OPZELURA 15mg / g cream medication leaflet

Opzelura 15 mg/g cream

One gram of cream contains 15 mg of ruxolitinib (as phosphate).

Propylene glycol (E1520), 150 mg/g of cream

Cetyl alcohol, 30 mg/g of cream

Stearyl alcohol, 17.5 mg/g of cream

Methyl parahydroxybenzoate (E218), 1 mg/g of cream

Propyl parahydroxybenzoate, 0.5 mg/g of cream

Butylated hydroxytoluene (as an antioxidant in paraffin, white soft) (E321)

Polysorbate 20 (E432)

For the full list of excipients, see section 6.1.

Cream

White to off-white cream.

Opzelura is indicated for the treatment of non-segmental vitiligo with facial involvement in adults andadolescents from 12 years of age.

Opzelura should be initiated and supervised by physicians with experience in the diagnosis andtreatment of non-segmental vitiligo.

The recommended dose is a thin layer of cream applied twice daily to the depigmented skin areas upto a maximum of 10% of body surface area (BSA), with a minimum of 8 hours between twoapplications of ruxolitinib cream. 10% BSA represents an area as large as 10 times the palm of onehand with the 5 fingers. Ruxolitinib cream should be used at the smallest skin area necessary.

No more than two tubes of 100 grams a month should be used.

Satisfactory repigmentation may require treatment beyond 24 weeks. If there is less than 25%repigmentation in treated areas at week 52, treatment discontinuation should be considered.

Once satisfactory repigmentation is achieved, treatment in those areas can be stopped. Ifdepigmentation recurs after treatment discontinuation, therapy can be reinitiated on the affected areas.

There is no need to consider tapering therapy.

No studies with ruxolitinib cream have been performed in patients with hepatic impairment. However,due to limited systemic exposure, dose adjustment is not necessary in patients with hepaticimpairment.

No studies with ruxolitinib cream have been performed in patients with renal impairment. However,due to limited systemic exposure, dose adjustment is not necessary in patients with renal impairment.

As a precautionary measure, ruxolitinib cream should not be used by patients with end stage renaldisease, due to lack of data regarding the safety.

A limited number of patients aged 65 years and above have been enrolled in the clinical studies with

Opzelura in vitiligo to determine whether they respond differently from younger subjects (seesection 5.1). No dose adjustment is required in patients aged 65 years and above.

For adolescents (12-17 years) the posology is the same as for adults.

The safety and efficacy of ruxolitinib cream in children below 12 years of age have not beenestablished. No data are available.

The cream is for cutaneous use only.

Avoid washing treated skin for at least 2 hours after application of ruxolitinib cream.

The cream should not be applied to the lips to avoid its ingestion.

Patients should be instructed to wash their hands after applying the cream, unless it is their hands thatare being treated. If someone else applies the cream to the patient, they should wash their hands afterapplication.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Pregnancy and breastfeeding (see section 4.6).

The cream is not for ophthalmic, oral, or intravaginal use (see section 4.2). In cases of accidentalexposure in the eyes or mucous membranes, the cream should be thoroughly wiped off and/or rinsedwith water.

Non-melanoma skin cancers (NMSCs), predominantly basal cell carcinomas, have been reported inpatients treated with topical ruxolitinib. Most of these patients had risk factors, such as priorphototherapy or prior NMSC. A causal relationship to topical ruxolitinib has not been established.

Periodic skin examination is recommended for all patients, particularly those with risk factors for skincancer.

This medicinal product contains 150 mg propylene glycol (E1520) in each gram of cream which maycause skin irritation.

Cetyl alcohol and stearyl alcohol

This medicinal product contains cetyl alcohol and stearyl alcohol which may cause local skin reactions(e.g. contact dermatitis).

Parahydroxybenzoates

This medicinal product contains methyl parahydroxybenzoate (E218) and propyl parahydroxybenzoatewhich may cause allergic reactions (possibly delayed).

Butylated hydroxytoluene

This medicinal product contains butylated hydroxytoluene (E321) which may cause local skinreactions (e.g. contact dermatitis), or irritation to the eyes and mucous membranes.

Polysorbate 20

This medicinal product contains polysorbate 20 (E432) which may cause allergic reactions.

No interaction studies have been performed with topically administered ruxolitinib.

The potential for interactions with ruxolitinib is considered to be low because of the limited systemicexposure following topical administration.

Based on in vitro data, ruxolitinib is predominantly cleared by cytochrome P450 3A4 (CYP3A4)metabolism. Interaction potential was evaluated for oral ruxolitinib in dedicated clinical pharmacologystudies that included co-administration of strong or moderate CYP3A4 inhibitors or a strong inducer.

The plasma AUC is approximately doubled with co-administration of a potent inhibitor of CYP3A4while only a modest increase was seen with co-administration of a moderate CYP3A4 inhibitor.

The use of ruxolitinib cream in combination with other topical medicinal products used to treat vitiligohas not been evaluated and co-application on the same skin areas is not recommended. The efficacyand safety of the combination of ruxolitinib cream with narrow-band ultraviolet B (NB-UVB)phototherapy has not been established; no recommendation can be made.

Other topical medicinal products used to treat other conditions on the same skin areas should beapplied with a minimum of 2 hours after the application of ruxolitinib cream. This is also applicable tothe use of sunscreen or emollients.

Contraception in women of childbearing potential

Women of childbearing potential have to use effective contraception during treatment and for 4 weeksafter discontinuation of treatment.

There are no or limited amount of data from the use of ruxolitinib in pregnant women. Data onsystemic absorption of topical ruxolitinib during pregnancy are lacking. There could also be individualfactors (e.g. damaged skin barrier, excessive use) that contribute to an increased systemic exposure.

Animal studies have shown that ruxolitinib is embryotoxic and foetotoxic following oraladministration. Teratogenicity was not observed in rats or rabbits (see section 5.3). Opzelura iscontraindicated during pregnancy (see section 4.3).

No data are available regarding the presence of ruxolitinib in human milk, the effects on the breastfedchild, or the effects on milk production after topical application of Opzelura. Following oraladministration of ruxolitinib to lactating rats, ruxolitinib and/or its metabolites were present in themilk with a concentration 13-fold higher than the maternal plasma concentration. In juvenile ratstudies, oral administration of ruxolitinib resulted in effects on growth and bone measures (seesection 5.3). Opzelura is contraindicated during breast-feeding (see section 4.3) and treatment must bediscontinued approximately 4 weeks before the beginning of breastfeeding.

There are no human data on the effect of ruxolitinib on fertility. In animal studies, no effect of oralruxolitinib on fertility was observed.

Ruxolitinib cream has no or negligible influence on the ability to drive and use machines.

The most common adverse reaction is application site acne (5.8%).

Adverse reactions are ranked under headings of frequency, with the most frequent first, using thefollowing convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to< 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated fromthe available data).

Table 1: Adverse reactions

System Organ Class Frequency Adverse Reaction

General disorders and Common Application site acneadministration site conditions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Overdose following cutaneous administration is unlikely. If too much of the cream has been applied,the excess can be wiped off.

In cases of accidental ophthalmic, oral mucosa, or intravaginal exposure, the cream should bethoroughly wiped off and/or rinsed with water (see sections 4.2 and 4.4).

Pharmacotherapeutic group: Other dermatological preparations, agents for dermatitis, excludingcorticosteroids, ATC code: D11AH09

Ruxolitinib is a Janus Kinase (JAK) inhibitor with selectivity for the JAK1 and JAK2 isoforms.

Intracellular JAK signalling involves recruitment of STATs (signal transducers and activators oftranscription) to cytokine receptors, and subsequent modulation of gene expression. Autoimmune

IFNγ producing cytotoxic T lymphocytes are thought to be directly responsible for melanocytedestruction in human vitiligo. Recruitment of cytotoxic lymphocytes to lesional skin is mediated via

IFNγ dependent chemokines, such as CXCL10. Downstream signalling of IFNγ is JAK1/2 dependentand treatment with ruxolitinib reduces CXCL10 levels in vitiligo patients.

Two double-blind, randomised, vehicle-controlled studies of identical design (TRuE-V1 and

TRuE-V2) enrolled a total of 674 patients who have vitiligo on the face and total body vitiligo area(facial and nonfacial) not exceeding 10% BSA, with disease extent at initiation ranging from 3.2% to10.1% of BSA, aged 12 years and older (10.7% of patients were 12 to 17 years of age and 6.7% were65 years or older). Females constituted 53.1% of patients, 81.9% of patients were White, 4.7% were

Black, and 4.2% were Asian. The majority of patients had Fitzpatrick skin types III, IV, V, or VI(67.5%).

In both studies, patients were randomised 2:1 to treatment with ruxolitinib cream or vehicle twicedaily for 24 weeks with affected BSA not exceeding 10%, followed by an additional 28 weeks oftreatment with ruxolitinib cream BID for all patients. The primary efficacy endpoint was theproportion of patients achieving a 75% repigmentation in the facial Vitiligo Area Scoring Index(F-VASI75) at week 24. Key secondary endpoints included the proportions of patients achieving a90% repigmentation in F-VASI (F-VASI90), 50% improvement in total body Vitiligo Area Scoring

Index (T-VASI50), and a Vitiligo Noticeability Scale (VNS) score of 4 or 5 (vitiligo 'a lot lessnoticeable' or 'no longer noticeable').

Repigmentation of treated vitiligo lesions and superiority of ruxolitinib cream over vehicle cream wereobserved for both studies, as demonstrated by statistically significant differences in response rates for

F-VASI75/90, T-VASI50, and VNS score of 4 or 5 at week 24 (Table 2).

The treatment effect difference from vehicle emerges numerically as early as week 12. Continuedrepigmentation as assessed by VASI and VNS scores was observed through week 52 for patients whohad continuously applied ruxolitinib cream twice daily from baseline. The proportion of patients whoachieved F-VASI75 over the 52-week treatment period in pooled data from study TRuE-V1 and

TRuE-V2 are shown in Figure 1.

Similar treatment responses at week 52 are seen for those who crossed over from vehicle to ruxolitinib(Figure 1).

Table 2: Percent of patients with vitiligo achieving the primary and key secondaryendpoints at week 24 (intent-to-treat)a

TRuE-V1 TRuE-V2

Opzelura Vehicle Opzelura Vehicle(N = 221) (N = 109) (N = 222) (N = 109)

F-VASI75 (%) 29. 8 7. 4 30.9 11.4

Response rate 22.3b - 19.5c -difference (95% CI) (14.214, 30.471) (10.537, 28.420)

F-VASI90 (%) 15. 3 2.2 16.3 1.3

Response rate 13.2d - 15.0e -difference (95% CI) (7.497, 18.839) (9.250, 20.702)

T-VASI50 (%) 20.6 5.1 23.9 6.8

Response rate 15.5d - 17.1c -difference (95% CI) (8.339, 22.592) (9.538, 24.721)

VNS 4 or 5 (%) 24.5 3.3 20.5 4.9

Response rate 21.2c - 15.5d -difference (95% CI) (14.271, 28.143) (8.515, 22.561)a Primary and key secondary outcomes were corrected using multiple imputation method.b p-value < 0.0001c p-value < 0.001d p-value < 0.005e p-value < 0.01

Figure 1: Proportion of patients achieving F-VASI75 during the 52 week treatment period(Intent-to-treat) - pooled data from study TRuE-V1 and TRuE-V2

At week 52, the observed response rate for F-VASI90, T-VASI50 and VNS was 30.3%, 51.1%, and36.3% respectively for the ITT pooled population.

Durability of response

A Phase 3, double-blind, vehicle-controlled, randomised, withdrawal and treatment-extension study ofruxolitinib cream twice daily enrolled 458 eligible patients with vitiligo who had completed either ofthe parent studies using ruxolitinib (TRuE-V1 and TRuE-V2; week 52); patients were assigned toeither cohort A or B with a follow-up up to 104 weeks.

Cohort A comprised 116 patients who reached ≥ F-VASI90 at week 52 of the parent study. Thesepatients were re-randomised to either ruxolitinib or vehicle (i.e. withdrawal) to study relapse(< F-VASI75). A relapse occurred in 15% of patients in the ruxolitinib group, and in 29% of patientsin the vehicle group. In the latter group, the majority of relapses (9/16) occurred during the first 4months after stopping ruxolitinib cream. Among the 16 patients in the vehicle group who relapsed andwere retreated, re-treatment resulted in a regained F-VASI75 in 12 (75%) patients in a median of 12weeks and F-VASI90 was regained by 11 (69%) patients in a median of 15 weeks.

Cohort B comprised 342 patients who reached < F-VASI90 at week 52 of the parent study. Thesepatients continued with open-label ruxolitinib treatment; at week 104, among patients originallyrandomised to ruxolitinib cream twice daily, 66% reached F-VASI75, and 34% reached F-VASI90.

Safety

Safety in the long-term extension study up to 104 weeks cumulatively was consistent with the profilereported in the parent studies up to 52 weeks.

A total of 72 adolescents (12 to < 18 years; n = 55 ruxolitinib cream, n = 17 vehicle) were included inthe pivotal studies. Adolescents showed equal response rates in primary and key secondary endpointsat 24 weeks when treated with ruxolitinib, as compared to adults from 18-65 years of age.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Opzelura in one or more subsets of the paediatric population for the treatment of vitiligo (see section4.2 for information on paediatric use).

The pharmacokinetics of ruxolitinib cream were investigated in 429 subjects with vitiligo aged12 years and older (12.6% were 12-17 years of age) with a mean ± STD BSA involvement of7.31 ± 2.02% (range 3.2% to 10.0%). Subjects applied approximately 1.58 mg/cm2 of ruxolitinibcream (dose range was approximately 0.18 grams to 8.4 grams of ruxolitinib cream per application) tothe same skin areas twice daily for 24 weeks.

The mean ± STD steady-state trough plasma concentrations was 56.9 ± 62.6 nM with a projected

AUC0-12h at 683 ± 751 h*nM, which is approximately 25% of the observed mean AUC0-12h at steadystate (2716 h*nM) following 15 mg twice daily oral administration in healthy participants. The mean(geometric mean) topical bioavailability for ruxolitinib cream in vitiligo participants in the pooled dataof the two Phase 3 studies was 9.72% (5.78%).

Based on an in vitro study, ruxolitinib is 97% bound to human plasma proteins, mostly to albumin.

Ruxolitinib is metabolised by CYP3A4 and to a lesser extent by CYP2C9.

The mean elimination half-life of orally administered ruxolitinib is approximately 3 hours. The meanapparent terminal half-life of ruxolitinib following topical application of Opzelura was estimated in9 adult and adolescent patients with ≥ 25% BSA involvement with atopic dermatitis and isapproximately 116 hours, reflecting the slow drug absorption rate rather than the drug elimination rate.

The estimated AUC which is adjusted for the pharmacological activity of ruxolitinib plus themetabolites increases approximately two-fold in case of end stage renal disease (ESRD). As aprecautionary measure, Opzelura should not be used by patients with ESRD, due to lack of dataregarding the safety.

Although the AUC was increased following oral administration of ruxolitinib to patients with hepaticimpairment, there was no clear relationship between the severity of hepatic impairment and theincrease in AUC. A dosing advice for patients with hepatic impairment is not necessary.

Ruxolitinib has been evaluated in safety pharmacology, repeated dose toxicity, genotoxicity andreproductive toxicity, and carcinogenicity studies following oral administration. Additional studieswere conducted following dermal administration in minipigs and mice. Target organs associated withthe pharmacological action of ruxolitinib in repeated dose oral studies include bone marrow,peripheral blood and lymphoid tissues. Infections generally associated with immunosuppression werenoted in dogs. Margins (based on unbound AUC) at non-adverse levels in chronic toxicity studieswere approximately 6- and 200-fold in male and female rats, and 10-fold in dogs, relative to systemicexposure observed in patients with vitiligo that applied 1.5% ruxolitinib cream twice daily. Adversedecreases in blood pressure along with increases in heart rate were noted in a dog telemetry study, andan adverse decrease in minute volume was noted in a respiratory study in rats. The margins (based onunbound Cmax) at the non-adverse level in the dog and rat studies were approximately 300-fold and100-fold greater, respectively, than systemic exposure observed in patients with vitiligo that applied1.5% ruxolitinib cream twice daily. No adverse effects were noted in an evaluation of theneuropharmacological effects of ruxolitinib in rats.

A 3-month dermal repeat dose study revealed decreased lymphocyte counts in mice. Margins (basedon unbound AUC) at non-adverse levels were approximately 10-fold in male and 24-fold in femalemice relative to systemic exposure observed in patients with vitiligo that applied 1.5% ruxolitinibcream twice daily. Non-adverse decreased peripheral lymphocyte counts were also noted in minipigsin a 9-month dermal toxicity study. Margins (based on unbound AUC) at non-adverse levels inminipigs were approximately 3-fold relative to systemic exposure observed in patients with vitiligothat applied 1.5% ruxolitinib cream twice daily. This effect was not observed in a 3-month dermaltoxicity study in minipigs. No evidence of systemic toxicity was observed in Gottingen minipigsfollowing topical administration of 1.5% ruxolitinib cream formulation twice daily for up to 9 months.

In juvenile rat studies, oral administration of ruxolitinib resulted in effects on growth and bonemeasures. Reduced bone growth was observed at doses ≥ 5 mg/kg/day when treatment started onpostnatal day 7 (comparable to human newborn) and at ≥ 15 mg/kg/day when treatment started onpostnatal days 14 or 21 (comparable to human infant, 1-3 years). Fractures and early termination ofrats were observed at doses ≥ 30 mg/kg/day when treatment was started on postnatal day 7. Based onunbound AUC, the exposure at the NOAEL (no observed adverse effect level) in juvenile rats treatedas early as postnatal day 7 was approximately 20-fold that of adult patients with vitiligo, whilereduced bone growth and fractures occurred at exposures that were 22- and 150-fold that of adultpatients with vitiligo, respectively. The effects were generally more severe in males and whenadministration was initiated earlier in the postnatal period. Other than bone development, the effects ofruxolitinib in juvenile rats were similar to those in adult rats. Juvenile rats are more sensitive thanadult rats to ruxolitinib toxicity.

In embryofetal development studies, oral administration of ruxolitinib to rats and rabbits duringgestation resulted in decreased foetal weight and increased post-implantation loss at doses associatedwith maternal toxicity. There was no evidence of a teratogenic effect in rats and rabbits. Margins(based on unbound AUC) at non-adverse levels for developmental toxicity in rats were approximately25-fold the systemic exposure observed in patients with vitiligo that applied 1.5% ruxolitinib creamtwice daily. No effects of oral ruxolitinib were noted on fertility in male or female rats. In a pre- andpostnatal development study, a slightly prolonged gestation period, reduced number of implantationsites, and reduced number of pups delivered were observed. In the pups, decreased mean initial bodyweights and short period of decreased mean body weight gain were observed. In lactating rats,ruxolitinib and/or its metabolites were excreted into the milk with a concentration that was 13-foldhigher than the maternal plasma concentration. Ruxolitinib was not mutagenic or clastogenic.

Ruxolinitib showed no carcinogenic potential following topical administration in mice or followingoral administration in Sprague-Dawley rats and Tg.rasH2 mice.

Butylated hydroxytoluene (as an antioxidant in paraffin, white soft) (E321)

Cetyl alcohol

Dimeticone (E900)

Disodium edetate (E385)

Self -emulsifying Glyceryl stearate

Macrogol

Medium chain triglycerides

Methyl parahydroxybenzoate (E218)

Paraffin (E905), Liquid light

Paraffin (E905), White soft

Phenoxyethanol

Phosphoric acid (E338)

Polysorbate 20 (E432)

Propylene glycol (E1520)

Propyl parahydroxybenzoate

Purified water

Stearyl alcohol

Xanthan gum (E415)

Not applicable

21 months

After first opening: 6 months.

Do not store above 30ºC.

Laminate tube with an inner lining of low-density and high-density polyethylene with a polypropylenecap, or aluminium tube with internal lacquer coating with a polypropylene puncture cap.

Tube of 100 g. One tube per carton.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Incyte Biosciences Distribution B.V.

Paasheuvelweg 251105 BP Amsterdam

Netherlands

EU/1/23/1726/001

EU/1/23/1726/002

Date of first authorisation: 19 April 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.