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

Manufacture: Galderma Laboratories
Country: Canada
Condition: Acne, Acne rosacea (Rosacea), Acne Vulgaris (Acne), Pimples (Acne)
Class: Topical acne agents
Form: Cream, gel, liniment or balm, lotion, ointment, etc
Ingredients: Adapalene, benzoyl peroxide, hydrous, acrylamide/sodium acryloyldimethyltaurate copolymer, docusate sodium, edetate disodium, glycerin, isohexadecane, poloxamer 124, polysorbate 80, propylene glycol, sorbitan oleate, and purified water

Pharmaceutical Information

Drug Substance

Adapalene

Proper name: adapalene
Chemical name: 6-(4-methoxy-3-tricyclo[3.3.1.13,7]dec-1-ylphenyl)naphthalene-2-carboxylic acid
Molecular formula: C28H28O3
Mmolecular mass: 412.5
Structural formula:


Physicochemical properties: Adapalene is a white to off-white powder, which is sparingly soluble in tetrahydrofuran, practically insoluble in ethanol and in water.

Drug Substance

Benzoyl Peroxide

Proper name: benzoyl peroxide, hydrous
Chemical name: Dibenzoyl peroxide
Molecular formula: C14H10O4 (anhydrous)
Molecular mass: 242.2 (anhydrous)
Structural formula:


Physicochemical properties: Benzoyl peroxide is a white, granular powder, which is soluble in acetone and methylene chloride, slightly soluble in alcohol and insoluble in water.

Hydrous benzoyl peroxide contains not less than 20% water. However, the product is formulated to contain the labelled amount of benzoyl peroxide on an anhydrous basis.

Clinical Trials

Study Demographics and Trial Design

Table 1 Summary of patient demographics for North American Phase III clinical trials with TACTUPUMP in acne vulgaris
Study # Trial design Dosage, route of administration and duration Study subjects
(n=number) 
Mean age y (Range) Gender 
% M/F
RD.06.SRE.18094 Double-blind, multi-center, randomized, four treatment arms, controlled (active and vehicle) (517) 16.4 60/40
- Adapalene 0.1%/BPO 2.5% gel 149 (12 – 56)
- Adapalene gel 148
- BPO gel 149
- Gel vehicle 71
Topical
12 weeks
RD.06.SRE.18087 Double-blind, multi-center, randomized, four treatment arms, controlled (active and vehicle) (1668) 18.2 49/51
- Adapalene 0.1%/BPO 2.5% gel 415 (12 – 58)
- Adapalene gel 420
- BPO gel 415
- Gel vehicle 418
Topical
12 weeks
RD.06.SRE.18089 Open-label, long term, multi-center - Adapalene 0.1%/BPO 2.5% gel
Topical
1 year
(452) 18.3
(12 – 50)
49/51

Male and female subjects, 12 years of age or older, were eligible to enroll in the clinical trials outlined in Table 1. In Study 18094, subjects of any race with mild and moderate acne vulgaris (20 to 50 inflammatory lesions and 30 to 100 noninflammatory lesions) on the face were enrolled while subjects with nodules and cysts were excluded. These criteria were also applied to the long-term Study 18089.

In Study 18087, subjects with acne vulgaris with 20 to 50 inflammatory lesions and 30 to 100 noninflammatory lesions, one nodule and additionally specifying an Investigator Global Assessment (IGA) score of “3” (moderate) were eligible for inclusion (see Table 2). Subjects with facial and truncal acne vulgaris could also enroll.

Table 2 Global Severity Assessment
Investigator’s Global Assessment
0 Clear Residual hyperpigmentation and erythema may be present.
1 Almost Clear A few scattered comedones and a few small papules.
2 Mild Some comedones and some papules and pustules. No nodules present.
3 Moderate Many comedones, papules and pustules. One nodule present.
4 Severe Covered with comedones, numerous papules and pustules and a few nodules and cysts may be present.
5 a Very Severe Highly inflammatory acne covering the face; with nodules and cysts present.

a 5= very severe IGA grading was used in Study 18094, per established definitions in force at the time of conduct of the studies. Subsequent Study 18087 used a 4-point scale lacking the very severe grade 5.

Study Results

Table 3 Results of Study 18094 in acne vulgaris at Week 12 (ITT Population)
PRIMARY EFFICACY RESULTS STUDY 18094, ITT Week 12-LOCFa
Primary Endpoints TACTUPUMP Adapalene 0.1%/ BPO 2.5% Gel
N = 149
Adapalene Gel
N = 148
BPO Gel
N = 149
Gel Vehicle
N = 71
Success Rateb
n (%) 32
(21.5%)
18
(12.2%)
18
(12.1%)
4
(5.6%)
[p values vs Adapalene/BPO] - p = 0.029 p = 0.009 p = 0.002
Mean % lesion count reduction
Total lesions 48.6% 34.0% 33.4% 29.7%
[p values vs Adapalene/BPO] - p < 0.001 p < 0.001 p < 0.001
Inflammatory lesions 52.4% 39.9% 35.8% 31.8%
[p values vs Adapalene/BPO] - p < 0.001 p < 0.001 p < 0.001
Noninflammatory lesions 45.9% 29.6% 32.2% 27.8%
[p values vs Adapalene/BPO] - p < 0.001 p < 0.001 p < 0.001

a Week 12 LOCF: The last available data observed during the study. Baseline value was used if no post-Baseline data were available.

b Success Rate was defined as the proportion of subjects with an Investigator’s Global Assessment (IGA) Score of ‘0’ or ‘1’ (clear / almost clear) with at least a two grade improvement from baseline on the global, static, dichotomized, six-point scale.

Efficacy of TACTUPUMP (adapalene/benzoyl peroxide) topical gel vs. gel vehicle was observed early in Study 18094, with significant differences in Success Rate observed at Week 8 and sustained to the end of treatment. For Percent Change in Lesion Counts, the significant differences from gel vehicle were demonstrated at Week 1 for inflammatory lesions and at Week 4 for noninflammatory and total lesion counts, and were sustained to the end of treatment.

TACTUPUMP topical gel had a significantly higher Success Rate (p≤0.029) for all analyses at Week 12 LOCF, ITT) as compared to either monad or gel vehicle in the ITT population (see Table 3). The 21.5% Success Rate (subjects rated “Clear/IGA 0” or “Almost Clear/IGA 1” with at least a two-grade improvement from baseline) for TACTUPUMP topical gel was 9% greater than either monad and 16% greater than the gel vehicle alone. All co-primary endpoints (percent change from baseline in inflammatory, noninflammatory and total lesion counts) showed significantly superior results for TACTUPUMP in the ITT population and were confirmed in the PP population (p-values ≤ 0.02 for all comparisons).

Table 4 Results of Study 18087 in acne vulgaris at Week 12 (ITT Population)
PRIMARY EFFICACY RESULTS STUDY 18087, ITT Week 12-LOCFa
Primary Endpoints TACTUPUMP Adapalene 0.1%/BPO 2.5% Gel
N = 415
Adapalene Gel
N = 420
BPO Gel
N = 415
Gel Vehicle
N = 418
Success Rate2b
n (%) 125 (30.1%) 83 (19.8%) 92 (22.2%) 47 (11.3%)
[p values vs Adapalene/BPO] - p < 0.001 p = 0.006 p < 0.001
Mean % lesion count reduction
Total lesions 50.0% 41.3% 41.2% 26.1%
[p values vs Adapalene/BPO] - p < 0.001 p < 0.001 p < 0.001
Inflammatory lesions 53.4% 41.7% 47.6% 30.2%
[p values vs Adapalene/BPO] - p < 0.001 p = 0.017 p < 0.001
Noninflammatory lesions 48.1% 40.8% 37.2% 23.2%
[p values vs Adapalene/BPO] - p = 0.007 p < 0.001 p < 0.001

aWeek 12 LOCF: The last available data observed during the study. Baseline value was used if no post-Baseline data were available.

bSuccess Rate was defined as the proportion of subjects with an Investigator’s Global Assessment (IGA) Score of ‘0’ or ‘1’ (clear / almost clear) with at least a two grade improvement from baseline on the global, static, dichotomized, six-point scale.

All analyses (ITT, PP, and sensitivity) for Success Rate in Study 18087 showed TACTUPUMP (adapalene/benzoyl peroxide) topical gel to be significantly more effective than either monad or the gel vehicle (p≤0.006 for primary ITT analyses; p < 0.001 for PP analyses) (see Table 4).

The percentage of subjects rated Success (“Clear/IGA 0” or “Almost Clear/IGA 1” with at least a two grade improvement from baseline) is significantly greater for TACTUPUMP (30.1%) than for adapalene gel (19.8%), benzoyl peroxide gel (22.2%), and gel vehicle (11.3%). There was a significant (p=0.004) early treatment effect for TACTUPUMP topical gel compared to gel vehicle starting at week 4 for Success Rate, and sustained until the end of the study.

Table 5 Results of TACTUPUMP (Adapalene 0.1% /BPO 2.5% Gel) in Acne vulgaris at Month 12, Study 18089 (ITT Population)
Summary of Percent Change at Month 12 in Study 18089
(ITT Population)
Percent Change at Month 12
N=327
Mean (range)
Inflammatory Lesions -66.4% (-100 to +44)
Noninflammatory Lesions -64.6% (-100 to +64.1)
Total Lesion Counts -65.1% (-100 to +36.8)

In Study 18089 at Month 12, the mean Percent Reduction in inflammatory, noninflammatory, and total lesion counts from Baseline was 64% or greater for all lesion counts (see Table 5). Reduction in lesion counts were observed starting as early as Week 1 and improvement continued to end of the study (see Fiqure 1).

Endpoint: The last available data observed during the study. Baseline value was used if no post-baseline data were available

In the open-label long-term safety and efficacy study 18089, early onset of efficacy was observed at Week 1 (21.5% reduction in mean inflammatory lesion counts) with mean percent reductions in inflammatory, non-inflammatory and total lesions of 64.6% to 66.4% at Month 12. A total of 46.2% and 62.2% of subjects assessed their acne vulgaris “marked improvement” or “complete improvement” after 6 and 12 months of treatment, respectively. No decrease in efficacy was observed during long-term use. No notable differences were seen between gender, race, and age subgroups.

Тable 6 Summary of patient demographics for a study in 9 – 11 years old pediatric patients treated with TACTUPUMP and presenting with acne vulgaris
Trial design Dosage, route of administration and duration Study subjects*
(n=number)
Mean age
(Range)
Gender %
M/F
Phase IV, double-blind, multi-center, randomized, vehicle-controlled - Adapalene/BPO gel
- Gel vehicle
- Topical
- 12 weeks

(285)
142
143

10.4
(9-11)

24/76

*At baseline, study subjects had a minimum of 20 inflammatory lesions and not more than 100 noninflammatory lesions, with an Investigator Global Assessment score of ‘Moderate’.

The safety and efficacy of TACTUPUMP Topical Gel were assessed in children 9 to 11 years old presenting with moderate acne, in a 12-week clinical study (Table 6). Overall, the efficacy of TACTUPUMP in these subjects is comparable to the efficacy observed in subjects aged 12 years and above treated with TACTUPUMP (Table 3, Table 7).

Table 7 Results of study in pediatric patients with Acne vulgaris (9 -11 years) with TACTUPUMP (Adapalene 0.1% and Benzoyl Peroxide 2.5%) at Week 12 (ITT Population)
Adapalene/BPO Gel
N = 142
Gel Vehicle
N = 143
IGA: Two Grade
Improvement and Clear
or Almost Clear
67 (47.2%) 22 (15.4%)
p < 0.001a
Mean reduction in Total Lesion
Count
(percent change)
28.4 (57.9%) 4.2 (10.4)
p < 0.001b
Mean reduction in Inflammatory
Lesions Count
(Percent change)
7.7 (39.8%) 0.5 (15.3%)
p < 0.001b
Mean reduction in Noninflammatory
Lesions Count
(Percent change)
20.8 (56.8%) 3.6 (3.2%)
p < 0.001b

aP-values were based on CMH test general association statistic, controlling for center

bP-values were based on ANCOVA model with ranked changes as dependent variable, ranked Baseline as a covariate, and treatment and center as main effects

The efficacy of TACTUPUMP FORTE gel applied once daily for 12 weeks for the treatment of acne vulgaris was assessed in a multicenter, randomized, double-blind, controlled study, comparing TACTUPUMP FORTE gel to TACTUPUMP gel and vehicle gel in acne subjects. In this study, 217 subjects were treated with TACTUPUMP FORTE gel, 217 subjects with TACTUPUMP gel and 69 subjects with the vehicle (Table 8).

Table 8 Summary of patient demographics for North American Phase III clinical trial with TACTUPUMP FORTE in moderate and severe acne vulgaris Study 18240
Trial design Dosage, route of administration and duration Study subjects
(n=number)
Mean age (Range) Gender % M/F
Double-blind, multi-center, randomized, three treatment arms, controlled (active and vehicle) Adapalene 0.3% /BPO 2.5% gel
Adapalene 0.1% /BPO 2.5% gel
Gel vehicle
Topical
12 weeks
(503)
217
217
69
19.6 (12-57) 48 / 52

Treatment response was defined as the percent of subjects who were rated ‘Clear’ or ‘Almost Clear’ at Week 12 with at least a two-grade improvement based on the Investigator’s Global Assessment (IGA), and mean absolute change from baseline at Week 12 in both inflammatory and noninflammatory lesion counts. An IGA score of ‘Clear’ corresponded to clear skin with no inflammatory or noninflammatory lesions. An IGA score of ‘Almost Clear’ corresponded to a few scattered comedones and a few small papules.

At Baseline, 50% of enrolled patients had acne severity assessed as “moderate” (IGA = 3) and 50% had scores of “severe” (IGA=4). For lesion counts, subjects had an average of 98 total lesions (range: 51-226), of which the mean number of inflammatory lesions was 38 (range: 20-99) and the mean number of non-inflammatory lesions was 60 (range: 30-149).The age of the patients ranged from 12 to 57 years, with 273 (54.3%) patients 12 to 17 years of age. A similar number of males (47.7%) and females (52.3%) were enrolled.

Table 9 Efficacy Results of Study 18240 in the overall population: subjects with moderate and severe acne vulgaris, Week 12 (MIa, ITT Population
TACTUPUMP FORTE Gel
(N=217)
TACTUPUMP Gel
(N=217)
Vehicle Gel
(N=69)
Success Rate: IGA at least two-grade
improvement and
“clear” or “almost clear”

p-value vs Vehicle Gel
33.7%




<0.001
27.3%




0.014
11.0%




-
Mean reduction in Inflammatory Lesions
Count (percent change)

p-value vs Vehicle Gel
27.8 (68.7%)



<0.001
26.5 (69.3%)



<0.001
13.2 (39.2%)


-
Mean reduction in Non-inflammatory
Lesions Count (percent change)

p-value vs Vehicle Gel
40.5 (68.3%)



<0.001
40.0 (68.0%)



<0.001
19.7 (37.4%)


-

aMI: Missing data was imputed using multiple imputation methodology

Superiority of TACTUPUMP FORTE gel over vehicle gel was demonstrated in the overall study population of subjects with moderate and severe acne (IGA=3 and IGA=4) at Week 12 for Success Rate (subjects rated “Clear” or “Almost Clear” on the IGA with at least 2-grade improvement [33.7% vs. 11.0%, p<0.001]) and for changes in inflammatory (-27.8 vs -13.2, p<0.001) and noninflammatory lesion counts (-40.5 vs -19.7, p<0.001)

The primary efficacy analyses were also confirmed in the PP analyses and sensitivity analyses using traditional imputation methodology for missing data. Results of primary efficacy analyses are shown in Table 9.

In addition, in the subjects with severe acne (IGA= 4), TACTUPUMP FORTE was shown to be superior to gel vehicle for the same endpoints (Table 10).

Table 10 Efficacy Results of Study 18240 in the overall population: subjects with moderate and severe acne vulgaris, Week 12 (MIa, ITT Population
TACTUPUMP FORTE Gel
(N=106)
TACTUPUMP Gel<
(N=112)
Vehicle Gel
(N=34)
Success Rate: IGA at least two-grade
improvement and
“clear” or “almost clear”

p-value vs Vehicle Gel
31.9%




0.029
20.5%




0.443
11.8%




-
Mean reduction in Inflammatory Lesions:
Count (percent change)

p-value vs Vehicle Gel
37.2 (74.4%)



<0.001
30.2 (68.0%)



<0.001
14.3 (33.0%)


-
Mean reduction in Non-inflammatory
Lesions Count (percent change)

p-value vs Vehicle Gel
46.3 (72.0%)



<0.001
43.9 (68.4%)



<0.001
17.8 (30.8%)


-

aMI: Missing data was imputed using multiple imputation methodology

Both TACTUPUMP FORTE and TACTUPUMP were superior to Vehicle in terms of each lesion type, inflammatory and non -inflammatory. However, when analyzing Success rate, where IGA required to be improved by at least 3 grades, only TACTUPUMP FORTE was shown superior to Vehicle (31.9% vs 11.8%, p=0.029), while TACTUPUMP was not (20.5% vs 11.8%, p=0.443).

Detailed Pharmacology

Adapalene

Adapalene is a chemically stable, retinoid-like compound. Biochemical and pharmacological profile studies have demonstrated that adapalene is a potent modulator of cellular differentiation, keratinization and inflammatory processes all of which represent important features in the pathology of acne vulgaris. Mechanistically, adapalene binds to specific retinoic acid nuclear receptors but, unlike tretinoin, does not bind to the cytosolic receptor protein. Although the exact mode of action of adapalene is unknown, current evidence suggests that topical adapalene normalizes the differentiation of follicular epithelial cells resulting in decreased microcomedone formation. Studies in acne patients provide clinical evidence that topical adapalene is effective in reducing the noninflammatory acne lesions (open and closed comedones). Adapalene inhibits the chemotactic (directional) and chemokinetic (random) responses of human polymorphonuclear leucocytes in in vitro assay models; it also inhibits the metabolism of arachidonic acid, by lipoxidation, to inflammatory mediators. In vitro studies with adapalene have shown inhibition of the AP-1 factors and the inhibition of the expression of toll like receptors 2. This profile suggests that the cell mediated inflammatory component of acne is modified by adapalene. Studies in human patients provide clinical evidence that topical adapalene is effective in reducing the inflammatory components of acne (i.e., papules and pustules).

Benzoyl Peroxide

Benzoyl peroxide is an oxidizing agent with a broad spectrum bactericidal activity, in particular against Propionibacterium acnes (P. acnes), which is abnormally present in the acne-affected pilosebaceous unit. Additionally benzoyl peroxide has demonstrated exfoliative and keratolytic activities.

As both active substances (adapalene and benzoyl peroxide) are well-characterized pharmacologically, and as no interactions are likely to occur, no specific nonclinical pharmacology studies were performed with TACTUPUMP. Safety pharmacological studies for both individual active substances (adapalene and benzoyl peroxide) suggest no overall impairment of the major physiological body systems (including central nervous system, cardiovascular and respiratory functions).

Human Pharmacology

Pharmacokinetics

In Vitro Studies

The penetration of each active substance (adapalene and benzoyl peroxide) is not statistically significantly modified when the substances were administered together in the proposed commercial fixed combination formulations (TACTUPUMP or TACTUPUMP FORTE).

The in vitro penetration and metabolism of 14C-adapalene from adapalene/benzoyl peroxide gel was investigated using Reconstructed Human Epidermis (RHE). Parent adapalene was the only radioactive component found in all of the samples analyzed, indicating that adapalene is not metabolized by RHE. The metabolism and the penetration of adapalene are not modified by the presence of benzoyl peroxide in the formulation.

In Vitro Studies

Plasma levels of adapalene were assessed in subjects with acne vulgaris following daily applications of adapalene 0.1% / benzoyl peroxide 2.5% gel for 10 days and 30 days and following daily application of adapalene 0.3% / Benzoyl Peroxide 2.5% gel for 30 days. Systemic exposure to benzoyl peroxide was not assessed because the molecule is entirely and rapidly metabolized in the skin, and the metabolite, benzoic acid, is considered safe in humans. Systemic exposure to adapalene following cutaneous application to subjects with acne vulgaris was low. This is consistent with the finding for adapalene 0.1% or 0.3% gel and other adapalene formulations. Benzoyl peroxide has no effect on the penetration of adapalene following repeated applications, and there is no evidence of a pharmacokinetic interaction of benzoyl peroxide with adapalene.

Pharmacodynamics

In a cumulative irritation potential study with TACTUPUMP, under the conditions tested, the fixed combination adapalene 0.1% / benzoyl peroxide 2.5% gel is not more irritating than either component applied alone (i.e., adapalene 0.1% gel and benzoyl peroxide 2.5% gel), or than benzoyl peroxide 10% gel.

In a cumulative irritation potential study with TACTUPUMP FORTE, the only treatment emergent adverse events were skin irritation conditions; similar results were observed for skin sites exposed to the fixed combination adapalene 0.3% / benzoyl peroxide 2.5% gel, to adapalene 0.3% gel. All study drugs were well tolerated except for sodium lauryl sulfate. No reaction was observed with white petrolatum.

In a sensitization potential study the maximized conditions of application (occlusion) greatly increased the irritation potential of the benzoyl peroxide-containing products, thereby increasing their sensitization potential. As a consequence, a high level of sensitization to both adapalene/benzoyl peroxide gel, the fixed combination, and benzoyl peroxide 2.5% gel was observed. The sensitization level of these two products was similar.

The results of a phototoxicity study demonstrate that the combination of adapalene with benzoyl peroxide in adapalene/benzoyl peroxide gel does not increase the phototoxic potential of benzoyl peroxide 2.5% gel administered alone.

In a photoallergy study neither adapalene/benzoyl peroxide gel nor its individual active components showed any photosensitization potential. It was concluded that adapalene/benzoyl peroxide gel is not a photosensitizer.

Microbiology

No microbiological studies were conducted with TACTUPUMP and TACTUPUMP FORTE.

Toxicology

The toxicology of the individual active substances, adapalene and benzoyl peroxide, is well characterised. Repeat-dose dermal toxicity studies and local tolerance studies performed with TACTUPUMP (adapalene 0.1%/benzoyl peroxide 2.5%) and with TACTUPUMP FORTE (adapalene 0.3%/benzoyl peroxide 2.5%) showed skin irritation and a potential for sensitization (Table 11,Table 12and Table 13) which are expected with adapalene and benzoyl peroxide.

Repeat-Dose Toxicity

Table 11 Summary of Principal Findings in Repeat-Dose Toxicity Studies Conducted with TACTUPUMP gel (Adapalene 0.1%/Benzoyl Peroxide 2.5%)
Species and Strain Method of Administration  Duration of Dosing Doses
(g/kg/day)
Gender & No. per Group Noteworthy Findings
Rat
Sprague-Dawley
Dermal 4 weeks 2 g/kg/day of:

- Prototype adapalene 0.1% /BPO 2.5% gel

- Prototype adapalene 0.1% gel

- Prototype gel vehicle
10M + 10F/group(3 groups)

TK:6M + 6F/group(test and monad)

1M + 1F(gel vehicle)
7Treatment-related effects were local skin irritations at the treatment site (e.g., desquamation, acanthosis, hyperkeratosis and sebaceous gland hypertrophy). The incidence was higher in rats treated with adapalene/BPO gel than in rats treated with adapalene alone.
TK: Systemic exposure to adapalene was higher at the end than at the beginning of the treatment. Adapalene plasma concentrations were higher in females than in males.
Dog
Beagle
Dermal 4 weeks 2 g/kg/day of:

- Prototype adapalene 0.1% /BPO 2.5% gel

- Prototype adapalene 0.1% gel

- Prototype gel vehicle
3M + 3F/group (3 groups)

TK: 3M + 3F/group(3 groups)
Treatment-related effects were local irritations at the treatment sites (erythema and desquamation). Findings were associated with epithelial hyperplasia and perivascular mononuclear cell infiltration in the dermis at microscopical observation. Findings were considered indicative of a hyperplastic dermatitis caused by local irritation. Effects were more pronounced in animals treated with adapalene/BPO gel vs. adapalene alone. Application was not associated with any systemic clinical changes or macroscopic findings.
TK: Systemic exposure to adapalene was higher at the end than at the beginning of the treatment. Adapalene plasma concentrations were higher in females than in males.
Minipig
Göttingen
Dermal 4 weeks 1.75 g/kg/day of Adapalene 0.1% /BPO 2.5% gel 2M + 2F (1 group) Adverse dermal reactions (e.g., erythema combined with bloody crust formation, suppurating of the skin, and wounds with crust formation) were observed in the treated skin area. Histopathological changes were observed including crust formation, epidermal hyperplasia, epidermal/subdermal edema and epidermal/subepidermal inflammatory cells.
Minipig Göttingen Dermal 13 weeks 2 g/kg/day of:

- Adapalene 0.1% /BPO 2.5% gel

- Gel vehicle
4M + 4F/group(2 groups) Due to severe local reactions and the absence of recovery, the study was stopped prior to time. Treatment took place for a maximum of 16 Days for the adapalene/BPO gel and until Day 34 for the gel vehicle. Study was terminated on study day 35. Animals were killed and no examinations (e.g., ECG, ophthalmoscopy, clinical pathology, histopathology, toxicokinetics) were performed.
Minipig
Göttingen
Dermal 13 weeks - Adapalene/BPO gel at 0.125, 0.25 and 0.75 g/kg/day

- Gel vehicle at 0.75 g/kg/day

- Non-treated group
4M + 4F/group (5 groups)

TK:4M + 4F /group (5 groups)
Local reactions (slight to severe erythema) and cutaneous microscopic signs (minimal to slight acanthosis and minimal to moderate hyperkeratosis) were observed. Frequency and incidence of these findings generally increased with dose level and appeared from the second week of treatment until the end of the treatment period.
TK: For Day 0, all samples BLQ. After 13 weeks, all samples were BLQ except for 5 animals: 2 females in 0.25 g/kg/day group and 1 male and 2 females in 0.75 g/kg/day group had low adapalene plasma exposure.

BLQ: Below the limit of quantification; BPO: Benzoyl Peroxide; ECG: Electrocardiogram; F: Female; M: Male; TK: Toxicokinetics.

Table 12 Summary of Principal Findings in Repeat-Dose Toxicity Studies Conducted with TACTUPUMP FORTE (Adapalene 0.3%/Benzoyl Peroxide 2.5%)
Species and Strain Method of Administration Duration of Dosing Doses
(g/kg/day)
Gender & No. per Group Noteworthy Findings
Minipig
Göttingen
Dermal 4 weeks 0.25, 0.5, 0.75 or 1 g/kg/day of Adapalene 0.3% /BPO 2.5%gel 1M + 1F / group (4 groups) Moderate to severe cutaneous reactions recorded throughout this study for all animals treated at 0.5, 0.75 or 1 g/kg/day leading to treatment discontinuation. Discrete to slight erythema induced at 0.25 g/kg/day but dose volume overall well tolerated over four consecutive weeks
Minipig
Göttingen
Dermal 13 weeks - Adapalene 0.3% /BPO 2.5% gel at 0.25 g/kg/day

- Gel vehicle at 0.25 g/kg/day
4M + 4F/group(2 groups)

TK:4M + 4F/group(2 groups)
Slight to severe erythema and desquamation at the application-sites, correlated with cutaneous microscopic findings including acanthosis, parakeratosis and/or hyperkeratosis, exocytosis / spongiosis and minimal dermal inflammatory infiltrates. No treatment-related systemic effects.
TK: After repeated dermal applications (Day 91), adapalene was quantifiable in 3 animals out of 8 with a maximal concentration reaching 1.34 ng/mL.

BPO: Benzoyl Peroxide; F: Female; M: Male; TK: Toxicokinetics

Local Tolerance

Table 20 Summary of Principal Findings in Local Tolerance Studies Conducted with TACTUPUMP and TACTUPUMP FORTE (Adapalene 0.1%/Benzoyl Peroxide 2.5% Gel and Adapalene 0.3% / Benzoyl Peroxide 2.5% Gel)
Species and Strain Method of Administration Duration of Dosing Dose Concentration (% w/w) Gender & No. per Group Noteworthy Findings
Primary Skin Irritation Studies
Rabbit
New Zealand
White
Dermal Single 24h occlusive dose 0.5 mL per site (abraded and intact skin) of prototype adapalene 0.1%BPO 2.5%gel 3M (1 group) - Erythema was observed at the abraded and intact skin application sites.

- Erythema persisted in the abraded and intact skin after 72 hours.

- The cutaneous primary irritation index (CPII) score was 1.5 – slight irritant.
Rabbit
New Zealand
White
Dermal Single 24h semi-occlusive dose Adapalene 0.3% / Benzoyl Peroxide 2.5% gel or gel placebo 3M / group (2 groups) - Adapalene 0.3%/Benzoyl Peroxide 2.5% gel: primary cutaneous irritation index was 2.33 – irritant
- Gel placebo: primary cutaneous irritation index was 0.33 – non irritant
Bovine Corneal Opacity and Permeability test
Isolated
bovine cornea
Ocular (in vitro) Single application Adapalene 0.3% / Benzoyl Peroxide 2.5% gel or gel placebo Na - In Vitro Irritancy Score: -0.9 and 0.1
- Adapalene 0.3% / Benzoyl Peroxide 2.5% gel and its gel placebo: Not severe irritant or corrosive
Single dose ocular irritation study
Rabbit
Japanese
White
Ocular Single application followed or not by washing 0.1 mL to the left eye:
- Adapalene 0.1% / Benzoyl Peroxide 2.5% gel
- gel placebo
6F (3 unwashed and 3 washed) - Unwashed eyes: fixed combination and placebo were ‘minimally irritating’
- Washed eyes (100 mL of water for injection after 30 seconds): fixed combination was ‘practically nonirritating’ and placebo was ‘minimally irritating’
Sensitization Potential Studies
Guinea Pig
Dunkin-Hartley
Dermal

Modified Bühler Test (9 doses + challenge)
Induction: 9 non-consecutive days

Filter paper impregnated (0.4mL) / application site under occlusion for 6 hours/day

Rest: 11 days

Challenge: 1 day25μL/application site under occlusion for 6 hours/day
- Prototype adapalene/BPO gel

(Adapalene 0.1% / Benzoyl Peroxide 2.5% Gel)

- Prototype gel vehicle

- Positive control (DNCB at 1%)

- Negative control (water)
10M + 10F /group (test and vehicle)

5M + 5F /group (2 controls)
- Marked dermal reactions in 19 of 20 animals (e.g., erythema, desquamation, scabs).

- Sensitization rate: 95% (classified: extreme).

- No skin sensitization with the gel vehicle.
Guinea pig
Hartley
Dermal
Modified Bühler Test (9 doses + challenge)
Induction (3 weeks): 9 applications of 0.5 mL / application site under occlusion for 6 hours/day
Rest: 9 days
Challenge: one application of 0.5 mL under occlusion (6 hours/day)
Induction and Challenge:
- Adapalene 0.3% / BPO 2.5% Gel
- Gel placebo
- Negative control – water for injection
- Positive control – DNCB 1%
10 M + 10 F (test, vehicle and positive control)

5 M + 5 F(negative control)
- Sensitization rate 75%: Adapalene 0.3% / Benzoyl peroxide 2.5% Gel was classified strong sensitizer
- No skin sensitization with the vehicle
Phototoxicity and Photosensitization Studies
Guinea Pig
Dunkin-Hartley
Dermal Induction: 6 applications in 8 days

Concentrations of the test item were gradually reduced from 100% to 10% (Days 1 and 2: 100%; Days 3 and 6: 50%; Day 7: 25%; Day 8: 10%)

Rest: 20 days

Challenge: 1 day 0.1 mL/application site
- Prototype adapalene/BPO gel with and without UVA/UVB irradiation

- Prototype gel vehicle with UVA/UVB irradiation

- Untreated control with UVA/UVB irradiation
15M (5M: test item; 10M test item with UVA/UVB)

5M /group (vehicle and untreated)
- No evidence of phototoxic or photoallergenic potential.

- Cutaneous reactions (e.g., erythema, dryness of the skin, beige coloration of the skin and sometimes crusts) were observed in the adapalene/BPO gel treated group.

- Results indicated a slight and cumulative irritant effect of the test item.

BPO: Benzoyl Peroxide; DNCB: Dinitrochlorobenzene; F: Female; M: Male; UVA/UVB: Ultraviolet A/Ultraviolet B.

In summary, the fixed combination exhibited local dermal adverse events. Under the conditions tested, no new toxicological concerns were identified up to 4 weeks in rats and dogs for TACTUPUMP: adapalene 0.1% / benzoyl peroxide 2.5% gel) and up to three month in minipigs for both strengths.

Genotoxicity

No genotoxicity studies were conducted with TACTUPUMP or TACTUPUMP FORTE.

In a series of in vivo and in vitro tests, adapalene did not demonstrate any mutagenic or genotoxic activity.

Bacterial mutagenicity assays (Ames test) with benzoyl peroxide has provided mixed results, mutagenic potential was observed in a few but not in a majority of investigations. Benzoyl peroxide has been shown to produce single-strand DNA breaks in human bronchial epithelial and mouse epidermal cells, it has caused DNA-protein cross-links in the human cells, and has also induced a dose-dependent increase in sister chromatid exchanges in Chinese hamster ovary cells.

Carcinogenicity

No carcinogenicity studies were conducted with TACTUPUMP or TACTUPUMP FORTE.

Lifetime studies with adapalene have been completed in mice at topical doses of 0.6 (0.03%), 2 (0.1%) and 6 (0.3%) mg/kg/day and in rats at oral doses of 0.15, 0.5 and 1.5 mg/kg/day and demonstrated no carcinogenic effect. However, a high incidence of splenic extra-medullary haematopoiesis was observed in male mice treated with 6 mg/kg/day (0.3%) topically applied adapalene gel. Oral administration of adapalene to Sprague-Dawley rats at a dose of 1.5 mg/kg/day for two years resulted in a higher incidence in males, relative to controls, of benign phaeochromocytoma of the adrenal medulla. These neoplastic changes are considered to have no relevance to the topical use of adapalene in humans in clinical conditions.

Animal studies have shown an increased tumourigenic risk with the use of related drugs (e.g., tretinoin) when combined with exposure to the ultraviolet (UV) light in sunlight, or from other UV sources. Studies to determine whether adapalene may accelerate the tumourigenic effects of UV radiation have not been conducted.

Benzoyl peroxide has been shown to be a tumour promoter and progression agent in a number of animal studies. The clinical significance of this is unknown.

Benzoyl peroxide in acetone at doses of 5 and 10 mg administered twice per week induced skin tumours in transgenic TG.AC mice in a study using 20 weeks of topical treatment. However, in 2- year dermal oncogenicity studies, there was no evidence of carcinogenic potential at doses up to 45 mg/day in Fischer 344 rats or doses up to 25 mg/day in B6C3F1 mice.

In a photocarcinogenicity study conducted with 5% benzoyl peroxide carbopol gel, no increase in UV-induced tumour formation was observed in hairless mice topically treated for 40 weeks.

Reproductive and Developmental Toxicity

No reproductive and developmental toxicity studies and no studies in juvenile animals were conducted with TACTUPUMP or TACTUPUMP FORTE.

Adapalene administered orally at doses of ≥25 mg/kg/day can induce major structural changes including cleft palate, cranial abnormalities and spina bifida in rat and rabbit fetuses. Similar teratogenic effects have also been reported with other retinoids.

Dermal teratology studies conducted in rats and rabbits at doses of 0.6-6.0 mg adapalene/kg/day exhibited no foetotoxicity. Increases in supernumerary fetal ribs were recorded in both rats and rabbits. In the rat, there were also other minor bone variations such as small additional fissure in the parietal bone and asymmetric pelvis. In the rabbit, the other minor bone variations were small additional fissures in the inter-parietal bone, fissured or absent 27 pre-sacral vertebrae, incomplete ossification of the head of limb long bones, and tail anomalies. The AUC at the No Observable Adverse Effect Level in the rat (6.0 mg/kg/ day, the most sensitive species) corresponds to a safety margin of 32 and 102 when compared respectively to the exposure data in humans with TACTUPUMP FORTE (adapalene 0.3%/benzoyl peroxide 2.5%) Topical Gel and TACTUPUMP (adapalene 0.1%/benzoyl peroxide 2.5%) Topical Gel.

No effects of adapalene (doses up to 20 mg/kg/day) were found in rats on the reproductive performance or fertility of the F0 males or females. Total litter loss was suffered by 3 out of 25 F0 female rats (12%) orally dosed at 15 mg/kg/day; these females had pale and inactive mammary tissues. There were no detectable effects on the growth, development and subsequent reproductive function of the F1 offspring.

A reproductive and developmental toxicity study conducted in rats exposed groups to oral doses of benzoyl peroxide of up 1000 mg/kg/day (5 mL/kg). A decrease in the testes and epididymides weights associated with marked testes degeneration was observed in males with incomplete recovery. The copulation and fertility indexes were not modified in any of the treated groups when compared with controls. The number of births, the male:female ratio, and the survival rate were not affected by the treatment. In the newborn rats, one case of spina bifida was found and 118 runts were born in the treatment group compared to 8 runts born in the positive control group. No variants were found in any of the groups. Benzoyl peroxide did not induce teratogenicity or effects on reproductive function at doses up to 500 mg/kg/day.

Simulgel 600 PHA (Non-Medicinal Ingredient)

Single-dose, mutagenicity, and in vitro toxicity studies were conducted with the non-medicinal ingredient Simulgel 600 PHA. No untoward results were observed in the single-dose toxicity study when the excipient was administered orally (at a dose of 2000 mg/kg) to rats. No cytotoxic or genotoxic effects were observed in the in vitro bacterial cell mutagenicity study using Salmonella typhimurium and Escherichia coli exposed to Simulgel 600 PHA concentrations up to 5000 µg/plate. In a Mouse Lymphoma assay (MLA), Simulgel 600 did not induce mutation at doses up to 200 µg/mL (maximum dose) in a 3-hour incubation period. Statistically significant increase in mutation frequencies were reported for the 24-hour incubation period. Results were considered equivocal and of doubtful biological relevance. Other in vitro toxicity studies found that the excipient was non-irritating when Simulgel 600 was applied at a concentration of 5% in chorioallantoic membrane (chicken egg) and mucous membrane (sheep red blood cell) models.