Ivermectin 1% Cream for Rosacea
Gita Gupta, MD1,2; Deanne Daigle, MSc;2; Aditya K. Gupta, MD, PhD, FRCPC2,3; Linda Stein Gold, MD4
1Wayne State University, Detroit, MI, USA
2Mediprobe Research Inc., London, ON, Canada
3Department of Medicine, University of Toronto School of Medicine, Toronto, ON, Canada
4Henry Ford Medical Center, Department of Dermatology, Detroit, MI, USA
The etiology of papulopustular rosacea (PPR) is not well understood yet appears to involve both the innate and adaptive immune
response in addition to possible infestation with Demodex mites. Current treatments for PPR consist mainly of antibiotics. Ivermectin
cream 1%, a new topical treatment for PPR, possesses both anti-inflammatory and anti-parasitic properties. After 12 weeks of
treatment, subjects treated with ivermectin cream 1% had significantly greater reductions in PPR symptoms and enhanced diseaserelated
quality of life improvements compared to subjects who received vehicle. Furthermore, PPR symptoms continued to improve
with prolonged treatment (40 weeks). Ivermectin cream 1% offers a multi-pronged approach to combat the complex pathophysiology
anti-parasitic, avermectin, Demodex, erythema, inflammation, insecticide, papulopustular rosacea, Rosiver®, Soolantra®,
Rosacea is a chronic inflammatory condition affecting the
central facial skin of the cheeks, nose, chin and forehead.
Rosacea typically affects females approximately 30 years of
age and increases in severity throughout the lifespan.1 The
exact cause of rosacea is unknown and its pathogenesis is not
well understood.2,3 Innate and adaptive immune responses,
vascular abnormalities, dermal microorganism imbalances,
and environmental factors may interact to produce chronic
inflammation and the development of fibrosis.2 Four subtypes of
rosacea have been identified: 1) erythematotelangiectatic rosacea,
2) papulopustular rosacea (PPR), 3) phymatous rosacea, and
4) ocular rosacea2; yet, whether these represent a distinct
variation or a continuum of disease severity remains a matter of
debate.2 PPR, previously known as acne rosacea, is characterized
by erythema, telangiectasia, papules, pustules, edema, and
sometimes pain, stinging or burning.4 Patients report that
symptoms are a cause of low self-esteem, as they are a source of
shame, embarrassment, and physical discomfort.5 Treatment is
strongly encouraged to moderate the detrimental effect on patient
quality of life (QoL) and to prevent the condition from worsening.
Few therapeutic alternatives exist for the treatment of PPR. There
is some evidence supporting the efficacy of azelaic acid, topical
metronidazole and sub-antimicrobial dose doxycycline in the
treatment of moderate to severe rosacea, although it remains
unclear which agent is most effective.6
Ivermectin is derived from avermectin, a class of broadspectrum
anti-parasitic agents isolated from the fermentation
of Streptomyces avermitilis.7 Ivermectin possesses both antiparasitic
and anti-inflammatory properties and has been shown
to reduce the number of Demodex mites in demodicidosis and
blepharitis and to inhibit the production of lipopolysaccharide
inflammatory cytokines, such as tumor necrosis factor-alpha
and interlukin (IL)-1b, while upregulating the production of the anti-inflammatory cytokine IL-10.8 Because PPR is recognized
as an inflammatory condition whose pathogenesis may involve
parasitic infestation with Demodex mites, vehicle-controlled and
active comparator trials were undertaken to evaluate the efficacy
and safety of topical ivermectin 1% cream in the treatment of
Pivotal Phase 3 Studies
Two pivotal phase 3 trials assessed the efficacy and safety of
ivermectin cream 1% for moderate to severe PPR.9 These trials
were part of a larger study comprised of a second long-term
active comparator trial10 and a 4 week follow-up safety study. The
pivotal phase 3 studies were identically designed multicenter,
randomized, double-blind, vehicle-controlled trials that enrolled
participants aged 18 years or older with moderate to severe
PPR and 15-70 inflammatory facial lesions.9 Subjects were
randomized in a 2:1 ratio to receive either ivermectin 1% cream
or vehicle cream for 12 weeks. Participants were instructed to
apply their respective cream to the face once daily at bedtime
while avoiding the upper and lower eyelids and lips. Participants
were also asked to avoid known rosacea triggers, such as specific
foods and environments, whenever possible. Evaluations occurred
at baseline and at weeks 2, 4, 8 and 12. Co-primary efficacy
outcomes for this study included the percentage of participants
who achieved an Investigator Global Assessment (IGA) of "clear"
or "almost clear" and mean change in inflammatory lesion counts
between groups at week 12. Other efficacy outcomes were percent
change in inflammatory lesion counts from baseline, subjective
assessment of rosacea improvement, and QoL scores on the
Dermatology Life Questionnaire Index (DLQI) and the Rosacea
Quality of Life Index (RosaQoL™). Adverse events (AEs) and
laboratory parameters (hematology and blood chemistry) were
||Ivermectin 1% cream
|Ivermectin 1% cream
|IGA 'clear' or 'almost clear'
|Reduction in inflammatory lesion count from baseline
|Subjective rosacea improvement
'excellent' or 'good'
Table 1. Efficacy endpoints for the pivotal phase 3 trials of ivermectin 1% cream vs. vehicle|
IGA = Investigator global assessment; †P<0.001
Study 1 enrolled 683 participants and Study 2 enrolled 688
participants, the majority of whom were female (Study 1: 68.2% and Study 2: 66.7%) and approximately 50 years of age on average.
Participants in Study 1 had an average of 30.9 lesions, while
subjects in Study 2 had an average 32.9 inflammatory lesions at
baseline. The proportion of participants with an IGA of 'severe'
was 18% and 24.1% in Studies 1 and 2, respectively. There were no
differences in DLQI scores between treatment groups at baseline.
Efficacy results are presented in Table 1. In both studies, a
significantly higher percentage of participants who received
ivermectin 1% had an IGA of 'clear' or 'almost clear' at week 12
compared to vehicle (P<0.001) and the significant difference
between active and control arms was noted at week 4 (10.9%
and 11.8% vs. 5.6% and 5.7%, respectively; P<0.05 for both).
The mean difference in inflammatory lesion counts between
ivermectin 1% and vehicle from baseline to week 12 was -8.13
and -8.22 for Studies 1 and 2, respectively (ivermectin 1% vs.
vehicle, both P<0.001). There was also a significant difference
in the median reduction in lesion count from baseline between
the ivermectin 1% and vehicle groups (both studies P<0.001)
observed as early as week 2. In both studies, a significantly higher
proportion of participants who received ivermectin 1% cream
reported improvement of their rosacea symptoms as 'excellent' or
'good' compared to participants who received vehicle (P<0.001).
QoL scores also improved in the ivermectin 1% groups compared
to vehicle at the end of 12 weeks. In both studies, a significantly
greater proportion of participants in the ivermectin 1% group
(approximately 53%) than the vehicle group (approximately 35%)
considered their rosacea had no effect on their QoL (P<0.001).
Improvement in RosaQoL scores was also significantly higher for
ivermectin 1% compared to vehicle (-0.64 ± 0.7 and -0.60 ± 0.6 vs.
-0.35 ± 0.5 in both vehicle groups; P=0.001 for Studies 1 and 2).
For Studies 1 and 2, no serious treatment-related AEs were
reported in either the ivermectin 1% cream or vehicle groups.
Burning (1.8% for ivermectin 1% cream and 2.6% for vehicle) was
the most commonly reported treatment-related AE in Study 1,
while pruritus and dry skin were the most commonly reported
treatment-related AEs in Study 2 (pruritus: 0.7% vs. 0% and
dry skin: 0.7% vs. 0.9% for ivermectin 1% cream vs. vehicle).
Furthermore, treatment-related AEs with active drug were less
than with vehicle alone. Laboratory tests showed no clinically
Ivermectin 1% Cream vs. Azelaic Acid 15% Gel
Ivermectin 1% cream was then evaluated against azelaic acid
15% gel in a 40 week extension study.10 In this continuation of the
pivotal phase 3 trials, participants with PPR originally assigned to ivermectin 1% cream once daily in the 12-week study continued
to be treated as such and participants initially randomized to
vehicle were switched to azelaic acid 15% gel twice daily for 40
weeks. Efficacy was assessed at 4 week intervals using the IGA.
Safety assessments were comprised of documentation of AEs,
tolerability signs and symptoms, and laboratory tests.
Six hundred and twenty-two and 683 participants enrolled in the
40-week extension studies (see previous section for participant
demographics). The efficacy of ivermectin 1% cream increased
over time as IGA scores of 'clear' and 'almost clear' increased
from 38.4% to 71.1% by the end of Study 1 and from 40.1% to
76% by the end of Study 2; 59.4% and 57.9% of participants who
received azelaic acid had an IGA of 'clear' or 'almost clear' by the
end of Studies 1 and 2, respectively. No statistical comparisons
were made because of the differing treatments lengths between
the ivermectin 1% and azelaic acid 15% groups. Furthermore,
because the ivermectin group had already been treated with
ivermectin for 3 months, while the azaleic acid group had
previously received vehicle, baseline factors may not have been
comparable between groups.
The incidence of treatment-related AEs in the ivermectin 1%
cream and azelaic acid 15% gel groups was 1.9% vs. 6.7% and
2.1% vs. 5.8% in Studies 1 and 2, respectively. No severe or serious
AEs were deemed related to ivermectin 1% cream in Studies 1
or 2 and no serious AEs were considered related to azelaic acid
15% gel in either study; however, 1 severe case of skin irritation
was considered related to azelaic acid in Study 2. In Study 1,
4 participants in the azelaic acid group and 5 in the ivermectin
group discontinued the study as a result of AEs. In Study 2,
5 participants in the azelaic acid group and 3 in the ivermectin
group discontinued the study due to AEs. None of the AEs in
either study were considered related to ivermectin 1% cream;
however, in the azaleic acid group, 3 AEs in Study 1 and 4 AEs
in Study 2 were considered related to azaleic acid (Study 1: skin
irritation, eye and skin irritation, and skin pain and burning;
Study 2: skin irritation, skin burning, skin discomfort, and skin
burning and pruritus).
|IGA 'clear' or 'almost clear'
|Reduction in inflammatory
lesion count from baseline
Table 2. Efficacy endpoints for the phase 3 trial of ivermectin
1% cream vs. metronidazole 0.75% cream|
IGA = Investigator global assessment; †P<0.001
Ivermectin 1% Cream vs. Metronidazole 0.75% Cream
Another phase 3, investigator-blinded, randomized trial conducted in Europe explored the efficacy and safety of
ivermectin 1% cream compared to metronidazole 0.75% cream
for the treatment of moderate to severe PPR (Table 2).1 Nine-hundred
and sixty-two participants age 18 years or older with moderate or severe PPR and presenting with 15-70 facial lesions
were randomized 1:1 to receive either ivermectin 1% cream
(n=478) once daily or metronidazole 0.75% gel (n=484) twice
daily for 16 weeks. Treatments were applied to the entire face,
avoiding the upper and lower eyelids and lips. Participants were
also asked to avoid known rosacea triggers. Study visits were
at baseline and at weeks 3, 6, 9, 12 and 16. Efficacy endpoints
included inflammatory lesion counts, the IGA, participants'
subjective evaluation of rosacea improvement, and the DLQI. The
safety evaluation consisted of AE assessments over the course of
the study, as well as local tolerance and laboratory parameters.
At baseline, the majority of participants had moderate rosacea
(16.7% severe) with an average 32.5 inflammatory lesions.
Participants had a mean age of 52 years and were primarily
female (65.2%). In terms of efficacy at week 16, ivermectin was
significantly more effective than metronidazole 0.75% cream
in reducing the percentage of inflammatory lesions (83% vs.
73.7%; P<0.001) with a significant difference between the two
treatments observed at week 3. The IGA of disease severity was
also significantly better for ivermectin 1% cream compared to
metronidazole 0.75%, with 84.9% of the ivermectin 1% cream
and 75.4% of the metronidazole 0.75% cream groups rated as
'clear' or 'almost clear' at week 16 (P<0.001), with the greatest
difference in IGA noted at week 12. Approximately 86% of the
ivermectin group rated their global improvement as 'excellent'
or 'good' compared to 74.8% in the metronidazole 0.75% group.
Although the DLQI scores were similar between treatment groups
at baseline (6.93 and 6.05 for ivermectin and metronidazole,
respectively), participants treated with ivermectin 1% cream
showed a greater improvement in QoL as indicated by a reduction
in their DLQI scores (-5.18 vs. -3.92; P<0.01).
A similarly low proportion of participants experienced a
treatment-related AE (1.9% in the ivermectin 1% cream group
and 2.5% in the metronidazole 0.75% group). The most common
treatment-related AE was skin irritation experienced by 3 and
4 participants in the ivermectin 1% cream and metronidazole
0.75% cream groups, respectively. Three participants in the
ivermectin 1% cream group discontinued the study because
of skin irritation and hypersensitivity, while 10 participants
in the metronidazole 0.75% cream group discontinued the
study due to skin irritation, allergic dermatitis, aggravation of
rosacea, erythema, pruritus and feeling hot. Worsening of local
tolerance parameters from baseline was more pronounced in
the metronidazole 0.75% group than the ivermectin 1% cream
group for stinging/burning (15.5% vs. 11.1%), dryness (12.8%
vs. 10%), and itching (11.4% vs. 8.8%). No clinically significant
abnormalities in laboratory parameters were found.
Ivermectin 1% cream is markedly more effective than vehicle
in reducing inflammatory lesions of rosacea as it results in
a significant reduction in lesion counts after only 2 weeks of
treatment and produces substantially greater improvements in
IGA ratings of 'clear' or 'almost clear' as early as week 4.9 The
efficacy of ivermectin 1% cream increases with prolonged
treatment as evidenced in the 40 week trials.10 Also, when
compared to the standard treatment for PPR, metronidazole
0.75% cream, topical ivermectin was markedly superior to
metronidazole in terms of reducing inflammatory lesions
and IGA ratings.1 Ivermectin 1% cream had a significantly
greater positive impact on patient QoL compared to vehicle or
metronidazole 0.75%.1,9 Ivermectin 1% cream was well-tolerated
and demonstrated a favorable safety profile across phase 3
studies, with skin irritation being the most common treatmentrelated
In phase 3 trials, ivermectin 1% cream produced greater objective
and subjective outcomes and improvements in disease-specific
QoL over vehicle and an active comparator. Topical ivermectin
represents a novel approach to the treatment of PPR that appears
to confer superior efficacy and tolerability as compared to current
treatment options, while offering the added convenience of once
daily dosing. Since ivermectin possesses both anti-parasitic and
anti-inflammatory properties, its effectiveness in treating PPR
may be attributed to its ability to combat several pathogenic
factors linked to the condition. Further studies are needed to
elucidate the contribution of the anti-parasitic versus the antiinflammatory
modes of action of ivermectin.
- Taieb A, Ortonne JP, Ruzicka T, et al. Superiority of ivermectin 1% cream over metronidazole 0.75% cream in treating inflammatory lesions of rosacea: a randomized, investigator-blinded trial. Br J Dermatol. 2015 Apr;172(4):1103-10.
- Crawford GH, Pelle MT, James WD. Rosacea: I. Etiology, pathogenesis, and subtype classification. J Am Acad Dermatol. 2004 Sep;51(3):327-41.
- Diamantis S, Waldorf HA. Rosacea: clinical presentation and pathophysiology. J Drugs Dermatol. 2006 Jan;5(1):8-12.
- Steinhoff M, Schauber J, Leyden JJ. New insights into rosacea pathophysiology: a review of recent findings. J Am Acad Dermatol. 2013 Dec;69(6 Suppl 1): S15-26.
- van der Linden MM, van Rappard DC, Daams JG, et al. Health-related quality of life in patients with cutaneous rosacea: a systematic review. Acta Derm Venereol. 2015 Apr 15;95(4):395-400.
- van Zuuren EJ, Kramer SF, Carter BR, et al. Effective and evidence-based management strategies for rosacea: summary of a Cochrane systematic review. Br J Dermatol. 2011 Oct;165(4):760-81.
- Merck & Co. Inc. Stromectal (ivermectin) tablets [Internet]. 2010 [cited 2015 Feb 20]. Available from: https://www.merck.com/product/usa/pi_ circulars/s/stromectol/stromectol_pi.pdf. Accessed May 28, 2015.
- Ci X, Li H, Yu Q, et al. Avermectin exerts anti-inflammatory effect by downregulating the nuclear transcription factor kappa-B and mitogenactivated protein kinase activation pathway. Fundam Clin Pharmacol. 2009 Aug;23(4):449-55.
- Stein 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 Mar;13(3):316-23.
- Stein Gold L, Kircik L, Fowler J, et al. Long-term safety of ivermectin 1% cream vs azelaic acid 15% gel in treating inflammatory lesions of rosacea: results of two 40-week controlled,investigator-blinded trials. J Drugs Dermatol. 2014 Nov;13(11):1380-6.
In this issue:
- Hidradenitis Suppurativa: A Review with a Focus on Treatment Data
- Ivermectin 1% Cream for Rosacea
- Update on Drugs and Drug News - July-August 2015