Postcode of Segrate manufacturer changed.

Section 4.4 Special warnings and precautions for use:

New warning:

Care should be taken when using Skinoren Gel to avoid contact with the eyes, mouth and other mucous membranes, and patients should be instructed accordingly (see section 5.3 Preclinical safety data). 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 Skinoren Gel.

Warning regarding benzoic acid updated/quantified in line with the EU Excipients guideline:

Skinoren Gel contains 1 mg benzoic acid in each g. Benzoic acid may cause local irritation.

Excipient with known effect statement added regarding propylene glycol:

Skinoren Gel contains 120 mg propylene glycol in each g.

Section 4.8

HPRA suspected adverse event reporting details updated.

Additional changes in line with QRD

No previous SPC pdf document uploaded

Summary of Changes

Deleted             Added

 4.2  Posology and method of administration

[…]

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.

[…]

4.6     Fertility, pregnancy and lactation

Pregnancy

There are no adequate and well-controlled studies of topically administered azelaic acid in pregnant women.

Animal studies do not indicate direct or indirect harmful the potential for effects with respect to pregnancy, embryonal-foetal development, parturition or postnatal development. However, the dose levels without observed adverse effects in animals ranged across studies from 3-32 times the maximum recommended human dose based on body surface area (see section 5.3 Preclinical safety data).

Caution should be exercised when prescribing azelaic acid to pregnant women.

[…]

Fertility

There are no data on the effect of Skinoren gel on human fertility. Results from animal studies showed no effect on fertility in male or female rats (see section 5.3 Preclinical safety data).

4.8     Undesirable effects

[…]

*   for indication Rosacea

** for indication Acne

¹     These adverse reactions have been reported during post-approval use of Skinoren gel.

[…]

5.1     Pharmacodynamic properties

[…]

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.

The mechanism by which azelaic acid interferes with the pathogenic events in rosacea is unknown. Several in vitro and ex vivo investigations indicate that azelaic acid may exert an anti-inflammatory effect by reducing the formation of pro-inflammatory, reactive oxygen species.

[…]

5.2     Pharmacokinetic properties

[…]

A portion of the azelaic acid absorbed through the skin is excreted in unchanged form with in the urine. The remaining portion is broken down by b-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 Skinoren 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 Skinoren Gel does not alter the systemic burden of azelaic acid derived from dietary and endogenous sources in a clinically meaningful way.

5.3     Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, 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. No teratogenic effects were observed. The embryofetal NOAEL was 32 time the MRHD based on BSA in rats, 6.5 times the MRHD based on BSA in rabbits and 19 time the MRHD based on BSA in monkeys(see section 4.6 Fertility, pregnancy and lactation)

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, Skinoren 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.

6.1     List of excipients

Benzoic acid (E 210)

Carbomers

Disodium edetate

Lecithin

Triglycerides medium chain

Polysorbate 80

Propylene glycol

Purified water

Carbomers 980

Sodium hydroxide

Disodium edetate

Purified water

Benzoic acid (E 210)

Triglycerides medium chain

·         In section 4.8 on the reporting of adverse effects details were updated to include HPRA contact details instead of the IMB

·         In section 7 the MA holder has been changed to Bayer Limited, The atrium, Blackthorn Road, Dublin 18, Ireland

·         In section 8 the Marketing Authorisation Number has been changed from 1407/6/1 to 1410/72/2

·         In section 10 the Date of Revision has been updated to August 2014

(Inserted text; Deleted text)

2        QUALITATIVE AND QUANTITATIVE COMPOSITION

…

Excipients with known effect:

1 mg Benzoic acid/g Gel

0.12 g Propylene glycol/g Gel

For a the full list of excipients, see section 6.1.

4.2     Posology and method of administration

Skinoren 15 % Gel is intended for cutaneous use only.

Posology

Skinoren 15% Gel is intended for cutaneous use only. Skinoren 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 Skinoren Gel is administered to adolescents aged 12‑18 years.

The safety and efficacy of Skinoren Gel for the treatment of acne vulgaris in children below the age of 12 years have not been established.

The safety and efficacy of Skinoren Gel for the treatment of papulopustular rosacea in children below the age of 18 years have not been established.

Method of administration

Before Skinoren Gel is applied, the skin should be thoroughly cleaned with plain water and dried. A mild skin-cleansing agent may be used.

…

Pediatric population

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

The safety and efficacy of Skinoren Gel for the treatment of acne vulgaris in children below the age of 12 years have not been established.

The safety and efficacy of Skinoren Gel for the treatment of papulopustular rosacea in children below the age of 18 years have not been established.

4.3     Contraindications

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

4.4     Special warnings and precautions for use

…

It is advisable to avoid the concomitant use of alcoholic cleansers, tinctures and astringents, abrasives and peeling agents when in patients using Skinoren Gel for treatment of papulopustular rosacea.

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

4.6     Fertility, pPregnancy and lactation

Pregnancy

There are no adequate and well-controlled studies of topically administered azelaic acid in pregnant women.

…

Lactation

Infants must not come into contact with treated skin/breast.

...

since aAzelaic acid is not concentrated in milk and systemic uptake of  less than 4 % of topically applied azelaic acid is systemically absorbed, did not increasinge endogenous azelaic acid exposure above physiological levels. However, caution should be exercised when Skinoren Gel is administered to a nursing woman.

Infants must not come into contact with treated skin/breast.

4.8     Undesirable effects

Only cutaneous treatment related adverse events were reported in clinical studies. In the great majority of cases the symptoms were mild or moderate; the frequency of irritative symptoms gradually decreased during the course of therapy.

In 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).

Acne:

*   for indication Rosacea

** for indication Acne

Rosacea:

Hypersensitivity has been reported rarely in post-marketing surveillance. Generally, local skin irritation regresses in the course of the treatment.

Worsening of asthma in patients treated with azelaic acid has been reported rarely during post-marketing surveillance (the frequency is not known).

...

10      DATE OF REVISION OF THE TEXT

November 2010 April 2013

4.2     Posology and method of administration

Re-wording of text

More complete information included re paediatric patients:

Pediatric population

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

The safety and efficacy of Skinoren Gel for the treatment of acne vulgaris in children below the age of 12 years have not been established.

The safety and efficacy of Skinoren Gel for the treatment of papulopustular rosacea in children below the age of 18 years have not been established.

4.4     Special warnings and precautions for use

Editorial revision of text

Additional sentence included:

It is advisable to avoid alcoholic cleansers, tinctures and astringents, abrasives and peeling agents when using Skinoren Gel for treatment of papulopustular rosacea.

4.6 Pregnancy and lactation

Current text:

Data on a limited number of exposed pregnancies (n=2) indicate no adverse effects of azelaic acid on pregnancy or on the health of the foetus/newborn child. To date, no other relevant epidemiological data are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development.

Caution should be exercised when prescribing azelaic acid to pregnant women.

Infants must not come into contact with treated skin/breast.

The amount of azelaic acid potentially transferred per day during breast-feeding is negligible and should not imply any risk to the infant.

Revised to:

Pregnancy

There are no adequate and well-controlled studies of topically administered azelaic acid in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3 Preclinical safety data).

Caution should be exercised when prescribing azelaic acid to pregnant women.

Lactation

Infants must not come into contact with treated skin/breast.

It is not known if azelaic acid is secreted into human milk in vivo. However an in vitro equilibrium dialysis experiment demonstrated that passage of drug into maternal milk may occur. But the distribution of azelaic acid into maternal milk is not expected to cause a significant change from baseline azelaic acid levels in the milk since azelaic acid is not concentrated in milk and systemic uptake of topically applied azelaic acid did not increase  endogenous azelaic acid exposure above physiological levels. However, caution should be exercised when Skinoren Gel is administered to a nursing woman.

4.8 Undesirable effects

Current text:

Only cutaneous treatment-related adverse events were reported in clinical trials comprising 269 acne patients treated with Skinoren 15% Gel for up to 4 months and 457 rosacea patients treated with Skinoren 15% Gel for up to 15 weeks. In the great majority of cases the symptoms were mild or moderate; the frequency of cutaneous adverse events gradually decreased during the course of therapy.

The spectrum of undesirable cutaneous effects related to Skinoren 15% Gel was similar in acne and rosacea.

Rosacea:

Acne:

Revised to:

Only cutaneous treatment-related adverse events were reported in clinical studies. In the great majority of cases the symptoms were mild or moderate; the frequency of irritative symptoms gradually decreased during the course of therapy.

In clinical studies, the most frequently observed side effects included application site pruritus, application site burning and application site pain.

Acne:

Rosacea:

Hypersensitivity has been reported rarely in post-marketing surveillance.

Worsening of asthma in patients treated with azelaic acid has been reported rarely during post-marketing surveillance (the frequency is not known).

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 Skinoren Gel was similar for the groups aged 12-17 years (40%), aged ³18 years (37%) and for the entire patient population (38%). This similarity also applied to the group aged 12-20 years (40%).

5.3 Preclinical safety data

Current text:

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

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.

Revised to:

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

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.

6.5 Nature and contents of container

Current text:

Standard aluminium tube with membrane closure, internal coating with epoxide resin, white coloured outside, with screw cap made of high-density polyethylene.

Tubes of 5g, 30g, 50g.

Not all pack sizes may be marketed.

Revised text:

Aluminium tube with internal epoxide coating and polyethylene screw cap.

Tubes of 5, 30, 50, 2 x 50 g.

Not all pack sizes may be marketed.

10. Date of Revision of the Text

Revised to November 2010