Rosiver - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology.
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Rosiver - Scientific Information

Manufacture: Galderma Laboratories
Country: Canada
Condition: Rosacea
Class: Topical anti-infectives
Ingredients: ivermectin, carbomer copolymer type B, cetyl alcohol, citric acid monohydrate, dimeticone 20 Cst, disodium edetate, glycerol, isopropyl palmitate, macrogol cetostearyl ether, methyl parahydroxybenzoate, oleyl alcohol, phenoxyethanol, propyl parahydroxybenzoate, propylene glycol, purified water, sodium hydroxide, sorbitan stearate, stearyl alcohol

Pharmaceutical Information

Drug Substance

Proper name: Ivermectin
Chemical name: Ivermectin is a mixture of component H2B1a and H2B1b

Component H2B1a:
5-O-demethyl-22,23-dihydroavermectin A1a

Component H2B1b:
5-O-demethyl-25-de(1-methylpropyl)-25-(1-methylethyl)-22,23-dihydroavermectin A1a
Molecular formula and (molecular mass): Component H2B1a: C48H74O14 (875)
Component H2B1b: C47H72O14 (861)
Structural formula:



Component H2B1a: R = C2H5, Component H2B1b: R = CH3.

Physicochemical properties: Ivermectin is a white or yellowish-white, crystalline powder, slightly hygroscopic. Practically insoluble in water, freely soluble in methylene chloride and soluble in ethanol (96%).

Clinical Trials

ROSIVER (ivermectin) Cream, 1% applied once daily at bedtime was evaluated in the treatment of inflammatory lesions of rosacea in two pivotal randomized, double-blind, vehicle-controlled clinical trials, which were identical in design.

Study Demographics and Trial Design

Table 1 - Summary of patient demographics
Study Trial design Dosage, route of
administration and duration
Study
subjects, N
Mean age
(Range)
Gender, N
Study 1 Multicenter,
randomized,
double-blind,
parallel-group,
vehicle-controlled
Ivermectin 1% Cream once
daily
Ivermectin Cream Vehicle once
daily
Once daily Topical (facial application)
12 weeks
683 50.4
(19-88)
Male, 217
Female, 466
Study 2 Multicenter,
randomized,
double-blind,
parallel-group,
vehicle-controlled
Ivermectin 1% Cream once
daily
CD5024 Cream Vehicle once
daily
Topical (facial application)
12 weeks
688 50.2
(18-89)
Male, 229
Female, 459

Results

The co-primary efficacy endpoints in both pivotal trials were the success rate based on the IGA outcome (percentage of subjects “clear” and “almost clear” at Week 12 of the study) and absolute change from baseline in inflammatory lesion counts. The IGA scale is based on the following definitions:

Grade Score Clinical Description
Clear 0 No inflammatory lesions present, no erythema
Almost Clear 1 Very few small papules/pustules, very mild erythema
Mild 2 Few small papules/pustules, mild erythema
Moderate 3 Several small or large papules/pustules, moderate erythema
Severe 4 Numerous small and/or large papules/pustules, severe erythema

Using the 5-point Investigator Global Assessment (IGA) scale, 79% of subjects were scored as moderate (IGA=3) and 21% scored as severe (IGA= 4) at baseline.

The following table presents efficacy outcomes from both pivotal studies.

Table 2 - Results of Phase III pivotal studies
Study 1 Study 2
ROSIVER
(N=451)
Vehicle
(N=232)
ROSIVER
(N=459)
Vehicle
(N=229)
Investigator Global Assessment
Number (%) of Subjects Clear or Almost
Clear in the IGA at Week 12
173 (38.4) 27 (11.6) 184 (40.1) 43 (18.8)
Inflammatory Lesions
Mean Inflammatory Lesion Count
at Baseline
31.0 30.5 33.3 32.2
Mean Inflammatory Lesion Count
at Week 12
10.6 18.5 11.0 18.8
Mean Absolute Change (% Change) in
Inflammatory Lesion Count
from Baseline at Week 12
-20.5
(-64.9)
-12.0
(-41.6)
-22.2
(-65.7)
-13.4
(-43.4)
p-value <0.001 - <0.001 -

The results from both pivotal clinical studies demonstrated that ROSIVER applied once daily for 12 weeks was statistically more effective than vehicle cream in terms of IGA success rate and absolute change in inflammatory lesion counts (p<0.001).

Starting from 4 weeks of treatment, ROSIVER was significantly more effective than vehicle cream for both the co-primary efficacy endpoints (p<0.05).

IGA was assessed during the 40-week investigator-blinded extension of the two pivotal studies and the percentages of subjects treated with ROSIVER achieving an IGA score of 0 (“clear”) or 1 (“almost clear”) continued to increase up to 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 ROSIVER in the treatment of inflammatory lesions of rosacea were also evaluated in another supportive randomized, investigator-blinded, active-controlled clinical study. The study was conducted in 962 subjects aged 18 years and older who were treated for 16 weeks with either ROSIVER once daily or Metronidazole 0.75% w/w cream twice daily. In this study, 99.7% of subjects were Caucasian and 65.2% were female; on the IGA scale, 83.3% of subjects were scored as moderate (IGA=3) and 16.7% scored as severe (IGA=4) at baseline.

The results of the study demonstrated that ROSIVER was statistically more effective than Metronidazole 7.5 mg/g cream on the primary efficacy endpoint (Mean Percent Change in Inflammatory Lesion Counts) with a reduction of 83.0% and 73.7% from baseline after 16 weeks of treatment for the ivermectin and metronidazole groups respectively (p<0.001). The superiority of ROSIVER at Week 16 was confirmed by the Success Rate based on IGA and Absolute Change in Inflammatory Lesion Counts (secondary endpoints (p<0.001)).

Detailed Pharmacology

Primary Pharmacodynamics

The mechanism of action of ivermectin in ROSIVER in treating rosacea is unknown.

Secondary Pharmacodynamics

Animal Models of inflammation:

In mouse ear edema models, topical ivermectin treatment showed anti-inflammatory activities (dose-dependent reduction of ear edema, reduction of tumor necrosis factor alpha).

In a mouse model of allergen-induced atopic dermatitis, topical application of ivermectin reduced all inflammation symptoms including ear edema, epidermal thickness, skin eosinophil peroxidase, skin mastocyte count, and serum IgE content.

The pharmacological activity of the 2 major human ivermectin metabolites has not been studied.

Microbiology

Microbiological activity was not specifically studied in the development of ROSIVER. Ivermectin is known to bind selectively to specific neurotransmitter receptors that function in the peripheral motor synapses of parasites, producing an endectocidal effect in nematodes, arthropods and insects.

Toxicology

General Toxicology

Repeat-dose dermal application studies of ivermectin 1% cream in minipigs did not show systemic toxic effects or local toxicity. The exposure in minipigs via dermal application at the highest dose given in the study was comparable to the systemic exposure in humans at the therapeutic dose of ROSIVER.

Genotoxicity

Ivermectin was not mutagenic in vitro in bacterial and photo-bacterial reverse mutation assays, in the mouse lymphoma assay, and in vivo in the oral micronucleus test in rats.

Carcinogeniticy

Chronic (1 year) repeated topical application of ROSIVER enhanced simulated solar ultraviolet radiation-induced non-melanoma skin carcinogenesis in albino Skh HR-1 hairless mouse (tumour potency factor in both sexes combined was 1.69; 1.74 in male mice and 1.51 in female mice - compared with an expected no adverse effect tumour potency factor of 1.00). Increased incidence of skin irritation induced by both the vehicle cream and by ROSIVER cream in this study is very likely to be the cause for increased incidence of UV radiation-induced skin tumors in these groups, when compared to mice only exposed to UV radiation.

In a 2-year topical carcinogenicity study in mice (without simulated solar light exposure), ROSIVER was not tumorigenic when applied daily at doses corresponding to up to 10 mg/kg/day of ivermectin. At this dose, the plasma AUC in mice was 645.54 (m)/352 (f) times the human plasma AUC associated with the maximum recommended topical use of ROSIVER.

In a 2-year oral carcinogenicity study in rats, ivermectin was considered not tumorigenic when administered daily at doses up to 3 mg/kg/day. At this dose, the plasma exposure of animals represented at least 282 times the human plasma AUC associated with the maximum recommended topical use of ROSIVER. An increase in the incidence of benign hepatocellular adenomas and related hepatic pre-neoplastic changes was reported in males only (at a 9mg/kg/day ivermectin oral dose [832 times the human plasma AUC associated with the maximum recommended topical use of ROSIVER]). There was also a higher incidence of pancreatic benign islet cell adenomas in males, and islet cell carcinoma with no evidence of distant metastasis in females. These neoplastic changes in rodents are not currently considered to be relevant to humans.

Reproductive and Developmental Toxicology

Ivermectin was found to have no effect on the fertility of male and female rats at oral doses up to 9 mg/kg/day (animal:human AUC ratio ≈ 484).

Teratology studies in the rabbit demonstrated maternal toxicity and carpal flexures in the fetus at an oral ivermectin dose of 4.5mg/kg/day. The NOAEL was established at 3.5 mg/kg/day, a dose corresponding to plasma levels 68 times higher than those obtained at the maximum recommended human dose by topical route (1g application of ROSIVER once daily).

In the rat, cleft palates were observed at the oral ivermectin dose of 12 mg/kg/day. The dose of 4 mg/kg/day was the NOAEL for maternal toxicity and embryofetal development, a dose corresponding to plasma levels 334 times higher than those obtained at the maximum recommended human dose by topical route (1g application of ROSIVER once daily).

The neonatal toxicity in oral rat studies was not related to in-utero exposure, but to postnatal exposure through maternal milk which resulted in high levels of ivermectin in the brain and in plasma of offspring.

Special Toxicology Studies

Local tolerance studies in rabbits showed that ivermectin 1% cream is irritant on the skin and non-irritant in the eye. Guinea pig studies showed that ivermectin 1% cream is a potential sensitizer and photosensitizer (as is the vehicle cream). Ivermectin 1% cream is not phototoxic following a single topical application followed by ultraviolet radiation.