically meaningful differences in safety or effectiveness were observed between adult and pediatric subjects.

The safety and effectiveness of OPZELURA in pediatric patients younger than 12 years of age have not been established.

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 40% the MRHD clinical systemic exposure.

8.5 Geriatric Use

Of the 1249 total subjects with atopic dermatitis in clinical trials with OPZELURA, 115 were 65 years of age and older [see Clinical Studies (14)]. No clinically meaningful differences in safety or effectiveness were observed between patients less than 65 years and patients 65 years and older.

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

Cardiac Electrophysiology

Under the conditions of clinical use, OPZELURA is not expected to prolong the QT interval.

12.3 Pharmacokinetics

The pharmacokinetics of ruxolitinib were evaluated in a study involving 20 adult subjects and 21 pediatric subjects 13 years 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/cm2 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 (Cmax) and area under the concentration time curve from 0 to 12 hours post dose (AUC0 – 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 adolescent subjects with atopic dermatitis (13 – 17 years of age), the mean ± SD Cmax and AUC0 – 12 for ruxolitinib on Day 1 were 110 ± 255 nM and 801 ± 2019 h*nM, respectively.

Drug Interactions

Clinical Studies

Drug interaction studies with OPZELURA have not been conducted.

Strong CYP3A4 inhibitors

The Cmax 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 Cmax 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 Cmax 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.

13.1 Carcinogenesis, 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.