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DESCRIPTION
Picato® (ingenol mebutate) gel, 0.015% or 0.05% is a clear colorless gel for topical administration, which contains the active substance ingenol mebutate, an inducer of cell death.
The chemical name of ingenol mebutate is:
2-Butenoic acid, 2-methyl-, (1aR,2S,5R,5aS,6S,8aS,9R,10aR)-1a,2,5,5a,6,9,10,10a-octahydro-5,5a-dihydroxy-4-(hydroxymethyl)-1,1,7,9-tetramethyl-11-oxo-1H-2,8a-methanocyclopenta [a]cyclopropa[e]cyclodecen-6-yl ester, (2Z) -
or
(1aR,2S,5R,5aS,6S,8aS,9R,10aR)-5,5a-dihydroxy-4-(hydroxymethyl)-1,1,7,9-tetramethyl-11-oxo-1a,2,5,5a,6,9,10,10a-octahydro-1H 2,8a-methanocyclopenta[a]cyclopropa[e]cyclodecen-6-yl (2Z) 2 methylbut-2-enoate.
The molecular formula is C25H34O6 and molecular weight is 430.5. Ingenol mebutate is represented by the following structural formula:
Ingenol mebutate is a white to pale yellow crystalline powder.
Picato® gel, 0.015% and 0.05% contains 150 mcg and 500 mcg of ingenol mebutate, respectively in each gram of gel consisting of isopropyl alcohol, hydroxyethyl cellulose, citric acid monohydrate, sodium citrate, benzyl alcohol and purified water.
Picato® gel is clear colorless gel and supplied in unit dose laminate tubes, for single use, containing a nominal fill weight of 0.47 g, with a deliverable weight of 0.25 g. The tubes should be discarded after single use.
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CLINICAL PHARMACOLOGY
Mechanism of Action
The mechanism of action by which Picato® gel induces cell death in treating AK lesions is unknown.
Pharmacodynamics
The pharmacodynamics of Picato® gel is unknown.
Pharmacokinetics
Absorption
Drug Interactions
In vitro studies demonstrated that [3H]-ingenol mebutate undergoes extensive metabolism in human hepatocytes.
In vitro studies to assess the potential of ingenol mebutate to inhibit or induce human cytochrome P450 (CYP) enzymes demonstrated that ingenol mebutate does not inhibit CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 or induce CYP 1A2, 2C9, and 3A4. The estimated expected systemic exposure (< 0.1 ng/mL) following topical application of Picato® gel, 0.05% to AK subjects in the pharmacokinetic studies described above is negligible compared to the concentrations of ingenol mebutate evaluated in the in vitro studies.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal studies have not been performed to evaluate the carcinogenic potential of Picato
®
gel or ingenol mebutate. The effects of ingenol mebutate on fertility have not been evaluated.
Ingenol mebutate was negative in the Ames test, in vitro mouse lymphoma assay, and in vivo rat micronucleus test, but positive in the Syrian hamster embryo (SHE) cell transformation assay.
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CLINICAL STUDIES
Actinic Keratosis of the Face and Scalp
In two double-blind, vehicle-controlled, clinical trials, 547 adult subjects with AK on the face or scalp were randomized to treatment with either Picato® gel, 0.015% or vehicle gel for 3 consecutive days, followed by an 8 week follow-up period. The studies enrolled subjects with 4 to 8 clinically typical, visible, discrete AK lesions within a 25 cm2 contiguous treatment area. Hypertrophic and hyperkeratotic lesions were excluded from treatment. On each scheduled dosing day, the study gel was applied to the entire treatment area. A total of 536 subjects (98%) completed these studies. Study subjects ranged from 34 to 89 years of age (mean 64 years) and 94% had Fitzpatrick skin type I, II, or III. Approximately 85% of subjects were male, and all Picato®-treated subjects were Caucasian.
Efficacy was assessed at Day 57. Complete clearance rate was defined as the proportion of subjects with no (zero) clinically visible AK lesions in the treatment area. Partial clearance rate was defined as the proportion of subjects with 75% or greater reduction in the number of AK lesions at baseline in the selected treatment area. Table 5 presents the efficacy results for each trial.
Table 5 Number and Percent of Subjects Achieving Complete and Partial Clearance at Day 57 in Each Trial
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Study 1
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Study 2
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Picato® gel, 0.015%
(N=135)
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Vehicle
(N=134)
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Picato®
gel, 0.015%
(N=142)
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Vehicle
(N=136)
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Complete
Clearance Rate
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50 (37%)
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3 (2%)
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67 (47%)
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7 (5%)
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Partial Clearance
Rate (≥ 75%)
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81 (60%)
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9 (7%)
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96 (68%)
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11 (8%)
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Table 6 presents the response rates by anatomical location for each trial.
Table 6 Number and Percent of Subjects Achieving Complete Clearance at Day 57 by Anatomical Location and by Trial
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Study 1
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Study 2
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Picato® gel, 0.015%
(N=135)
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Vehicle
(N=134)
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Picato® gel, 0.015%
(N=142)
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Vehicle
(N=136)
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Scalp
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4/26 (15%)
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0/25 (0%)
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9/31 (29%)
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1/25 (4%)
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Face
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46/109 (42%)
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3/109 (2%)
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58/111 (52%)
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6/111 (5%)
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Subjects who achieved complete clearance at Day 57 in Study 1 and Study 2 entered a 12-month follow-up period. Based on 108 Picato® gel-treated subjects who achieved complete clearance in Study 1 and Study 2, the recurrence rate at 12 months was 54% where recurrence was defined as the percentage of subjects with any identified AK lesion in the previously treated area who achieved complete clearance at Day 57.
Actinic Keratosis of the Trunk and Extremities
In two double-blind, vehicle-controlled clinical trials, 458 adult subjects with AK on the trunk or extremities were randomized to treatment with either Picato® gel, 0.05% or vehicle gel for 2 consecutive days, followed by an 8 week follow-up period. The studies enrolled subjects with 4 to 8 clinically typical, visible, discrete AK lesions within a 25 cm2 contiguous treatment area. Hypertrophic and hyperkeratotic lesions were excluded from treatment. On each scheduled dosing day, the study gel was applied to the entire treatment area. A total of 447 subjects (98%) completed these studies. Study subjects ranged from 34 to 89 years of age (mean 66 years) and 94% had Fitzpatrick skin type I, II, or III. Approximately 62% of subjects were male, and all Picato®-treated subjects were Caucasian.
Efficacy was assessed at Day 57. Complete clearance rate was defined as the proportion of subjects with no (zero) clinically visible AK lesions in the treatment area. The partial clearance rate was defined as the proportion of subjects with 75% or greater reduction in the number of AK lesions at baseline in the selected treatment area. Table 7 presents the efficacy results for each study.
Table 7 Number and Percent of Subjects Achieving Complete and Partial Clearance at Day 57 in Each Trial
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Study 3
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Study 4
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Picato®
gel, 0.05%
(N=126)
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Vehicle
(N=129)
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Picato® gel, 0.05%
(N=100)
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Vehicle
(N=103)
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Complete
Clearance Rate
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35 (28%)
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6 (5%)
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42 (42%)
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5 (5%)
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Partial Clearance Rate (≥ 75%)
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56 (44 %)
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9 (7 %)
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55 (55 %)
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7 (7 %)
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Table 8 presents the response rates by anatomical location for each study.
Table 8 Number and Percent of Subjects Achieving Complete Clearance at Day 57 by Anatomical Location and by Trial
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Study 3
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Study 4
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Picato® gel, 0.05%
(N=126)
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Vehicle
(N=129)
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Picato® gel, 0.05%
(N=100)
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Vehicle
(N=103)
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Arm
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22/84 (26 %)
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4/82 (5 %)
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27/59 (46 %)
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3/67 (5 %)
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Back of Hand
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4/25 (16 %)
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0/29 (0%)
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6/28 (21 %)
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0/27 (0 %)
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Chest
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8/9 (89 %)
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1/8 (13 %)
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3/5 (60 %)
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1/3 (33 %)
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Othera
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1/8 (13 %)
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1/10 (10 %)
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6/8 (75 %)
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1/6 (17 %)
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aOther includes shoulder, back, leg.
Subjects who achieved complete clearance at Day 57 in Study 4 entered a 12-month follow-up period. Based on 38 Picato® gel-treated subjects who achieved complete clearance in Study 4, the recurrence rate at 12 months was 50% where recurrence was defined as the percentage of subjects with any identified AK lesion in the previously treated area who achieved complete clearance at Day 57.
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