Solantra cream 10 mg tube 30 g

Instructions for Soolantra cream 10 mg tube 30 g

Composition

active ingredient: ivermectin;

1 g of cream contains ivermectin 10 mg;

excipients: glycerin; isopropyl palmitate; carbomer copolymer type B; dimethicone 20 Cst; disodium edetate; citric acid, monohydrate; cetyl alcohol; stearyl alcohol; macrogol cetostearyl ether; sorbitan stearate; methyl parahydroxybenzoate (E 218); propyl parahydroxybenzoate (E 216); phenoxyethanol; propylene glycol; oleyl alcohol; sodium hydroxide; purified water.

Dosage form

Cream.

Main physicochemical properties: cream from white to pale yellow.

Pharmacotherapeutic group

Dermatological products. Other dermatological preparations.

ATX code D11A X22.

Pharmacological properties

Pharmacodynamics

Mechanism of action

Ivermectin belongs to the avermectin class. Avermectins exert their anti-inflammatory effects by inhibiting lipopolysaccharide-induced production of inflammatory cytokines. The anti-inflammatory properties of ivermectin when applied to the skin have been observed in animal models of skin inflammation. Ivermectin also causes parasite death, primarily by selective binding with high affinity to glutamate-gated chloride channels found in invertebrate nerve and muscle cells. The precise mechanism of action of Soolantra® Cream in the treatment of inflammatory lesions of rosacea is unknown, but it may be related to the anti-inflammatory effects of ivermectin, as well as to the death of the Demodex mite, which has been reported to be a contributor to skin inflammation.

Clinical efficacy and safety

Two randomized, double-blind, placebo-controlled clinical trials, identical in design, examined the treatment of inflammatory lesions of rosacea with Soolantra® cream applied once daily at bedtime. The study enrolled 1,371 patients aged 18 years and older who received Soolantra® cream or placebo once daily for 12 weeks.

Overall, 96% of participants were Caucasian and 67% were female. Based on the 5-point Investigator Global Assessment (IGA) scale, 79% of participants had moderate (IGA = 3) and 21% had severe (IGA = 4) lesions at baseline.

Co-primary efficacy endpoints in both clinical trials were the rate of successful treatment based on the IGA score (percentage of patients assessed as “clear” or “almost clear” at week 12 of the study) and the absolute change in the number of inflammatory lesions from baseline. The IGA score was based on the definitions provided in Table 1.

Table 1

Investigator Global Assessment Scale (IGA)

Results from both clinical trials demonstrated that Soolantra® cream, when applied once daily for 12 weeks, was significantly superior to placebo in terms of IGA success rate and absolute change in inflammatory lesion count (p < 0.001, see Table 2).

The table below shows the efficacy results obtained in both studies.

Table 2

Performance indicators results

The IGA score was used to assess patients during the 40-week extension of both clinical studies, and the percentage of patients treated with Soolantra® cream who achieved an IGA score of 0 or 1 continued to increase through week 52. The success rate (IGA = 0 or 1) at week 52 was 71% and 76% in Studies 1 and 2, respectively.

The efficacy and safety of this medicinal product for the treatment of inflammatory lesions of rosacea was also studied in a randomized, investigator-blinded, active-controlled clinical trial. The study included 962 patients aged 18 years and older who were treated with Soolantra® cream once daily or metronidazole cream 7.5 mg/g twice daily for 16 weeks. In this study, 99.7% of participants were Caucasian, 65.2% were female, and at baseline, 83.3% of participants had IGA moderate lesions (IGA = 3) and 16.7% had severe lesions (IGA = 4).

The results of this study demonstrated that Soolantra® Cream was significantly superior to metronidazole 7.5 mg/g cream in terms of the primary efficacy endpoint (mean percent change in inflammatory lesion score): after 16 weeks of treatment, this score decreased from baseline in 83.0% and 73.7% of patients in the ivermectin and metronidazole groups, respectively (p < 0.001). The superiority of Soolantra® Cream at 16 weeks was also confirmed in terms of the IGA treatment success rate and absolute changes in inflammatory lesion score (secondary endpoints; p < 0.001).

A total of approximately 300 subjects aged 65 years and older participated in all clinical trials of this medicinal product. No significant differences in the efficacy and safety profile were observed between elderly patients and subjects aged 18 to 65 years.

The safety profile described in the Adverse Reactions section remained stable with long-term use, observed during long-term treatment courses of up to one year.

Treatment with ivermectin in combination with doxycycline in the form of 40 mg modified-release capsules.

The ANSWER clinical trial evaluated the relative efficacy of Soolantra (IVM) in combination with doxycycline 40 mg modified-release capsules (DMR) versus IVM plus placebo (PBO) in the treatment of severe rosacea. It was a 12-week, randomized, blinded, parallel-group controlled trial in 273 male and female subjects ≥ 18 years of age with 20–70 facial inflammatory lesions (papules and pustules) and an IGA score of 4.

The primary efficacy endpoint was the change in inflammatory lesion count at week 12 as a percentage of baseline. A significantly greater mean percentage reduction in inflammatory lesion count was observed in patients in the IVM + DMR group compared with patients in the IVM + PBO group (mean ± SD: -80.29 ± 21.65% vs. -73.56 ± 30.52%; p = 0.032).

Children

The European Medicines Agency has waived the obligation to submit the results of studies with Soolantra® cream in all subsets of the paediatric population with papular-pustular rosacea.

Pharmacokinetics

Absorption

The absorption of ivermectin from Soolantra® cream was evaluated in a clinical study in adult subjects with severe papulopustular rosacea under maximally active conditions. At steady state (after 2 weeks of treatment), the highest mean (± standard deviation) plasma ivermectin concentration was achieved within 10 ± 8 hours after dosing (Cmax 2.1 ± 1.0 ng/mL, range 0.7-4.0 ng/mL), and the highest mean (± standard deviation) AUC0-24h was 36 ± 16 ng.h/mL (range: 14-75 ng.h/mL). After two weeks of treatment, systemic exposure to ivermectin reached a plateau (under steady state conditions). During the longest treatment courses in the Phase 3 studies, systemic exposure to ivermectin was similar to that observed after two weeks of treatment. At steady state, systemic exposure to ivermectin (AUC0-24h 36 ± 16 ng.h/ml) was lower than that after a single oral dose of 6 mg ivermectin in healthy volunteers (AUC0-24h 134 ± 66 ng.h/ml).

Distribution

In vitro studies have shown that ivermectin is more than 99% bound to plasma proteins, primarily human serum albumin. No significant binding of ivermectin to erythrocytes was observed.

Metabolism

In vitro studies using human liver microsomes and recombinant CYP450 enzymes have demonstrated that ivermectin is metabolized primarily by CYP3A4 enzymes.

In vitro studies have shown that ivermectin does not inhibit cytochrome P450 isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, 4A11, and 2E1. In human hepatocyte cultures, ivermectin does not induce the expression of CYP450 enzymes (1A2, 2B6, 2C9, and 3A4).

Breeding

In a clinical pharmacokinetic study with maximum ivermectin use in patients who applied the drug to the skin once daily for 28 days, the terminal elimination half-life averaged 6 days (mean 145 hours, range 92-238 hours). Elimination after topical application of Soolantra® Cream is dependent on adsorption. The pharmacokinetics of ivermectin in patients with renal or hepatic impairment have not been studied.

Preclinical safety data

In repeated-dose animal studies of up to 9 months with 10 mg/g ivermectin cream applied to the skin, there were no toxic effects or signs of local toxicity at systemic exposure levels seen in clinical use.

Ivermectin has not been shown to be genotoxic in in vitro and in vivo experiments. In a two-year carcinogenicity study, 10 mg/g ivermectin cream applied to the skin of animals did not result in an increased incidence of tumors.

In reproductive toxicity studies following oral administration of ivermectin, teratogenic effects were observed in rats (cleft palate) and rabbits (wrist curvature) at high doses (the exposure limit before reaching the NOAEL was at least 70 times higher than the clinical exposure).

Neonatal toxicity in oral animal studies was not related to in utero exposure but to postnatal exposure through breast milk, which resulted in high concentrations of ivermectin in brain tissue and plasma of the offspring. Ivermectin cream 10 mg/g caused skin irritation, sensitization, and photosensitization in animals, but did not cause phototoxic effects.

Environmental Risk Assessment (ERA)

Ivermectin is highly toxic to invertebrates and has been shown to pose a risk to the aquatic environment, sediments and terrestrial environment. Appropriate precautions should be taken to prevent environmental contamination, especially aquatic pollution.

Indication

For the topical treatment of inflammatory lesions caused by rosacea (papular-pustular form) in adult patients.

Contraindication

Hypersensitivity to the active substance or to any of the excipients of the drug.

Interaction with other medicinal products and other types of interactions

Drug interaction studies have not been conducted.

The concomitant use of Soolantra® cream with other drugs for the topical or systemic treatment of rosacea has not been studied.

In vitro studies have shown that ivermectin is metabolized primarily by the CYP3A4 enzyme. Therefore, ivermectin should be used with caution when administered concomitantly with potent CYP3A4 inhibitors, as plasma exposure may be significantly increased.

Application features

Patients may experience a temporary exacerbation of rosacea due to the death of Demodex mites, which usually resolves within 1 week with continued treatment.

In case of severe deterioration of the patient's condition with the development of a pronounced skin reaction, treatment should be discontinued.

The effect of Soolantra® cream in patients with renal or hepatic impairment has not been studied.

This medicine contains:

cetyl alcohol and stearyl alcohol, which may cause local skin reactions (e.g. contact dermatitis);

methyl parahydroxybenzoate (E 218) and propyl parahydroxybenzoate (E 216), which may cause allergic reactions (possibly delayed);

propylene glycol, which may cause skin irritation.

Use during pregnancy or breastfeeding

Pregnancy

There is no or limited information on the use of topical ivermectin in pregnant women. Oral reproductive toxicity studies with ivermectin have shown that ivermectin is teratogenic in animals, but due to the low systemic exposure following topical administration at the recommended dosage, the likelihood of harm to human embryos is low. Soolantra® Cream is not recommended for use during pregnancy.

Breast-feeding

Ivermectin is excreted in human milk in low concentrations after oral administration. Excretion into human milk after topical administration has not been studied. Available pharmacokinetic/toxicological data in animals also indicate excretion of ivermectin into breast milk. A risk to the breastfed infant cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Soolantra® Cream therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Reproductive function

There is no information on the effects of ivermectin on human reproductive function. In animals, there is no effect on mating or fertility following treatment with ivermectin.

Ability to influence reaction speed when driving vehicles or other mechanisms

Soolantra® cream has no or negligible influence on the ability to drive and use machines.

Method of administration and doses

The drug should be applied once a day, daily, throughout the entire course of treatment, but not longer than 4 months. The course of treatment can be repeated.

Soolantra® cream can be used as monotherapy or as part of combination treatment.

If there is no improvement after 3 months, treatment should be discontinued.

Certain patient groups

Kidney dysfunction

Dosage adjustment is not necessary.

Liver dysfunction

Use with caution in patients with severe hepatic impairment.

Elderly patients

No dosage adjustment is required for the geriatric patient population.

Method of application

Soolantra® cream is for use on the face only.

Apply a small amount of the medicine (about the size of a pea) to each of the five areas of the face: forehead, chin, nose and both cheeks. Spread the medicine in a thin layer over the skin of the entire face, avoiding the area of the eyes, lips and mucous membranes.

You should wash your hands after applying this medicine.

Cosmetics can be applied only after the cream has dried.

Children

The safety and effectiveness of Soolantra® cream in children (under 18 years of age) have not been studied. Data are not available.

Overdose

There have been no reports of overdose with Soolantra® cream.

In the event of accidental or significant human exposure to unknown amounts of ivermectin veterinary medicinal products, by ingestion, inhalation, injection or exposure to body surfaces, the most commonly reported adverse reactions were rash, oedema, headache, dizziness, asthenia, nausea, vomiting and diarrhoea. Other adverse reactions reported included convulsions, ataxia, dyspnoea, abdominal pain, paraesthesia, urticaria and contact dermatitis.

In case of accidental ingestion of the drug, supportive therapy is carried out, which, if indicated, may include parenteral administration of fluids and electrolytes, respiratory support (if necessary, oxygen and mechanical ventilation), as well as vasopressor drugs in the presence of clinically significant hypotension. If necessary, to prevent absorption of the swallowed substance, artificially induce vomiting and/or perform gastric lavage, use laxatives and take other measures typical of poisoning.

Adverse reactions

The most commonly reported adverse reactions were burning sensation, skin irritation, itching and dry skin. The incidence of these reactions was ≤ 1% of the number of patients who used this medicine during clinical studies.

These adverse reactions are usually mild to moderate in severity and tend to decrease with continued treatment.

No clinically significant difference in the safety profile of this medicinal product was observed between patients aged 18-65 years and patients over 65 years.

Adverse reactions reported in clinical trials are classified by system organ class and frequency using the following categories: very common

(≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), frequency unknown (cannot be estimated from the available data) (see Table 3).

Table 3

Adverse reactions

* Data obtained in the post-registration period.

Reporting of suspected adverse reactions

Reporting adverse reactions after the registration of a medicinal product is important. This allows monitoring of the benefit/risk ratio when using this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the link: https://aisf.dec.gov.ua.

Expiration date

2 years.

After the first opening of the tube, the drug is suitable for use for 6 months.

Storage conditions

Does not require any special storage conditions. Keep out of the reach of children.

Packaging

30 g in a tube; one tube in a cardboard box.

Vacation category

According to the recipe.

Producer

HALDERMA LABORATORIES.

Location of the manufacturer and address of its place of business

ZI Mondesir 74540 ALBI-SUR-CHERAN, France.