Soolantra (Ivermectin) 1% Cream: A Novel, Antibiotic-Free Agent Approved for the Treatment of Patients with Rosacea

Rosacea is a chronic and progressive skin condition characterized by episodes of remission and exacerbations of its many cutaneous symptoms, including flushing, facial erythema, telangiectasia, edema, papules, pustules, ocular lesions, and rhinophyma.1 Approximately 16 million individuals in the United States are affected by rosacea.2 The incidence of rosacea is increasing with aging.2 Rosacea is more frequently observed in women than in men; however, men with rosacea often have more disfiguring skin changes than women.3

An expert committee of the National Rosacea Society described the 4 clinical subtypes of the disease as (1) erythematotelangiectatic, (2) papulopustular, (3) phymatous, and (4) ocular rosacea.1 Erythematotelangiectatic rosacea includes flushing and persistent central facial erythema. Papulopustular rosacea is characterized by persistent central facial erythema with transient papules, pustules, or both in a central facial distribution; papulopustular rosacea is one of the more common subtypes of rosacea and resembles acne vulgaris, without comedones. Phymatous rosacea is characterized by thickening skin, irregular surface nodularities, and enlargement. Ocular rosacea is characterized by symptoms specific to the eye, including watery or bloodshot eyes, foreign body sensation in the eye, burning, stinging, dryness, itching, light sensitivity, or lid and periocular erythema.1

The diagnosis of rosacea can be challenging, because it is based on the clinical signs and symptoms; no confirmatory laboratory test is available.3 Furthermore, the etiology of rosacea is not fully understood; the condition is believed to be an inflammatory disorder in the context of an altered immune response.4

The causative elements of rosacea include genetic and environmental factors, such as heat, sunlight, and stress. Digestive tract diseases, infestation with the Demodex mites, epidermal barrier defect, and childhood stye are also believed to affect the immune response and to trigger the inflammation seen in patients with rosacea.5–7

Various types of Demodex mites may infest the skin of the host, depending on the area of the skin. Human skin may be affected by 2 species of Demodex mites: Demodex folliculorum and Demodex brevis.5 D folliculorum is a parasite that resides in the hair follicles, and is especially prevalent in papulopustular rosacea. D brevis inhabits the deep part of the skin.5,8 Because the main food sources for these mites are epidermal cells and sebum components, they occupy areas that are rich in sebaceous glands, such as the face (especially the nose, cheeks, forehead, and chin).5

The clinical signs and symptoms of rosacea occur predominantly in the face.9 The impact of rosacea on the physical appearance of patients has been shown to negatively affect patients' emotional well-being, resulting in psychosocial comorbidities such as anxiety disorders, social phobias, and depression.10,11 In one National Rosacea Society survey of more than 400 patients with rosacea, 75% of respondents reported that their rosacea had lowered their self-esteem, and approximately 70% reported that rosacea made them feel embarrassed and frustrated.12 Furthermore, more than 50% of the respondents reported they had felt robbed of pleasure or happiness because of their rosacea.12 These findings underline the serious psychosocial impact of rosacea on patients' well-being and for the need for treatment of this dermatologic condition.

Similar to other chronic skin diseases with variable symptomatology, rosacea requires long-term treatment, and drug selection is often based on anecdotal evidence.7 The topical treatment options for papulopustular rosacea include azelaic acid, benzoyl peroxide, metronidazole, and sodium sulfacetamide/sulfur.7,13 Systemic interventions include tetracycline and azithromycin. A 2011 Cochrane Review showed that only topical metronidazole, azelaic acid, and doxycycline (40 mg) had some evidence to support their effectiveness in the treatment of patients with moderate-to-severe rosacea.7

In practice, mild cases of papulopustular rosacea are often managed with topical medications alone, whereas moderate-to-severe disease may require systemic therapy to achieve clearance of inflammatory skin lesions.3,14 The inflammatory changes in the skin usually respond to medical therapies and heal without scarring. Conversely, telangiectasias and phymatous changes may require laser or surgical interventions.3 All patients with rosacea should be advised to protect their skin from heat and cold, and to avoid factors that trigger disease exacerbations and cause skin irritation.3

Because antibiotics are consistently available and effective for many skin conditions, they are susceptible to overuse in the dermatologic setting.15 The potential for antibiotic resistance is an important concern for clinicians who treat patients with rosacea, as well as other conditions, including acne and skin infections.15 Topical rosacea agents offer an alternative to systemic antibiotics, but vehicle selection can be critical; the choice of a lotion, a cream, a gel, or a foam can influence the medication's efficacy, and the patient's adherence to and tolerability of the therapeutic agent.4

The cost and efficacy rates of topical and oral therapies for rosacea vary widely.16 Using published clinical trial data, researchers calculated the cost associated with successful management for 6 different rosacea therapies. The drug cost was combined with office visit costs to estimate the total treatment cost for a 15-week period. Published in 2009, this study showed that metronidazole 1% gel once daily was considerably less expensive than the other 5 branded and generic alternatives.16

The medication cost per treatment success of topical regimens ranged from $60.90 ($205.40 total, including office visits) for metronidazole 1% gel to $152.25 ($296.75 total) for azelaic acid 20% cream twice daily.16 Tetracycline 250 mg daily was the least expensive oral medication for the treatment of patients with rosacea, at $6.30 ($150.80 total) per treatment success.16

FDA Approves Ivermectin 1% Cream for Patients with Rosacea

On December 23, 2014, the US Food and Drug Administration (FDA) approved ivermectin 1% cream (Soolantra; Galderma Laboratories) for the once-daily treatment of patients with inflammatory lesions of rosacea.17 The FDA approval of ivermectin 1% cream for this indication was based on the results of 2 phase 3 randomized, double-blind, 12-week trials comparing ivermectin 1% cream with vehicle-controlled studies of patients with moderate-to-severe papulopustular rosacea.17,18 In both studies, ivermectin 1% cream was superior to the vehicle cream.

Responding to the FDA's approval of this new agent, Linda Stein Gold, MD, Director of Clinical Research, Dermatology, Henry Ford Hospital, Detroit, MI, and clinical investigator for the phase 3 clinical trials of ivermectin 1% cream, said, “While some rosacea treatments for the common bumps and pimples of the condition may take more than four weeks to show effect, Soolantra Cream may provide initial results as early as week two.”17

Mechanism of Action

The exact mechanism of action of ivermectin 1% cream in treating rosacea lesions is not known.19

One of the features of this topical agent is that it is not an antibiotic, thereby removing the concern of antibiotic resistance that is often associated with antibiotic creams.18,20 Ivermectin 1% cream is a member of the avermectin class of drugs, and has been used in veterinary medicine as a parenteral parasiticide.21 Ivermectin is also administered orally for the treatment of patients with onchocerciasis (river blindness), and ivermectin has demonstrated efficacy against other worm infestations, indicating that ivermectin has antiparasitic properties.18,22

In immunopharmacologic studies, ivermectin demonstrated anti-inflammatory properties, specifically the inhibition of inflammatory cytokine production and the upregulation of interleukin-10 production, an anti-inflammatory cytokine.23

Dosing and Administration

Ivermectin 1% cream should be applied once daily to the areas of the face and neck affected by rosacea.19 A pea-size amount should be used for each area with rosacea lesions, including the forehead, chin, nose, and each cheek. The cream should be spread in a thin layer, taking special precaution to avoid the lips and the eyes.19

Each gram of ivermectin 1% cream contains 10 mg of ivermectin. The drug is supplied in 30-g, 45-g, and 60-g tubes.19

Clinical Trials

Two randomized, double-blind, vehicle-controlled clinical trials were conducted to assess the efficacy and safety of ivermectin 1% cream for the treatment of patients with inflammatory lesions of rosacea.18,19 These clinical trials were identical in design. A total of 1371 adults (aged ≥18 years) with moderate-to-severe papulopustular rosacea were randomized to receive once-daily ivermectin 1% cream or a vehicle cream for 12 weeks.18,19

Both clinical trials had 2 coprimary efficacy end points, including (1) success rate according to the Investigator Global Assessment (IGA) scale, which was defined as the percentage of patients whose disease is categorized as clear (IGA = 0) and almost clear (IGA = 1); and (2) the absolute change in inflammatory lesion counts from baseline to week 12.18,19 Other assessments comprised patient-reported outcomes, including quality-of-life ratings and patients' assessments of rosacea improvement.18,19

Patient Population

In the 2 clinical trials of ivermectin 1% cream, the majority of patients with papulopustular rosacea were white (96%) and female (67%), and the patients' mean age was 50 years.18,19

Based on the 5-point IGA scale, 79% of patients had moderate papulopustular rosacea (IGA = 3), and 21% of patients had severe papulopustular rosacea (IGA = 4) upon randomization into the study.18,19 The patients' average inflammatory lesion count at baseline ranged from 31 to 33.18

Efficacy

Both randomized clinical trials demonstrated that ivermectin 1% cream was more effective than the vehicle cream based on the coprimary efficacy end points—IGA and absolute change in inflammatory lesion counts (P <.001; Table 1).18,19

Table 1.

Ivermectin Cream versus Vehicle Cream: Coprimary Efficacy Results at Week 12

Efficacy end point	Study 1		Study 2
	Ivermectin 1% cream (N = 451)	Vehicle cream (N = 232)	Ivermectin 1% cream (N = 459)	Vehicle cream (N = 229)
Investigator Global Assessment
Patients categorized as clear or almost clear, N (%)	173 (38)	27 (12)	184 (40)	43 (19)
P value	<.001		<.001
Inflammatory lesion counts
Mean absolute change from baseline, N (%)	20.5 (65)	12.0 (42)	22.2 (66)	13.4 (43)
P value	<.001		<.001

Source: Soolantra (ivermectin) 1% cream prescribing information; December 2014.

Significant differences in the 2 coprimary end points were observed after 4 weeks of treatment with ivermectin 1% cream.18 At week 12, significant improvements were seen in the 2 coprimary end points, as well as in secondary end points, including patient assessments (ie, general and rosacea-specific quality-of-life measures, patient assessments of rosacea improvement).

Table 2 summarizes patient-reported outcomes at week 12.18

Table 2.

Patient-Reported Outcomes: Ratings of Rosacea Improvement at Week 12

Patient ratings of rosacea improvement	Study 1		Study 2
	Ivermectin 1% cream, % (N = 451)	Vehicle cream, % (N = 232)	Ivermectin 1% cream, % (N = 459)	Vehicle cream, % (N = 229)
Excellent	34	10	32	7
Good	35	29	34	27
Moderate	20	31	22	35
No improvement	8	25	10	25
Worse	3	6	3	6
P value	<.001		<.001

NOTE: The totals of each study arm may not equal 100% because of rounding.

Source: Stein Gold L, Kircik L, Fowler J, et al. Efficacy and safety of ivermectin 1% cream in treatment of papulopustular rosacea: results of two randomized, double-blind, vehicle-controlled pivotal studies. J Drugs Dermatol. 2014;13:316–323.

After receiving ivermectin cream, 38% of patients in Study 1 and 40% of patients in Study 2 were categorized as clear or almost clear versus 12% of patients in Study 1 and 19% of patients in Study 2 who received the vehicle cream (Table 1).18,19

At week 12, more than 60% of patients who received ivermectin 1% cream in the 2 studies rated the improvement in their rosacea as excellent or very good compared with less than 40% of patients who received the vehicle cream in both studies (Table 2).18

Adverse Events and Safety

Overall, 2047 patients with inflammatory type of rosacea received once-daily ivermectin 1% cream in clinical trials; of these, 1555 patients used the cream for more than 12 weeks, and 519 patients used it for approximately 1 year.19

Ivermectin 1% cream was well tolerated and safe during the 12-week study period.18,19 Skin irritation and sensation of skin burning were reported in ≤1% of patients who received ivermectin 1% cream for 3 months or longer.19

Adverse events led to the discontinuation of ivermectin 1% cream in 1.3% of patients in Study 1 and in 0.2% of patients in Study 2, compared with a discontinuation rate of 1.7% among patients who received the vehicle cream in each study.18

Ivermectin 1% cream has no contraindications.19

Warnings and Precautions

The oral, ophthalmic, or intravaginal use of ivermectin 1% cream is not recommended.19

Use in Specific Populations

Pediatric patients. The safety and efficacy of ivermectin cream in pediatric patients have not been established.19

Geriatric use. Ivermectin cream has been studied in a total of 1371 patients with rosacea, of whom 12% were aged ≥65 years. There were no meaningful differences in the efficacy or the safety of ivermectin cream among the age cohorts.19

Pregnancy. Ivermectin cream should only be used during pregnancy if its potential benefit justifies its potential risk to the fetus. Adequate and well-controlled studies with ivermectin cream have not been conducted in pregnant women.19

Nursing mothers. Because of the potential for serious adverse reactions from ivermectin cream in nursing infants, the use of ivermectin cream or nursing should be discontinued, taking into account the importance of the drug to the mother.19

Conclusion

Because papulopustular rosacea is a common and challenging subtype of rosacea, basic and clinical research continue to focus on elucidating its etiology and its optimal management. Patients with this inflammatory cutaneous disorder are believed to have an altered immune response that is affected by multiple triggers, including environmental factors, genetic factors, and microbe challenges by pathogens such as D folliculorum.

Based on the results of 2 phase 3 clinical trials, ivermectin 1% cream demonstrated efficacy and safety in the treatment of patients with inflammatory lesions of rosacea. Administered once daily, this antibiotic-free treatment option possesses unique anti-inflammatory and antiparasitic properties. The FDA's approval of ivermectin 1% cream offers an innovative, convenient, and effective treatment option for patients with this debilitating condition.