4.1. Therapeutic indications

This medicinal product is indicated for cutaneous treatment of Acne vulgaris when comedones, papules and pustules are present (see section 4.2 and 5.1).

Adapalene/Benzoyl Peroxide Zentiva is indicated in adults and adolescents aged 12 years and over.

4.2. Posology and method of administration

The gel should be applied to the entire acne affected areas of the face and the trunk once a day in the evening on a clean and dry skin.

The duration of treatment should be determined by the Doctor on the basis of the clinical condition and on the therapeutic response to the treatment. Early signs of clinical improvement usually appear after 1 to 4 weeks of treatment. If no improvement is observed after 4‑8 weeks of treatment, the benefit of continued treatment should be reconsidered.

A lower strength of this gel is available (Adapalene/Benzoyl Zentiva 0.1%/2.5% gel) and this concentration should be considered in patients with moderate acne vulgaris (see section 5.1).

When the entire face is involved with numerous papulopustules, an increased clinical benefit was observed in the subjects treated with adapalene/ benzoyl peroxide 0.3%/2.5% gel compared with the reference therapy (adapalene/ benzoyl peroxide 0.1%/2.5% gel). Physicians may choose between the two concentrations based on the presenting patient's clinical condition and severity.

Special populations

Elderly

The safety and efficacy of adapalene/ benzoyl peroxide gel in geriatric patients aged 65 years and above have not been established.

Renal and hepatic impairment

This medicinal product has not been studied in patients with renal and hepatic impairment.

Paediatric population

The safety and efficacy of this medicinal product have not been studied in children below 12 years of age.

Method of administration

Cutaneous use only.

The gel should be applied in thin layer on the affected areas of the face and/or trunk once daily after washing. It is recommended to use a pea-sized amount for each area of the face (e.g. forehead, chin, each cheek), avoiding the eyes and lips (see section 4.4).

Patients should be instructed to wash their hands after applying the medicinal product.

Cosmetics may be applied after the medicinal product has dried.

If irritation occurs, the patient should be directed to apply non comedogenic moisturisers as needed, to use the medication less frequently (e.g. every other day), to suspend use temporarily, or to discontinue use altogether.

4.3. Contraindications

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

• Pregnancy (see section 4.6)

• Women planning a pregnancy (see section 4.6)

4.4. Special warnings and precautions for use

Adapalene/Benzoyl Peroxide Zentiva should not be applied to damaged skin, either broken (cuts or abrasions), eczematous or sunburned.

Adapalene/Benzoyl Peroxide Zentiva should not come into contact with the eyes, mouth, nostrils or mucous membranes. If product enters the eye, it should be washed immediately with warm water.

If a reaction suggesting sensitivity to any component of the formula occurs, the use of this medicinal product should be discontinued.

Excessive exposure to sunlight or UV radiation should be avoided.

Adapalene/Benzoyl Peroxide Zentiva should not come into contact with any coloured material including hair and dyed fabrics as this may result in bleaching and discoloration.

The efficacy and safety of adapalene/benzoyl peroxide gel in patients with severe nodular or deep nodulocystic acne have not been studied. As patients with severe nodular / nodulocystic acne are at increased risk of permanent scarring secondary to acne lesions, the use of this gel in these patients is not recommended due to the risk of insufficient therapeutic response.

Excipients

This product contains 40 mg of propylene glycol (E1520) in each gram of gel which is equivalent to 4.00% w/w that may cause skin irritation.

This medicine can contain up to 2.5 mg of benzoic acid per g of gel, as degradation product of benzoyl peroxide. Benzoic acid may cause local irritation.

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

No interaction studies have been performed.

From previous experience with adapalene and benzoyl peroxide, there are no known interactions with other medicinal products which might be used cutaneously and concurrently with the gel. However, other retinoids or benzoyl peroxide or medicinal products with a similar mode of action should not be used concurrently. Caution should be exercised if cosmetics with desquamative, irritant or drying effects are used, as they may produce additive irritant effects with this medicinal product.

Absorption of adapalene through human skin is low (see section 5.2), and therefore interaction with systemic medicinal products is unlikely.

The percutaneous penetration of benzoyl peroxide in the skin is low and the drug substance is completely metabolised into benzoic acid which is rapidly eliminated. Therefore, the potential interaction of benzoic acid with systemic medicinal products is unlikely to occur.

4.6. Fertility, pregnancy and lactation

Orally administered retinoids have been associated with congenital abnormalities. When used in accordance with the prescribing information, topically administered retinoids are generally assumed to result into low systemic exposure due to minimal dermal absorption. However, there could be individual factors (e.g. damaged skin barrier, excessive use) that contribute to an increased systemic exposure.

Pregnancy

Adapalene/benzoyl peroxide is contraindicated in pregnancy or in women planning a pregnancy (see section 4.3).

There are no or limited amount of data from the use of adapalene topically in pregnant women.

Animal studies by the oral route have shown reproductive toxicity at high systemic exposure (see section 5.3).

Clinical experience with locally applied adapalene and benzoyl peroxide in pregnancy is limited.

If the product is used during pregnancy, or if the patient becomes pregnant while using this medicinal product, treatment should be discontinued.

Breast-feeding

No study on animal or human milk transfer was conducted after cutaneous application of adapalene and benzoyl peroxide gel. Available pharmacokinetic data in rats have shown excretion of adapalene in milk after oral or intravenous administration of adapalene.

A risk to the suckling child cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from this therapy weighing the benefit of breast-feeding for the child and the benefit of therapy for the woman.

To avoid contact exposure of the infant, application of this gel to the chest should be avoided when used during breast-feeding.

Fertility

No human fertility studies were conducted with adapalene and benzoyl peroxide gel.

However, no effects of adapalene or benzoyl peroxide on fertility were found in rats in reproductive studies (See section 5.3).

4.7. Effects on ability to drive and use machines

Adapalene/Benzoyl Peroxide Zentiva has no or negligible effects on the ability to drive and use machines..

4.8. Undesirable effects

Summary of safety profile

Approximately 10% of patients can be expected to experience adverse skin reactions. Treatment-related adverse reactions typically associated with use of adapalene/benzoyl peroxide gel include mild to moderate application site reactions, such as skin irritation mainly characterised by scaling, dryness, erythema, and burning/stinging. Recommendation is to use moisturiser, temporarily reduce the application frequency to every other day, or temporarily discontinue its use until once daily schedule can be resumed.

These reactions usually occur early in the treatment and tend to gradually decrease over time.

Tabulated summary 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 adapalene/bezoyl peroxide gel in vehicle-controlled phase 3 clinical study (see Table 1).

Table 1: Adverse events

MedDRA System Organ Class

Frequency

Adverse drug reaction

Eye disorders

Uncommon

Erythema of eyelid

Not known*

Eyelid oedema

Immune system disorders

Not known *

Anaphylactic reaction

Nervous system disorders

Uncommon

Paresthesia (tingling at application site)

Respiratory, thoracic and mediastinal disorders

Not known *

Throat tightness, dyspnoea

Skin and subcutaneous tissue disorders

Common

Atopic dermatitis, eczema, skin burning sensation, skin irritation, erythema, skin exfoliation (scaling)

Uncommon

Dry skin, pruritus, rash

Not known *

Allergic contact dermatitis, swelling face, pain of skin (stinging pain), blisters (vesicles), skin discoloration (hyperpigmentation and hypopigmentation), urticaria, application site burn**

*Post marketing surveillance data reported since the global launch of adapalene/benzoyl peroxide 0.1%/2.5% gel, from a population of unknown size

**Most of the cases of “application site burn” were superficial burns but cases with second degree burn or severe burn reactions have been reported.

Skin‑related adverse events were more frequent with adapalene/benzoyl peroxide 0.3% / 2.5% gel than the lower concentration gel (adapalene 0.1% / benzoyl peroxide 2.5%) as compared to vehicle. In the pivotal study (see section 5.1), 9.2% of subjects in the combined population treated with adapalene/benzoyl peroxide 0.3%/2.5% gel had skin-related adverse events and 3.7% in the population treated with adapalene/benzoyl peroxide gel compared to Vehicle gel group (2.9%).

In addition to some of the above, other adverse drug reactions were reported in clinical trials with adapalene 0.1% / benzoyl peroxide 2.5% gel, the previously approved fixed combination of adapalene and benzoyl peroxide:

Other adverse drug reactions reported in clinical trials with adapalene/benzoyl peroxide gel are irritative contact dermatitis (common) and sunburn (uncommon).

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Adapalene/Benzoyl Peroxide Zentiva is for once-daily cutaneous use only. Excessive application of the gel may result in severe irritation. In this event, the patient must discontinue the treatment and wait until the skin has recovered.

In case of accidental ingestion, appropriate symptomatic measures should be taken.