The Medicines and Healthcare products Regulatory Agency, UK [1] and the European Medicines Agency (EMA) [2] have announced that marketing of Picato® Gel containing ingenol mebutate has been suspended. They have recommended that patients stop using the product pending an investigation into its safety with respect to skin cancer.
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The FDA approval for the use of ingenol mebutate gel was based on data from four Phase III studies in over 1000 people showing that ingenol mebutate gel applied once-daily for two or three consecutive days is significantly more effective than placebo at clearing actinic keratoses.
In two double-blind, vehicle-controlled, clinical trials, 547 adult subjects with actinic keratoses on the face or scalp were randomised to treatment with either ingenol mebutate 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 actinic keratoses within a 25 cm2 contiguous treatment area.
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). Approximately 85% of subjects were male, and all ingenol mebutate-treated subjects were Caucasian.
Efficacy was assessed at day 57. Complete clearance rate was defined as the proportion of subjects with no clinically visible actinic keratoses in the treatment area.
Partial clearance rate was defined as the proportion of subjects with 75% or greater reduction in the number of actinic keratoses lesions at baseline in the selected treatment area.
Key results are tabulated below.
Actinic keratosis of the face and scalp |
|||||
|---|---|---|---|---|---|
Study 1 |
Study 2 |
||||
Ingenol mebutate gel, 0.015% (n = 135) |
Vehicle (n = 134) |
Ingenol mebutate gel, 0.015% (n = 142) |
Vehicle (n = 136) |
||
Overall Complete clearance on day 57 |
50 (37%) |
3 (2%) |
67 (47%) |
7 (5%) |
|
Overall Partial clearance on day 57 |
81 (60%) |
9 (7%) |
96 (68%) |
11 (8%) |
|
Complete clearance of scalp lesions (day 57) |
4/26 (15%) |
0/25 (0%) |
9/31 (29%) |
1/25 (4%) |
|
Complete clearance of facial lesions (day 57) |
46/109 (42%) |
3/109 (2%) |
58/111 (52%) |
6/111 (5%) |
|
In two double-blind, vehicle-controlled clinical trials, 458 adult subjects with actinic keratoses on the trunk or extremities were randomized to treatment with either ingenol mebutate 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 actinic keratoses 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).
Approximately 62% of subjects were male, and all ingenol mebutate-treated subjects were Caucasian.
Complete and partial clearance rates were defined as in study 1.
Key results are tabulated below.
Actinic keratosis of the trunk and extremities |
|||||
|---|---|---|---|---|---|
Study 3 |
Study 4 |
||||
Ingenol mebutate gel, 0.05% (n = 126) |
Vehicle (n = 129) |
Ingenol mebutate gel, 0.05% (n = 100) |
Vehicle (n = 103) |
||
Overall Complete clearance on day 57 |
35 (28%) |
6 (5%) |
42 (42%) |
5 (5%) |
|
Overall Partial clearance on day 57 (≥75%) |
56 (44 %) |
9 (7 %) |
55 (55 %) |
7 (7 %) |
|
Complete clearance (CR) arm lesions (day 57) |
22/84 (26 %) |
4/82 (5 %) |
27/59 (46 %) |
3/67 (5 %) |
|
CR hand lesions (day 57) |
4/25 (16 %) |
0/29 (0%) |
6/28 (21 %) |
0/27 (0 %) |
|
CR chest lesions (day 57) |
8/9 (89 %) |
1/8 (13 %) |
3/5 (60 %) |
1/3 (33 %) |
|
CR (leg/shoulder/back) |
1/8 (13 %) |
1/10 (10 %) |
6/8 (75 %) |
1/6 (17 %) |
|
Long-term animal studies have not been performed to evaluate the carcinogenic potential of ingenol mebutate.
The effects of ingenol mebutate on fertility have not been evaluated.
Return to the page on ingenol mebutate gel.
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We suggest you refer to your national drug approval agency such as the Australian Therapeutic Goods Administration (TGA), US Food and Drug Administration (FDA), UK Medicines and Healthcare products regulatory agency (MHRA) / emc, and NZ Medsafe, or a national or state-approved formulary eg, the New Zealand Formulary (NZF) and New Zealand Formulary for Children (NZFC) and the British National Formulary (BNF) and British National Formulary for Children (BNFC).
