4.1. Therapeutic indications

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

4.2. Posology and method of administration

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.

4.3. Contraindications

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

Pregnancy and breastfeeding (see section 4.6).

4.4. Special warnings and precautions for use

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.

Herpes zoster

Cases of herpes zoster reactivation have been reported in patients treated with topical ruxolitinib. If a patient develops herpes zoster, temporary interruption of ruxolitinib cream therapy should be considered until the episode resolves.

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.

Polysorbate 20

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

4.5. Interaction with other medicinal products and other forms of interaction

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. The efficacy and 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 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.

4.6. Fertility, pregnancy and lactation

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.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

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

System Organ Class

Frequency

Adverse Reaction

General disorders and administration site conditions

Common

Application site acne

Infections and infestations

Uncommon

Herpes zoster

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.

4.9. Overdose

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).