Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL)

Topical treatment of acne vulgaris.

For the relief of mild to moderate papular-pustular acne of the facial area.

For the topical treatment of papulopustular rosacea.

Method of administration

Cutaneous use

Dosage regimen

Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Cream should be applied to the affected areas of skin twice daily (mornings and evenings), and rubbed in gently. As a guide 2.5 cm (approx. 0.5 g) of cream is sufficient for the entire facial area. If other areas of acne, in addition to the face require treatment, for example the chest and back, the amount of cream should be adjusted accordingly.

Patients with sensitive skin should be advised to use Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) only once a day (in the evening) for the first week of treatment and then proceed to twice daily applications.

Before Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Cream is applied, the skin should be thoroughly cleaned with plain water and dried. A mild skin-cleansing agent may be used.

The duration of use of Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Cream can vary from patient to patient and also depends on the severity of the acne.).

It is important to continue to use Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Cream regularly over the entire period of treatment. However, in the event of intolerable skin irritation , the amount of cream per application should be reduced or the frequency of use of Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Cream should be reduced to once a day until the irritation ceases. If required, treatment might have to be temporarily interrupted for a few days.

Additional information on special populations

Paediatric population

Use in adolescents (12 - 18 years of age): dose adjustment is not required when Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Cream is administered to adolescents aged 12 - 18 years.

The safety and efficacy of Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Cream in children below the age of 12 years have not been established.

Geriatric patients

No targeted studies have been performed in patients aged 65 and over.

Patients with hepatic impairment

No targeted studies have been performed in patients with hepatic impairment.

Patients with renal impairment

No targeted studies have been performed in patients with renal impairment.

Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) 15 % Gel is intended for cutaneous use only.

Posology

Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Gel should be applied to the affected skin areas twice a day (in the morning and in the evening) and rubbed in gently. Approximately 0.5 g = 2.5 cm (1 inch) of gel is sufficient for the entire facial area.

Pediatric population

Use in adolescents (12-18 years of age) for the treatment of acne vulgaris. Dose adjustment is not required when Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Gel is administered to adolescents aged 12- 18 years.

The safety and efficacy of Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Gel for the treatment of acne vulgaris in children below the age of 12 years have not been established.

The safety and efficacy of Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Gel for the treatment of papulopustular rosacea in children below the age of 18 years have not been established.

Geriatric patients

No targeted studies have been performed in patients aged 65 and over.

Patients with hepatic impairment

No targeted studies have been performed in patients with hepatic impairment.

Patients with renal impairment

No targeted studies have been performed in patients with renal impairment.

Method of administration

Before Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Gel is applied, the skin should be thoroughly cleaned with plain water and dried. A mild skin-cleansing agent may be used.

Occlusive dressing or wrappings should not be used, and hands should be washed after applying the gel.

In the event of skin irritation , the amount of gel per application should be reduced or the frequency of use of Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Gel should be reduced to once a day until the irritation ceases. If required, the treatment should be temporarily interrupted for a few days.

It is important to use Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Gel continuously over the entire period of treatment. The duration of use of Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Gel can vary from person to person and also depends on the severity of the skin disorder.

Acne: In general, a distinct improvement becomes apparent after 4 weeks. To obtain optimum results, Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Gel can be used over several months in accordance with the clinical outcome. In case of no improvement after 1 month or exacerbation of acne, Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Gel should be discontinued and other therapeutic options should be considered.

Rosacea: In general, a distinct improvement becomes apparent after 4 weeks of treatment. To obtain optimum results, Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Gel can be used over several months in accordance with the clinical outcome. In case of no improvement after 2 month or exacerbation of rosacea, Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Gel should be discontinued and other therapeutic options should be considered.

For external use only.

). In the event of accidental contact, the eyes, mouth and/or affected mucous membranes should be washed with large amounts of water. If eye irritation persists, patients should consult a physician. The hands should be washed after each application of Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Cream.

Worsening of asthma in patients treated with azelaic acid has been reported rarely during post-marketing surveillance.

Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) contains a small amount of benzoic acid, which is mildly irritating to the skin, eyes and mucous membranes.

Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) also contains propylene glycol, which may cause skin irritation.

For external use only.

Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Gel contains benzoic acid which is mildly irritant to the skin, eyes and mucous membranes and propylene glycol which may cause skin irritation.). In the event of accidental contact, the eyes, mouth and/or affected mucous membranes should be washed with large amounts of water. If eye irritation persists, patients should consult a physician. The hands should be washed after each application of Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Gel.

It is advisable to avoid the concomitant use of alcoholic cleansers, tinctures and astringents, abrasives and peeling agents in patients using Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Gel for treatment of rosacea.

Worsening of asthma in patients treated with azelaic acid has been reported rarely during post-marketing surveillance.

Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Cream has no influence on the ability to drive and use machines.

Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Gel has no influence on the ability to drive and use machines.

From clinical studies and post-marketing surveillance, the most frequently observed side-effects included application site burning, application site pruritus and application site erythema.

Frequencies of side-effects observed in clinical studies and post-marketing surveillance and given in the table below are defined according to the MedDRA frequency 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).

¹ These additional adverse reactions have been reported during post-approval use of Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) cream (frequency unknown).

² may occur with hypersensitivity

Generally, local skin irritation regresses in the course of treatment.

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 at: www.mhra.gov.uk/yellowcard.

From clinical studies and post-marketing surveillance, the most frequently observed side effects included application site pruritus, application site burning and application site pain.

Frequencies of side-effects observed in clinical studies and post-marketing surveillance and given in the table below are defined according to the MedDRA frequency convention:

Very common (>1/10), Common (>1/100, <1/10), Uncommon (>1/1,000; <1/100), Rare (>1/10,000, <1/1,000), Very rare (<1/10,000), Not known (cannot be estimated from the available data).

* for indication Rosacea

** for indication Acne

¹ These adverse reactions have been reported during post-approval use of Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) gel.

Generally, local skin irritation regresses in the course of the treatment.

Pediatric population

Treatment of acne vulgaris in adolescents 12-18 years of age:

In 4 clinical phase II and II/III studies involving adolescents 12-17 years of age (120/383; 31%), the overall incidence of adverse events for Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Gel was similar for the groups aged 12-17 years (40%), aged >18 years (37%) and for the entire patient population (38%). This similarity also applied to the group aged 12-20 years (40%).

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 at: www.mhra.gov.uk/yellowcard.

No known cases of azelaic acid overdosage resulting from topical administration of Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Cream have been reported. Results from acute toxicity studies do not indicate that any risk of acute intoxication is to be expected following a single dermal application of an overdose (application over a large area under conditions favourable to absorption) or inadvertent oral ingestion. Due to the very low local and systemic toxicity of azelaic acid intoxication is unlikely.

Due to the very low local and systemic toxicity of azelaic acid intoxication is unlikely.

Pharmacotherapeutic group: other anti-acne preparations for topical use.

ATC Code: D10AX03

The antimicrobial action and a direct influence on follicular hyperkeratosis are assumed to be the basis for the therapeutic efficacy of Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) in acne.

Clinically, a significant reduction of the colonization density of Propionibacterium acnes and a significant reduction of the fraction of free fatty acids in the skin surface lipids is observed.

In vitro and in vivo, azelaic acid inhibits the proliferation of keratinocytes and normalizes the disturbed terminal epidermal differentiation processes in acne. In the rabbit ear model, azelaic acid accelerates the comedolysis of tetradecane-induced comedones.

There is clinical experience for a continuous application time period of up to one year.

Pharmacotherapeutic group: Other anti-acne preparations for topical use, ATC code: D10A X03

Acne:

An antimicrobial action and a direct influence on follicular hyperkeratosis are assumed to be the basis for the therapeutic efficacy of azelaic acid in acne.

In vitro and in vivo, azelaic acid inhibits the proliferation of keratinocytes and normalizes the disturbed terminal epidermal differentiation processes in acne.

Clinically, a significant reduction of the colonization density of Propionibacterium acnes and a significant reduction in the fraction of free fatty acids in the skin surface lipids are observed.

In two double blind randomized clinical studies Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Gel was significantly superior to its vehicle in the median reduction of the sum of papules and pustules, and was 6 % less effective than benzoyl peroxide 5 % (p=0.056).

In these studies effectiveness of Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Gel on comedones has been evaluated as a secondary parameter. Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Gel was more effective than its vehicle in the median relative reduction of comedones, and was less effective in comparison to benzoyl peroxide 5 %.

Rosacea:

While the pathophysiology of rosacea is not completely understood, there is increasing consensus that inflammation involving the elevation of several pro- inflammatory effector molecules such as kallikrein-5 and cathelicidin as well as reactive oxygen species (ROS), is a central process of this disease.

Azelaic acid has been demonstrated to modulate the inflammatory response in normal human keratinocytes by: a) activating the peroxisome proliferator-activated receptor γ (PPARγ); b) inhibiting the trans-activation of nuclear factor-kB (NF-kB); c) inhibiting the production of pro-inflammatory cytokines and d) inhibiting the release of ROS from neutrophils, as well as direct scavenging effects on existing ROS.

In addition, azelaic acid has been shown to directly inhibit kallikrein-5 and cathelicidin expression in three models: in vitro (human keratinocytes), in murine skin and in the facial skin of patients with rosacea.

These anti-inflammatory properties of azelaic acid may play a role in the treatment of rosacea.

While the clinical significance of these findings regarding kallikrein-5 and cathelicidin and their impact on the pathophysiology of rosacea has not yet been fully demonstrated in a large clinical study, initial studies in human facial skin appear to confirm the in vitro and murine findings.

.

In the two vehicle controlled 12 week clinical studies in papulopustular rosacea, Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Gel was statistically significantly superior to its vehicle with regard to the reduction in inflammatory lesions, Investigator's Global Assessment, overall rating of improvement and with regard to improvement of erythema.

In the clinical study with the active comparator metronidazole 0.75 % gel in papulopustular rosacea, Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Gel showed significant superiority with regard to lesion count reduction (72.7 % versus 55.8 %), overall rating of improvement and with regard to improvement of erythema (56 % versus 42 %). The rate of cutaneous adverse events, which in most cases were mild to moderate, was 25.8 % with Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Gel and 7.1 % with metronidazole 0.75 % gel.

There was no noticeable effect on the teleangiectasias in the three clinical studies.

After dermal administration of the cream, azelaic acid penetrates into all layers of human skin. The penetration is more rapid into damaged skin than into intact skin. A total of 3.6% of the administered dose was absorbed percutaneously after a single topical administration of 1 g azelaic acid (5 g cream).

A portion of the azelaic acid which is absorbed through the skin is eliminated unchanged with the urine. The remaining portion is metabolized through beta- oxidation into short-chained dicarboxylic acids (C₇, C₅ carboxylic acids) which have likewise been found in the urine.

Azelaic acid penetrates into all layers of the skin after topical application of the gel. Penetration is faster into damaged skin than into intact skin. A total of 3.6 % of the dose applied was absorbed percutaneously after a single topical application of 1 g azelaic acid (administered as 5 g Skinoren 20 % Cream). Clinical investigations in acne patients indicated similar absorption rates of azelaic acid from Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Gel and Skinoren Cream.

A portion of the azelaic acid absorbed through the skin is excreted in unchanged form in the urine. The remaining portion is broken down by β-oxidation into dicarboxylic acids with shorter chain length (C₇, C₅), which have likewise been found in the urine.

Steady-state plasma levels of azelaic acid in rosacea patients after 8 weeks twice daily treatment with Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Gel were within the range also observed in volunteers and acne patients on normal diets. This indicates that the extent of percutaneous absorption of azelaic acid following twice daily application of Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Gel does not alter the systemic burden of azelaic acid derived from dietary and endogenous sources in a clinically meaningful way.

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

Embryofetal developmental studies with oral administration of azelaic acid to rats, rabbits, and cynomolgus monkeys during the period of organogenesis revealed embryotoxicity at doses where some maternal toxicity was noted.).

In a peri- and post-natal developmental study in rats where azelaic acid was administered orally from gestational day 15 to through day 21 postpartum slight disturbances in the post-natal development of fetuses were noted at oral doses that generated some maternal toxicity. The NOAEL was 3 times the MRHD based on BSA. No effects on sexual maturation of the fetuses were noted in this study.

Studies on impairment of fertility in animals have not produced any evidence for such a risk during therapeutic use of Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL).

If azelaic acid came into contact with the eyes of monkeys and rabbits, signs of moderate to severe irritation became evident. Therefore, contact with the eyes should be avoided.

Azelaic acid administered once intravenously had no effects on the nervous system (Irwin test), cardiovascular function, intermediary metabolism, smooth muscles and liver and kidney function

Non-clinical data reveal no special hazard for humans based on conventional studies of, repeated dose toxicity and toxicity to reproduction.

Embryofetal developmental studies with oral administration of azelaic acid to rats, rabbits, and cynomolgus monkeys during the period of organogenesis revealed embryotoxicity at doses where some maternal toxicity was noted.)

In a peri- and post-natal developmental study in rats where azelaic acid was administered orally from gestational day 15 to through day 21 postpartum slight disturbances in the post-natal development of fetuses were noted at oral doses that generated some maternal toxicity. The NOAEL was 3 times the MRHD based on BSA. No effects on sexual maturation of the fetuses were noted in this study

In vitro and in vivo studies with azelaic acid produced no evidence of mutagenic effects on germ and somatic cells. Conventional long-term carcinogenicity studies with oral administration of azelaic acid have not been performed. In a 26-week dermal carcinogenicity study using male and female transgenic (Tg.AC) mice, Leo (ANTIBACTERIALS _OTHER DERMATOLOGICAL) Gel and the gel vehicle did increase the number of papillomas in male animals after twice daily application at the treatment site. This effect was not observed after single administration in male and female mice. This effect may be associated with the vehicle application. The clinical relevance of the findings in animals to humans is not clear, especially in the light of the doubtful validity of the Tg.AC test system.

If azelaic acid came into contact with the eyes of monkeys and rabbits, signs of moderate to severe irritation became evident. Therefore, contact with the eyes should be avoided.

Azelaic acid administered once intravenously had no effects on the nervous system (Irwin test), cardiovascular function, intermediary metabolism, smooth muscles and liver and kidney function.

None known.

Not applicable.