One gram of gel contains 3.3 mg of brimonidine, equivalent to 5 mg of brimonidine tartrate. Excipient(s) with known effect: One gram of gel contains 1 mg methylparahydroxybenzoate (E218) and 55 mg propylene glycol. For the full list of excipients, see section 6.1.

PHARMACEUTICAL FORM

CLINICAL PARTICULARS

Posology and method of administration

One application per 24 hours, at any time suitable for the patient, for as long as facial erythema is present. The maximum daily recommended dose is 1 g of gel in total weight, divided into five pea size amounts.

The experience of use of Mirvaso in patients aged above 65 years is limited (see also section 4.8).

The safety and efficacy of Mirvaso in children and adolescents aged less than 18 years have not been established. No data are available. Mirvaso is contraindicated in children aged less than 2 years because of serious systemic safety risk (see section 4.3). Safety concerns related to the systemic absorption of brimonidine have also been identified for the age group 2 to 12 years (see section 4.9). Mirvaso should not be used in children or adolescents aged 2 to 18 years.

Cutaneous use only. Cutaneous application of a small pea size amount of medicinal product to each of the five areas of the face: forehead, chin, nose, each cheek. Mirvaso should be applied smoothly and evenly as a thin layer across the entire face avoiding the eyes, eyelids, lips, mouth and membrane of the inner nose. Mirvaso should be applied only to the face. Hands should be washed immediately after applying the medicinal product. Mirvaso can be used in conjunction with other cutaneous medicinal products for the treatment of inflammatory lesions of rosacea and with cosmetics. These products should not be applied immediately before the daily application of Mirvaso; they may be used only after the applied Mirvaso has dried.

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Children aged less than 2 years. Patients receiving monoamine oxidase (MAO) inhibitor therapy (for example selegiline or moclobemide) and patients on tricyclic (such as imipramine) or tetracyclic (such as maprotiline, mianserin or mirtazapin) antidepressants which affect noradrenergic transmission.

Special warnings and precautions for use

Mirvaso should not be applied on irritated skin or open wounds. In case of severe irritation or contact allergy, the treatment with the medicinal product should be discontinued. Mirvaso should not be applied close to the eyes. Mirvaso has not been studied in patients with renal or hepatic impairment. Any increase in the daily amount applied and/or frequency of daily application of the medicinal product should be avoided, since the safety of higher daily doses or repeated daily application has not been assessed. The concomitant use of other systemic alpha adrenergic receptor agonists may potentiate the undesirable effects of this class of medicinal products in patients:

The medicinal product contains methylparahydroxybenzoate (E218) which may cause allergic reactions (possibly delayed), and propylene glycol which may cause skin irritation.

Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed. Mirvaso is contraindicated in patients receiving monoamine oxidase (MAO) inhibitor therapy and patients on tricyclic or tetracyclic antidepressants which affect noradrenergic transmission (see section 4.3). The possibility of an additive or potentiating effect with central nervous system depressants (alcohol, barbiturates, opiates, sedatives, or anaesthetics) should be considered. No data on the level of circulating catecholamines after Mirvaso administration are available. Caution, however, is advised in patients taking substances which can affect the metabolism and uptake of circulating amines e.g. chlorpromazine, methylphenidate, reserpine. Caution is advised when initiating (or changing the dose of) a concomitant systemic substance (irrespective of pharmaceutical form) which may interact with alpha adrenergic receptor agonists or interfere with their activity i.e. agonists or antagonists of the adrenergic receptor e.g. (isoprenaline, prazosin). Brimonidine may cause clinically insignificant decreases in blood pressure in some patients. Caution is therefore advised when using medicinal products such as anti-hypertensives and/or cardiac glycosides concomitantly with brimonidine.

Fertility, pregnancy and lactation

There are no or limited amount of data from the use of brimonidine in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Mirvaso during pregnancy.

It is unknown whether brimonidine/metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. Mirvaso should not be used during breast-feeding.

Brimonidine did not present any special reproductive or developmental hazard in animal species.

Effects on ability to drive and use machines

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

Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions are erythema, pruritus, flushing and skin burning sensation, all occurring in 1.2 to 3.3% of patients in clinical studies. They are typically mild to moderate in severity, and usually do not require discontinuation of treatment. No meaningful differences in the safety profiles were observed between the elderly subject population and subjects 18 to 65 years of age.

Tabulated list of adverse reactions

The adverse reactions are classified by System Organ Class and frequency, 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) and were reported with Mirvaso in clinical studies (see Table 1).

Table 1 - Adverse reactions

System Organ Class	Frequency	Adverse reactions
Nervous system disorders	Uncommon	Headache, paraesthesia
Eye disorders	Uncommon	Eyelid oedema
Vascular disorders	Common	Flushing
Respiratory, thoracic and mediastinal disorders	Uncommon	Nasal congestion
Gastrointestinal disorders	Uncommon	Dry mouth
System Organ Class	Frequency	Adverse reactions
Skin and subcutaneous tissue disorders	Common	Erythema, pruritus, skin burning sensation
Skin and subcutaneous tissue disorders	Uncommon	Rosacea, dermatitis, skin irritation, skin warm, contact dermatitis, allergic contact dermatitis, dry skin, pain of skin, skin discomfort, rash papular, acne
General disorders and administration site conditions	Uncommon	Feeling hot, peripheral coldness

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 national reporting system listed in Appendix V.

Overdose

Overdoses after oral use of other alpha2-agonists have been reported to cause symptoms such as hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmias, miosis, apnoea, hypotonia, hypothermia, respiratory depression and seizure. Treatment of an oral overdose includes supportive and symptomatic therapy; a patent airway should be maintained. No cases of overdose after cutaneous use of Mirvaso were reported during the clinical development program.

Serious adverse reactions following inadvertent ingestion of Mirvaso by two young children of one clinical study subject have been reported. The children experienced symptoms consistent with previously reported oral overdoses of alpha2-agonist in young children. Both children were reported to have made a full recovery within 24 hours.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group: Other dermatological preparations, Other dermatologicals, ATC code: D11AX21.

Brimonidine is a highly selective alpha2-adrenergic receptor agonist that is 1000-fold more selective for the alpha2-adrenergic receptor than the alpha1-adrenergic receptor.

Cutaneous facial application of a highly selective alpha2-adrenergic receptor agonist reduces erythema through direct cutaneous vasoconstriction.

The efficacy of Mirvaso in the treatment of moderate to severe facial erythema of rosacea has been demonstrated in two randomised, vehicle controlled blinded clinical trials, which were identical in design. Moderate to severe erythema was defined as a grade 3 or greater on both the Clinician Erythema Assessment (CEA) scale and Patient Self-Assessment (PSA) scale. The studies were conducted in 553 randomised subjects aged 18 years and older who were treated once daily for 4 weeks with either Mirvaso or vehicle. Of these, 539 completed 29 days of treatment and had data available to be included in the efficacy analysis at Day 29, with the majority being Caucasians between 18 and 65 years of age. The primary endpoint was expressed in terms of composite success i.e. subjects responding with a 2-grade reduction on both baseline CEA score and baseline PSA score on Day 29. The results from both clinical studies demonstrated that Mirvaso was significantly more effective (p<0.001) in the reduction of facial erythema of rosacea than vehicle gel when applied once daily for 29 days (primary endpoint, see Table 2). For the population subset of patients with severe erythema at baseline Day 1 (i.e. subjects with CEA or PSA grade of 4) which represented 26% of the randomised subjects, the results on the primary endpoint on Day 29 were similar to those results observed in the overall population (see Table 3) and were statistically significant for both studies combined (p=0.003). In addition, for the overall population, Mirvaso demonstrated statistical superiority (p<0.001) over vehicle gel with respect to rapid initial onset of a clinically meaningful effect (1-Grade Composite Success for CEA and PSA) after the first application at 30 minutes on Day 1(secondary endpoint 27.9% vs. 6.9% for Study 1, 28.4% vs. 4.8% for Study 2), and to achievement of a clinically meaningful effect (1-Grade Composite Success for CEA and PSA) on Day 29 (tertiary endpoint, see Table 4). CEA and PSA were defined as follows: CEA: Clinician Erythema Assessment: 0=Clear skin with no signs of erythema, 1=Almost clear; slight redness, 2=Mild erythema; definite redness, 3=Moderate erythema+ marked redness and 4=Severe erythema+ fiery redness PSA: Patient Self-Assessment: 0=No redness, 1=Very mild redness, 2=Mild redness, 3=Moderate redness and 4=Severe redness

Table 2: Percentage of subjects with a 2-grade improvement in both CEA and PSA

Table 3: Percentage of subjects with severe erythema at baseline Day 1 (CEA or PSA grade 4) with 2-grade improvement in both CEA and PSA

Table 4: Percentage of subjects with a 1-grade improvement in both CEA and PSA

No clinically meaningful trends with respect to tachyphylaxis or rebound effects (worsening of baseline erythema after cessation of treatment) were observed with use of Mirvaso for 29 days. The results from a long term open label study in 449 patients, with continuous treatment for up to one year, confirmed that chronic use of Mirvaso is safe and effective. Daily reductions in erythema for the first month of use (as measured with the CEA and PSA scales) were similar to those observed in the controlled trials, and those reductions were achievable for up to 12 months with no apparent loss of effect over time. The overall frequencies of adverse reactions in this study are reflected in Table 1 above, with the highest rates occurring in the first 29 days of use. No adverse reactions had an increase in frequency over time, and there was no evidence that long-term use of Mirvaso conveyed an increased risk of occurrence of any specific type of adverse reaction. Concomitant use of Mirvaso with other medicinal products for the treatment of inflammatory lesions of rosacea has not been systematically investigated. However, in the long term open label study, the efficacy and safety of Mirvaso, as described above, was not affected by the concomitant use of cosmetics or other medicinal products (e.g. topical metronidazole, topical azelaic acid, and oral tetracyclines including low dose doxycycline) for the treatment of inflammatory lesions of rosacea in the concerned subpopulation (131/449 patients in the study used concomitant rosacea medicinal product).

The European Medicines Agency has waived the obligation to submit the results of studies with Mirvaso in all subsets of the paediatric population in treatment of rosacea (see section 4.2 for information on paediatric use).

Pharmacokinetic properties

The absorption of brimonidine from Mirvaso was evaluated in a clinical study in 24 adult subjects with facial erythema of rosacea. All enrolled subjects received a single-day ocular administration of a 0.2% eye drops solution of brimonidine followed by a once daily cutaneous application of Mirvaso for 29 days (intra-individual comparison of systemic exposure). On Day 1 of the study, all subjects received 1 drop of the 0.2% eye drops solution in each eye, every 8 hours over a 24-hour period (3 doses in total). After repeated cutaneous application of Mirvaso on facial skin, no drug accumulation in plasma was observed throughout the treatment duration: the highest mean (+- standard deviation) plasma maximum concentration (Cmax) and area under the concentration-time curve from 0 to 24 hours (AUC0-24hr) were 46 +- 62 pg/mL and 417 +- 264 pg.hr/mL respectively. These levels are significantly lower (2-fold) than those observed following single-day ocular administration of a 0.2% eye drops solution of brimonidine.

Urinary excretion is the major route of elimination of brimonidine and its metabolites.

Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.

PHARMACEUTICAL PARTICULARS

List of excipients

Carbomer Methylparahydroxybenzoate (E218) Phenoxyethanol Glycerol Titanium dioxide Propylene glycol Sodium hydroxide Purified water

Incompatibilities

Shelf life

Special precautions for storage

This medicinal product does not require any special storage condition. Do not freeze.

Nature and contents of container

Polyethylene (PE)/Aluminium (Al)/ Polyethylene (PE) laminated plastic tubes with a high density polyethylene (HDPE) head and polypropylene (PP) child resistant closure. Pack sizes: 1 tube of 2 g,10 g or 30 g. Not all pack sizes may be marketed.

Special precautions for disposal

MARKETING AUTHORISATION HOLDER

Galderma International Tour Europlaza, 20 avenue Andre Prothin - La Defense 4 La Defense Cedex 92927 France

MARKETING AUTHORISATION NUMBER(S)

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

DATE OF REVISION OF THE TEXT

{MM/YYYY} Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

Success day 29	Study 1		Study 2
Success day 29	Mirvaso Gel n=127	Vehicle Gel n=128	Mirvaso Gel n=142	Vehicle Gel n=142
3 hours after application	31.5%	10.9%	25.4%	9.2%
6 hours after application	30.7%	9.4%	25.4%	9.2%
9 hours after application	26.0%	10.2%	17.6%	10.6%
12 hours after application	22.8%	8.6%	21.1%	9.9%
Day 29 p-value	<0.001	-	<0.001	-

Success day 29	Study 1 + Study 2
Success day 29	Mirvaso Gel n=79	Vehicle Gel n=63
3 hours after application	22.8%	9.5%
6 hours after application	26.6%	7.9%
9 hours after application	20.3%	11.1%
12 hours after application	21.5%	4.8%
Day 29 p-value	0.003	-

Success Day 29	Study 1		Study 2
Success Day 29	Mirvaso Gel n=127	Vehicle Gel n=128	Mirvaso Gel n=142	Vehicle Gel n=142
3 hours after application	70.9%	32.8%	71.1%	40.1%
6 hours after application	69.3%	32.0%	64.8%	43.0%
9 hours after application	63.8%	29.7%	66.9%	39.4%
12 hours after application	56.7%	30.5%	53.5%	40.1%
Day 29 p-value	<0.001	-	<0.001	-

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

NAME OF THE MEDICINAL PRODUCT

QUALITATIVE AND QUANTITATIVE COMPOSITION