Opzelura 15 mg/g cream

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

Excipients with known effect

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)

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 and adolescents from 12 years of age.

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

Posology

Adults

The recommended dose is a thin layer of cream applied twice daily to the depigmented skin areas up to a maximum of 10% of body surface area (BSA), with a minimum of 8 hours between two applications of ruxolitinib cream. 10% BSA represents an area as large as 10 times the palm of one hand 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. If depigmentation recurs after treatment discontinuation, therapy can be reinitiated on the affected areas.

There is no need to consider tapering therapy.

Special populations

Hepatic impairment

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 hepatic impairment.

Renal impairment

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 renal disease, due to lack of data regarding the safety.

Elderly

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 (see section 5.1). No dose adjustment is required in patients aged 65 years and above.

Paediatric population

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 been established. No data are available.

Method of administration

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 that are being treated. If someone else applies the cream to the patient, they should wash their hands after application.

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 accidental exposure in the eyes or mucous membranes, the cream should be thoroughly wiped off and/or rinsed with water.

Non-melanoma skin cancer

Non-melanoma skin cancers (NMSCs), predominantly basal cell carcinomas, have been reported in patients treated with topical ruxolitinib. Most of these patients had risk factors, such as prior phototherapy 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 skin cancer.

Excipients with known effect

Propylene glycol

This medicinal product contains 150 mg propylene glycol (E1520) in each gram of cream which may cause 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 parahydroxybenzoate which may cause allergic reactions (possibly delayed).

Butylated hydroxytoluene

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

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 systemic exposure 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 pharmacology studies 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 CYP3A4 while 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 vitiligo has not been evaluated and co-application on the same skin areas is not recommended.

Other topical medicinal products used to treat other conditions on the same skin areas should be applied with a minimum of 2 hours after the application of ruxolitinib cream. This is also applicable to the 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 weeks after discontinuation of treatment.

Pregnancy

There are no or limited amount of data from the use of ruxolitinib in pregnant women. Data on systemic absorption of topical ruxolitinib during pregnancy are lacking. There could also be individual factors (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 oral administration. Teratogenicity was not observed in rats or rabbits (see section 5.3). Opzelura is contraindicated during pregnancy (see section 4.3).

Breast-feeding

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

Fertility

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

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

Summary of the safety profile

Safety was primarily evaluated in the pivotal studies, for up to one year. In the long-term extension study (see section 5.1), safety up to 2 years was consistent with the profile reported in the pivotal studies. The most common adverse reaction is application site acne (5.8%).

Tabulated list of adverse reactions

Adverse reactions are ranked under headings of frequency, with the most frequent first, using the following 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 from the available data).

Table 1: Adverse reactions

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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 be thoroughly wiped off and/or rinsed with water (see sections 4.2 and 4.4).

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

Mechanism of action

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 of transcription) to cytokine receptors, and subsequent modulation of gene expression. Autoimmune IFNγ producing cytotoxic T lymphocytes are thought to be directly responsible for melanocyte destruction 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 dependent and treatment with ruxolitinib reduces CXCL10 levels in vitiligo patients.

Clinical efficacy and safety

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% to 10.1% of BSA, aged 12 years and older (10.7% of patients were 12 to 17 years of age and 6.7% were 65 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 twice daily for 24 weeks with affected BSA not exceeding 10%, followed by an additional 28 weeks of treatment with ruxolitinib cream BID for all patients. The primary efficacy endpoint was the proportion 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 a 90% 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 less noticeable" or "no longer noticeable").

Repigmentation of treated vitiligo lesions and superiority of ruxolitinib cream over vehicle cream were observed 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. Continued repigmentation as assessed by VASI and VNS scores was observed through week 52 for patients who had continuously applied ruxolitinib cream twice daily from baseline. The proportion of patients who achieved 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 secondary endpoints at week 24 (intent-to-treat)^a

^a Primary and key secondary outcomes were corrected using multiple imputation method.

^b p-value < 0.0001

^c p-value < 0.001

^d p-value < 0.005

^e 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%, and 36.3% respectively for the ITT pooled population.

Durability of response

A Phase 3, double-blind, vehicle-controlled, randomised, withdrawal and treatment-extension study of ruxolitinib cream twice daily enrolled 458 eligible patients with vitiligo who had completed either of the parent studies using ruxolitinib (TRuE-V1 and TRuE-V2; week 52); patients were assigned to either 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. These patients 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 patients in the vehicle group. In the latter group, the majority of relapses (9/16) occurred during the first 4 months after stopping ruxolitinib cream. Among the 16 patients in the vehicle group who relapsed and were retreated, re-treatment resulted in a regained F-VASI75 in 12 (75%) patients in a median of 12 weeks 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. These patients continued with open-label ruxolitinib treatment; at week 104, among patients originally randomised to ruxolitinib cream twice daily, 66% reached F-VASI75, and 34% reached F-VASI90.

Paediatric population

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

The Medicines and Healthcare products Regulatory 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 section 4.2 for information on paediatric use).

Absorption

The pharmacokinetics of ruxolitinib cream were investigated in 429 subjects with vitiligo aged 12 years and older (12.6% were 12-17 years of age) with a mean ± STD BSA involvement of 7.31 ± 2.02% (range 3.2% to 10.0%). Subjects applied approximately 1.58 mg/cm² of ruxolitinib cream (dose range was approximately 0.18 grams to 8.4 grams of ruxolitinib cream per application) to the 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 AUC_0-12h at 683 ± 751 h*nM, which is approximately 25% of the observed mean AUC_0-12h at steady state (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 data of the two Phase 3 studies was 9.72% (5.78%).

Distribution

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

Biotransformation

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

Elimination

The mean elimination half-life of orally administered ruxolitinib is approximately 3 hours. The mean apparent terminal half-life of ruxolitinib following topical application of Opzelura was estimated in 9 adult and adolescent patients with ≥ 25% BSA involvement with atopic dermatitis and is approximately 116 hours, reflecting the slow drug absorption rate rather than the drug elimination rate.

Special populations

Renal impairment

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

Hepatic impairment

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

Ruxolitinib has been evaluated in safety pharmacology, repeated dose toxicity, genotoxicity and reproductive toxicity, and carcinogenicity studies following oral administration. Additional studies were conducted following dermal administration in minipigs and mice. Target organs associated with the pharmacological action of ruxolitinib in repeated dose oral studies include bone marrow, peripheral blood and lymphoid tissues. Infections generally associated with immunosuppression were noted in dogs. Margins (based on unbound AUC) at non-adverse levels in chronic toxicity studies were approximately 6- and 200-fold in male and female rats, and 10-fold in dogs, relative to systemic exposure observed in patients with vitiligo that applied 1.5% ruxolitinib cream twice daily. Adverse decreases in blood pressure along with increases in heart rate were noted in a dog telemetry study, and an adverse decrease in minute volume was noted in a respiratory study in rats. The margins (based on unbound C_max) at the non-adverse level in the dog and rat studies were approximately 300-fold and 100-fold greater, respectively, than systemic exposure observed in patients with vitiligo that applied 1.5% ruxolitinib cream twice daily. No adverse effects were noted in an evaluation of the neuropharmacological effects of ruxolitinib in rats.

A 3-month dermal repeat dose study revealed decreased lymphocyte counts in mice. Margins (based on unbound AUC) at non-adverse levels were approximately 10-fold in male and 24-fold in female mice relative to systemic exposure observed in patients with vitiligo that applied 1.5% ruxolitinib cream twice daily. Non-adverse decreased peripheral lymphocyte counts were also noted in minipigs in a 9-month dermal toxicity study. Margins (based on unbound AUC) at non-adverse levels in minipigs were approximately 3-fold relative to systemic exposure observed in patients with vitiligo that applied 1.5% ruxolitinib cream twice daily. This effect was not observed in a 3-month dermal toxicity study in minipigs. No evidence of systemic toxicity was observed in Gottingen minipigs following 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 bone measures. Reduced bone growth was observed at doses ≥ 5 mg/kg/day when treatment started on postnatal day 7 (comparable to human newborn) and at ≥ 15 mg/kg/day when treatment started on postnatal days 14 or 21 (comparable to human infant, 1–3 years). Fractures and early termination of rats were observed at doses ≥ 30 mg/kg/day when treatment was started on postnatal day 7. Based on unbound AUC, the exposure at the NOAEL (no observed adverse effect level) in juvenile rats treated as early as postnatal day 7 was approximately 20-fold that of adult patients with vitiligo, while reduced bone growth and fractures occurred at exposures that were 22- and 150-fold that of adult patients with vitiligo, respectively. The effects were generally more severe in males and when administration was initiated earlier in the postnatal period. Other than bone development, the effects of ruxolitinib in juvenile rats were similar to those in adult rats. Juvenile rats are more sensitive than adult rats to ruxolitinib toxicity.

In embryofetal development studies, oral administration of ruxolitinib to rats and rabbits during gestation resulted in decreased foetal weight and increased post-implantation loss at doses associated with 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 approximately 25-fold the systemic exposure observed in patients with vitiligo that applied 1.5% ruxolitinib cream twice daily. No effects of oral ruxolitinib were noted on fertility in male or female rats. In a pre- and postnatal development study, a slightly prolonged gestation period, reduced number of implantation sites, and reduced number of pups delivered were observed. In the pups, decreased mean initial body weights 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-fold higher than the maternal plasma concentration. Ruxolitinib was not mutagenic or clastogenic. Ruxolinitib showed no carcinogenic potential following topical administration in mice or following oral 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

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 30 °C.

Laminate tube with an inner lining of low-density and high-density polyethylene with a polypropylene cap, 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 local requirements.

Incyte Biosciences UK Ltd

First Floor Q1, The Square

Randalls Way, Leatherhead

KT22 7TW, UK

PLGB 42338/0021

04/07/2023

09/11/2023