Milrinone®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MILENON® (MYLENON®)

Composition:

Active ingredient: azelaic acid;

1 g of gel contains 150 mg of azelaic acid;

Excipients: propylene glycol, benzoic acid, soy lecithin, polysorbate 80, medium-chain triglycerides, purified water, disodium edetate, carbomer 980, sodium hydroxide.

Pharmaceutical form. Gel.

Main physicochemical properties: opaque, viscous gel, white to almost white in color.

Pharmacotherapeutic group. Medicinal products for the treatment of acne. Topical agents for the treatment of acne. ATC code D10AX03.

Pharmacological Properties

Pharmacodynamics

Acne

The therapeutic efficacy of azelaic acid gel in the treatment of acne is believed to result from its antimicrobial activity and direct effect on follicular hyperkeratosis.

In vitro and in vivo, azelaic acid inhibits keratinocyte proliferation and normalizes the impaired terminal differentiation processes of the epidermis associated with acne.

Clinically, a significant reduction in the density of Propionibacterium acnes colonies and a significant decrease in the proportion of free fatty acids in lipids on the skin surface are observed.

Rosacea

Although the pathophysiology of rosacea is not yet fully understood, experts agree that inflammation involves an increase in various effector molecules (such as kallikrein-5 and cathelicidin), as well as reactive oxygen species (ROS), which participate in pro-inflammatory reactions that are central to this disease.

Azelaic acid has been shown to modulate the inflammatory response in normal human keratinocytes by: activating peroxisome proliferator-activated receptors γ (PPARγ); inhibiting nuclear factor kappa B (NF-kB) transactivation; inhibiting the production of pro-inflammatory cytokines; and inhibiting the release of reactive oxygen species (ROS) by neutrophils, as well as exerting a scavenging effect on existing ROS.

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

These anti-inflammatory properties of azelaic acid may be relevant in the treatment of rosacea.

Pharmacokinetics

After topical application, azelaic acid penetrates all layers of human skin. Penetration occurs more rapidly into damaged skin than into intact skin. Overall, after a single topical application of 1 g of azelaic acid (5 g of 20% cream), 3.6% of the dose is absorbed through the skin. The rate of absorption of azelaic acid is the same for both gel and cream. Part of the azelaic acid absorbed by the skin is excreted unchanged in urine. The remainder is metabolized via β-oxidation into dicarboxylic acids with shorter chain lengths (C7, C5), which are also detected in urine.

The steady-state plasma concentration of azelaic acid in patients with rosacea after 8 weeks of treatment with 15% azelaic acid gel applied twice daily falls within the range observed in healthy volunteers and in patients with acne who follow a normal diet. This indicates that the extent of transdermal absorption of azelaic acid following application of 15% azelaic acid gel twice daily does not alter the systemic load of azelaic acid derived from dietary and endogenous sources.

Clinical Characteristics

Indications. For the treatment of mild to moderate facial papulopustular acne and papulopustular rosacea.

Contraindications. Hypersensitivity to the active substance or to any of the excipients of the gel.

Interaction with other medicinal products and other forms of interaction

Interaction studies have not been conducted. The composition of Milenon**®** gel does not indicate any undesirable interaction for individual components that could negatively affect the safety of the medicinal product. No pharmacospecific interactions have been observed.

Special precautions for use

For external use only.

The gel should not be allowed to enter the eyes, mouth, or come into contact with mucous membranes. If accidental contact occurs, rinse thoroughly with plenty of water immediately. If eye irritation persists, medical advice should be sought. Hands should be washed after each application of Milenon**®**.

During treatment of papulopustular rosacea with Milenon**®** gel, it is advisable to avoid using cleansing agents containing alcohol, alcohol-based solutions, dyes, astringents, abrasive agents, or peeling agents.

In rare cases, exacerbation of bronchial asthma has been reported in patients receiving azelaic acid.

Targeted clinical studies in patients with hepatic or renal impairment, as well as in patients aged 65 years and older, have not been conducted.

This medicinal product contains propylene glycol, which may cause skin irritation, and benzoic acid, which may mildly irritate the skin, eyes, and mucous membranes.

Use during pregnancy or breastfeeding

Pregnancy

Adequate and well-controlled studies of topically applied azelaic acid preparations in pregnant women have not been conducted.

Animal studies indicate a potential effect on pregnancy, embryonic/fetal development, parturition, or postnatal development. However, in animal studies using doses 3–32 times higher than the maximum recommended human dose based on body surface area, no adverse effects were observed. Milenon**®** gel should be used with caution in pregnant women.

Breastfeeding

Newborns should not come into contact with skin or mammary glands to which azelaic acid gel has been applied.

It is unknown whether azelaic acid is excreted in human breast milk in vivo. However, an in vitro study using equilibrium dialysis techniques demonstrated that transfer of the active substance into breast milk is possible. The distribution characteristics of azelaic acid do not suggest significant changes in azelaic acid levels in breast milk, as azelaic acid does not concentrate in breast milk and less than 4% of topically applied azelaic acid is systemically absorbed (without increasing endogenous exposure to the substance above physiological levels).

Nevertheless, azelaic acid gel should be used with caution in breastfeeding women.

Fertility

There are no available data on the effects of azelaic acid gel on human fertility. Animal studies did not reveal any effects on fertility.

Ability to affect reaction speed when driving or operating machinery
Azelaic acid gel has no influence on the ability to drive or operate machinery.

Method of Administration and Dosage

Milenon® gel is intended for topical application to the skin.

The gel should be applied twice daily (in the morning and evening) to affected skin areas and gently rubbed in. The amount sufficient for the entire facial area is a strip approximately 2.5 cm in length, corresponding to 0.5 g of gel.

Before applying the gel, the skin should be thoroughly washed with water or a mild cosmetic cleanser. Then the skin must be completely dried before application of the gel.

Avoid wearing tight clothing or using occlusive dressings at the site of application. Hands should also be thoroughly washed after applying the gel.

If skin irritation occurs, reduce the amount of gel applied each time or decrease the frequency of application to once daily until symptoms of irritation subside. If necessary, discontinue treatment for several days.

It is very important to use this gel continuously throughout the entire treatment period.

The duration of treatment may vary individually for each patient and depends, among other factors, on the severity of the skin condition.

Acne

Noticeable improvement is usually observed after approximately 4 weeks. However, to achieve optimal results, regular use of the gel for several months is recommended, depending on the clinical response. If no improvement is observed after 1 month, or if acne worsens, discontinue use of the medicinal product and consider alternative treatment options.

Rosacea

Noticeable improvement is usually observed after approximately 4 weeks. However, to achieve optimal results, regular use of the gel for several months is recommended, depending on the clinical response. If no improvement is observed after 2 months, or if rosacea worsens, discontinue use of the gel and consider alternative treatment options.

Children

No dose adjustment is required when using the gel for acne treatment in children aged 12–18 years.

The safety and efficacy of azelaic acid gel for acne treatment in children under 12 years of age have not been established.

The safety and efficacy of azelaic acid gel for treatment of papulopustular rosacea in children (under 18 years of age) have not been established.

Overdose. Due to the low toxicity of azelaic acid at both local and systemic levels, intoxication is unlikely to occur.

Adverse Reactions

In clinical trials and during post-marketing surveillance, the most frequently reported adverse effects were itching, burning, and pain at the application site.

Adverse reactions observed during clinical trials and post-marketing surveillance are listed in the table below by frequency of occurrence according to the MedDRA classification and organ systems: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000); frequency not known (cannot be estimated based on available data).

1 Identified during post-marketing use.

2 Local skin irritation usually resolves during treatment.

3 For the treatment of rosacea.

4 For the treatment of acne.

Pediatric use

Treatment of acne in children aged 12–18 years.

In four phase II and II/III clinical trials involving children aged 12 to 17 years (120 out of 383; 31%), the overall incidence of adverse reactions with azelaic acid gel was similar in the age group 12–17 years (40%), the age group ≥18 years (37%), and in the overall patient population (38%). Similar data were also observed in the age group 12–20 years (40%).

Reporting of suspected adverse reactions.

Reporting of adverse reactions after marketing authorization of the medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions

Store at a temperature not exceeding 25 °C in the original packaging.

Keep out of reach and sight of children.

Packaging

30 g in an aluminum tube, 1 tube per cardboard box.

Prescription status

Over-the-counter (without prescription).

Manufacturer

KUSUM HEALTHCARE PVT LTD /

KUSUM HEALTHCARE PVT LTD.

Manufacturer's address and location of manufacturing site

SP-289 (A), RIICO Industrial area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India /

SP-289 (A), RIICO Industrial area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India.