Picato

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 

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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Picato 150 micrograms/gram gel 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each gram of gel contains 150 mcg of ingenol mebutate. Each tube contains 70 mcg of ingenol 
mebutate in 0.47 g of gel. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Gel. 
Clear colourless gel. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Picato is indicated for the cutaneous treatment of non-hyperkeratotic, non-hypertrophic actinic 
keratosis in adults. 
 
4.2 Posology and method of administration 
 
Posology 
 
Actinic keratosis on the face and scalp in adults 
One tube of Picato 150 mcg/g gel (containing 70 mcg ingenol mebutate) should be applied once daily 
to the affected area for 3 consecutive days. 
 
Optimal therapeutic effect can be assessed approximately 8 weeks after treatment.  
 
A repeat treatment course of Picato can be given if an incomplete response is seen at a follow-up 
examination after 8 weeks or if lesions that are cleared at this examination recur in subsequent 
examinations. 
 
Paediatric population 
There is no relevant use of Picato in the paediatric population.  
 
Elderly population 
No dose adjustment is required (see section 5.1). 
 
Immunocompromised patients 
Clinical data on treatment in immunocompromised patients is not available, but systemic risks are not 
expected since ingenol mebutate is not absorbed systemically. 
 
Method of administration  
 

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The content of one tube covers a treatment area of 25 cm2 (e.g. 5 cm x 5 cm). The tube is for single 
use only and should be discarded after use (see section 6.6). 
 
The gel from the tube should be squeezed onto a fingertip and spread evenly over the entire treatment 
area, allowing it to dry for 15 minutes. The content of one tube should be used for one treatment area 
of 25 cm2.  
For single use only. 
 
For treatment of the neck: 
If more than half of the treatment area is located in the upper part of the neck, Picato 150 mcg/g gel 
should be used at the posology for face and scalp. If more than half of the treatment area is located in 
the lower part of the neck, Picato 500 mcg/g gel should be used at the posology for trunk and 
extremities. 
 
If an area on the face or scalp and another area on the trunk or extremities are simultaneously treated, 
then patients should be advised to ensure they use the appropriate strengths. Care should be exercised 
not to apply the Picato 500 mcg/g gel on the face or scalp as this could lead to a higher incidence of 
local skin responses. 
 
Patients should be instructed to wash their hands with soap and water, immediately after applying 
Picato and between topical applications if two different areas require different strengths. If treating the 
hands, only the fingertip which is used for applying the gel should be washed. 
Washing and touching the treated area should be avoided for a period of 6 hours after application of 
Picato. After this period, the treatment area may be washed using mild soap and water. 
 
Picato should not be applied immediately after taking a shower or less than 2 hours before bedtime. 
 
The treated area should not be covered with occlusive bandages after Picato is applied. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
4.4 Special warnings and precautions for use 
 
Eye exposure 
Contact with the eyes can cause chemical conjunctivitis and corneal burns. Patients should wash their 
hands thoroughly after applying the gel and following any contact with the treated area, to avoid 
inadvertent transfer of the gel to the eyes. If accidental exposure occurs, the eyes should be flushed 
immediately with large amounts of water, and the patient should seek medical care as soon as possible. 
Eye disorders such as eye pain, eyelid oedema and periorbital oedema should be expected to occur 
after accidental eye exposure of Picato (see section 4.8). 
 
Ingestion 
Picato must not be ingested. If accidental ingestion occurs the patient should drink plenty of water and 
seek medical care.  
 
General 
Administration of Picato is not recommended until the skin is healed from treatment with any previous 
medicinal product or surgical treatment and should not be applied to open wounds or damaged skin 
where the skin barrier is compromised. 
Picato should not be used near the eyes, on the inside of the nostrils, on the inside of the ears or on the 
lips. 
 
Local skin responses 
Local skin responses such as erythema, flaking/scaling, and crusting should be expected to occur after 
cutaneous application of Picato (see section 4.8). Localised skin responses are transient and typically 

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occur within 1 day of treatment initiation and peak in intensity up to 1 week following completion of 
treatment. Localised skin responses typically resolve within 2 weeks of treatment initiation when 
treating areas on the face and scalp and within 4 weeks of treatment initiation when treating areas on 
the trunk and extremities. Treatment effect may not be adequately assessed until resolution of local 
skin responses. 
 
Sun exposure 
Studies have been conducted to assess the effects of UV irradiation of the skin following single and 
multiple applications of ingenol mebutate gel, 100 mcg/g. Ingenol mebutate gel did not demonstrate 
any potential for photo irritation or photo allergic effects. However, due to the nature of the disease, 
excessive exposure to sunlight (including sunlamps and tanning beds) should be avoided or 
minimised.  
 
Keratoacanthoma, basal cell carcinoma, Bowen’s disease, squamous cell carcinoma 
Reports of keratoacanthoma, basal cell carcinoma, Bowen’s disease, squamous cell carcinoma 
occurring within the treatment area with a time to onset ranging from weeks to months following use 
of ingenol mebutate gel have been received from a post-authorisation clinical trial (see section 5.1) 
and post-marketing. Ingenol mebutate should be used with caution in patients with a history of 
cutaneous malignancy. Health care professionals should advise patients to be vigilant for any lesions 
developing within the treatment area and to seek medical advice immediately should any occur. 
 
Management of actinic keratosis 
Lesions clinically atypical for actinic keratosis or suspicious for malignancy should be biopsied to 
determine appropriate treatment. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed. Interactions with systemically absorbed medicinal 
products are considered unlikely as Picato is not absorbed systemically. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
There are no data from the use of ingenol mebutate in pregnant women. Animal studies showed slight 
embryo-fetal toxicity (see section 5.3). Risks to humans receiving cutaneous treatment with ingenol 
mebutate are considered unlikely as Picato is not absorbed systemically. As a precautionary measure, 
it is preferable to avoid the use of Picato during pregnancy.  
 
Breast-feeding 
No effects on the breastfed newborn/infant are anticipated as Picato is not absorbed systemically. The 
nursing mother should be instructed that physical contact between her newborn/infant and the treated 
area should be avoided for a period of 6 hours after application of Picato.  
 
Fertility 
No fertility studies have been performed with ingenol mebutate. 
 
4.7 Effects on ability to drive and use machines 
 
Picato has no or negligible influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
The most frequently reported adverse reactions are local skin responses including erythema, 
flaking/scaling, crusting, swelling, vesiculation/pustulation and erosion/ulceration at the application 
site of ingenol mebutate gel, see table 1 for MedDRA terms. Following the application of ingenol 

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mebutate, most patients (>95%) experienced one or more local skin response(s). Infection at the 
application site has been reported when treating face and scalp.  
 
Tabulated list of adverse reactions 
Table 1 reflects exposure to Picato 150 mcg/g or 500 mcg/g in 499 patients with actinic keratosis 
treated in four vehicle controlled phase 3 studies enrolling a total of 1,002 patients and post-marketing 
reports. Patients received field treatment (area of 25 cm2) with Picato at concentrations of 150 mcg/g 
or 500 mcg/g or vehicle once daily for 3 or 2 consecutive days respectively. 
 
The table below presents adverse reactions by MedDRA system organ class and anatomical location. 
 
Frequencies have been defined according to the following convention:  
Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 
to <1/1,000); very rare (<1/10,000) and not known (cannot be estimated from the available data). 
 
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 
 
Table 1 Adverse reactions by MedDRA System Organ Classification 
 Frequency 
System Organ Class Face and scalp Trunk and extremities 
Infections and infestations 
Application site pustules  Very common  Very common 
Application site infection Common  
Immune system disorders 
Hypersensitivity (including 
angioedema) 

Uncommon Uncommon 

Nervous system disorders 
Headache Common   
Eye disorders* 
Eye lid oedema Common   
Periorbital oedema  Common  
Chemical conjunctivitis, corneal 
burn** 

Uncommon Uncommon 

Eye pain Uncommon  
General disorders and administration site conditions 
Application site erosion Very common  Very common 
Application site vesicles  Very common Very common 
Application site swelling  Very common Very common 
Application site exfoliation Very common  Very common 
Application site scab  Very common Very common  
Application site erythema Very common  Very common 
Application site pain*** Very common  Common  
Application site pruritus  Common  Common  
Application site irritation  Common  Common 
Application site discharge Uncommon  
Application site paraesthesia  Uncommon  Uncommon 
Application site ulcer  Uncommon Uncommon 

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Application site pigmentation 
changes 

Uncommon Uncommon 

Application site warmth   Uncommon 
Application site scarring Rare Rare 
*: Application site swelling on the face or scalp may gravitate to the eye area 
**: Accidental eye exposure: Post-marketing reports of chemical conjunctivitis and corneal burn in 
connection with accidental eye exposure have been received (see sections 4.2 and 4.4 for prevention of 
eye exposure) 
***: Including application site burning. 
 
Description of selected adverse reactions 
The incidence of local skin responses that occurred at an incidence >1% in both the ‘face/scalp’ and 
the ‘trunk/extremities’, respectively are: application site erythema (94% and 92%), application site 
exfoliation (85% and 90%), application site scab (80% and 74%), application site swelling (79% and 
64%), application site vesicles (13% and 20%), application site pustules (43% and 23%) and 
application site erosion (31% and 25%). 
 
Severe local skin responses occurred with an incidence of 29% on the face and scalp and with an 
incidence of 17% on the trunk and extremities. The incidence of severe local skin responses that 
occurred at an incidence >1% in both the ‘face/scalp’ and the ‘trunk/extremities’, respectively are: 
application site erythema (24% and 15%), application site exfoliation (9% and 8%), application site 
scab (6% and 4%), application site swelling (5% and 3%) and application site pustules (5% and 1%). 
 
Long-term follow up 
A total of 198 patients with complete clearance at day 57 (184 treated with Picato and 14 treated with 
vehicle) were followed for additionally 12 months. In another study, 329 patients who were initially 
treated with cryotherapy on the face/scalp were randomised after three weeks to either Picato 
150 mcg/g (n=158) or vehicle (n=150) for 3 days in the same area. 149 patients in the Picato group 
and 140 in the vehicle group were followed for 12 months. In a later study 450 patients were initially 
treated with Picato 150 mcg/g, of these 134 patients were randomised to a second treatment course of 
Picato 150 mcg/g and the patients followed for up to 12 months after the first treatment.  
These results did not change the safety profile of Picato (see section 5.1). 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Overdosing of Picato could result in an increased incidence of local skin responses. Management of 
overdose should consist of treatment of clinical symptoms. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antibiotics and chemotherapeutics for dermatological use, other 
chemotherapeutics, ATC code: D06BX02. 
 
Mechanism of action 
The mechanism of action of ingenol mebutate for use in actinic keratosis remains to be fully 
characterised. In vivo and in vitro models have shown a dual mechanism of action for the effects of 
ingenol mebutate: 1) induction of local lesion cell death and 2) promoting an inflammatory response 

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characterised by local production of proinflammatory cytokines and chemokines and infiltration of 
immunocompetent cells.  
 
Pharmacodynamic effects 
Results from two clinical studies on biological effects of ingenol mebutate have shown that topical 
administration induced epidermal necrosis and a profound inflammatory response in both epidermis 
and the upper dermis of the treated skin, dominated by infiltrating T cells, neutrophils and 
macrophages. Necrosis in the dermis was rarely observed.  
Gene expression profiles of skin biopsies from the treated areas is suggestive of inflammatory 
responses and response to wounding, which is consistent with the histology assessments. 
Non-invasive examination of the treated skin by reflectance confocal microscopy have shown that the 
skin changes induced by ingenol mebutate were reversible, with almost complete normalisation of all 
measured parameters on day 57 after treatment, which is supported also by clinical findings and 
studies in animals. 
 
Clinical efficacy and safety 
The efficacy and safety of Picato 150 mcg/g, administered on the face or scalp for 3 consecutive days 
was studied in two double-blind, vehicle-controlled, clinical studies including 547 adult patients. 
Likewise the efficacy and safety of Picato 500 mcg/g, administered on the trunk and extremities for 2 
consecutive days was studied in two double-blind, vehicle-controlled, clinical studies including 458 
adult patients. Patients continued in the studies for an 8 week follow-up period during which they 
returned for clinical observations and safety monitoring. Efficacy, measured as complete and partial 
clearance rate, as well as median percent reduction, was assessed at day 57 (see table 2). 
 
Patients had 4 to 8 clinically typical, visible, discrete, non-hyperkeratotic, non-hypertrophic, actinic 
keratosis lesions within a contiguous 25 cm2 treatment area on the face or scalp or on the trunk or 
extremities. On each scheduled dosing day, the study gel was applied to the entire treatment area. 
The compliance rate was high, with 98% of the patients completing these studies. 
Study patients ranged from 34 to 89 years of age (mean 64 and 66 years, respectively, for the two 
strengths) and 94% had Fitzpatrick skin type I, II, or III. 
 
At day 57, patients treated with Picato had higher complete and partial clearance rates than patients 
treated with vehicle gel (p<0.001). The median percent reduction in actinic keratosis lesions was 
higher in the group treated with ingenol mebutate compared to the vehicle group (see table 2).  
 
Table 2 Rates of subjects with complete and partial clearance and median percent (%) lesion 
reduction in actinic keratosis 
 Face and scalp Trunk and extremities 
 Picato  

150 mcg/g 
(n=277 ) 

Vehicle 
(n=270 ) 

Picato 
500 mcg/g 
(n=226 ) 

Vehicle 
(n=232 ) 

Complete Clearance Ratea 42.2%d 3.7% 34.1%d 4.7% 

Partial Clearance Rateb (≥ 75%) 63.9% d 7.4% 49.1% d 6.9% 

Median % Reductionc 83% 0% 75% 0% 

a Complete clearance rate was defined as the proportion of patients with no (zero) clinically visible actinic 
keratosis lesions in the treatment area.  
b Partial clearance rate was defined as the percentage of patients in whom 75% or more of the number of 
baseline actinic keratosis lesions were cleared.  
c Median percent (%) reduction in actinic keratosis lesions compared to baseline. 
d p<0.001; compared to vehicle by logistic regression with treatment, study and anatomical location. 
 
The level of efficacy varied between the individual anatomical locations. Within each location the 
complete and partial clearance rates were higher in the group treated with ingenol mebutate compared 
to the vehicle group (see table 3 and 4).  

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Table 3 Number and percent (95% CI) of subjects achieving complete and partial clearance at 
day 57 by anatomical location face and scalp 

 

Complete Clearance Partial Clearance( ≥ 75%) 

Picato 150 mcg/g 
(n=277 ) 

Vehicle 
(n=270 ) 

Picato 150 mcg/g 
(n=277) 

Vehicle 
(n=270) 

Face 104/220 47% (41-54%) 
9/220 

4% (2-8%) 
157/220 

71% (65-77%) 
18/220 

8% (5-13%) 

Scalp 13/57 23% (13-36%) 
1/50 

2% (0-11%) 
20/57 

35% (23-49%) 
2/50 

4% (1-14%) 
 
Table 4 Number and percent (95% CI) of subjects achieving complete and partial clearance at 
day 57 by anatomical location trunk and extremities 

 

Complete clearance Partial clearance ( ≥ 75%) 

Picato 500 mcg/g 
(n=226) 

Vehicle 
(n=232) 

Picato 500 mcg/g 
(n=226) 

Vehicle 
(n=232) 

Arm 49/142 35% (27-43%) 
7/149 

5% (2-9%) 
75/142 

53% (44-61%) 
11/149 

7% (4-13%) 

Back of Hand 10/54 19% (9-31%) 
0/56 

0% (0-6%) 
16/54 

30% (18-44%) 
1/56 

2% (0-10%) 

Chest 11/14 79% (49-95%) 
2/11 

18% (2-52%) 
12/14 

86% (57-98%) 
2/11 

18% (2-52%) 

Othera 7/16 44% (20-70%) 
2/16 

13% (2-38%) 
8/16 

50% (25-75%) 
2/16 

13% (2-38%) 
 aOther includes shoulder, back, leg. 

 
Safety of Picato 150 mcg/g treatment for 3 days or Picato 500 mcg/g treatment for 2 days was assessed 
up to day 57, the majority of the reported adverse reactions and local skin responses were mild to 
moderate in intensity and all resolved without sequelae. 
 
Statistically significant differences in patient reported outcomes were observed in favour of patients 
receiving Picato compared to those receiving vehicle gel. Higher mean patient global satisfaction 
scores, indicating a higher level of overall satisfaction, were seen in the ingenol mebutate groups 
compared to the vehicle groups (p<0.001) as measured by the Treatment Satisfaction Questionnaire 
for Medication (TSQM). 
 
Long term efficacy  
Three prospective, observational long term 1 year follow-up studies were conducted to evaluate 
sustained efficacy by recurrence of actinic keratosis lesions in the treatment field, and safety in 
patients who had received treatment with Picato. One study included patients treated with Picato 
150 mcg/g on the face or scalp for 3 days and two studies included patients treated with Picato 
500 mcg/g on the trunk or extremities for 2 days. Only those patients who achieved complete 
clearance in the treated area at the end of the phase 3 studies (day 57) were eligible for long term 
follow-up. Patients were followed every 3 months for 12 months (see table 5). 
 
Table 5 Rate of recurrence of actinic keratosis lesions  
 Picato 

150 mcg/g gel 
Face and scalp 

Picato 
500 mcg/g gel 

Trunk and extremities 

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(n=108 ) (n=76c ) 
Recurrence Rate 12 months 
KM estimate (95% CI)a 

53.9% (44.6-63.7) 56.0% (45.1-67.6) 

Lesion Based Recurrence Rateb 12 months 
Mean (SD) 

12.8% (19.1) 13.2% (23.0) 

a The recurrence rate is the Kaplan-Meier (KM) estimate at the target study date of the visit expressed as a 
percentage (95% CI). Recurrence was defined as any identified actinic keratosis lesion in the previously 
treated area for patients who achieved complete clearance at day 57 in the previous phase 3 studies. 
b The lesion-based recurrence rate for each patient defined as the ratio of the number of actinic keratosis 
lesions at 12 months to the number of lesions at baseline in the previous phase 3 studies. 
c Of these, 38 subjects were previously treated in a vehicle controlled phase 3 study and 38 subjects were 
previously treated in an uncontrolled phase 3 study. 
 
Risk of progression to squamous cell carcinoma 
At end of study (day 57), the rate of squamous cell carcinoma (SCC) reported in the treatment area 
was comparable in patients treated with ingenol mebutate gel (0.3%, 3 of 1,165 patients) and in 
vehicle treated patients (0.3%, 2 of 632 patients) in the actinic keratosis clinical studies conducted 
with ingenol mebutate gel.  
 
SCC in the treatment area was reported in no patients (0 of 184 patients previously treated with 
ingenol mebutate gel) in the three prospective, observational long term 1 year follow-up studies. 
 
Experience with more than one treatment course 
In a double blind, vehicle-controlled study, up to two treatment courses of Picato 150 mcg/g were 
administered to 450 patients with 4-8 AKs in a 25 cm2 treatment area on the face or scalp. Patients, in 
whom a first treatment course did not lead to complete clearance of all AKs in the treatment area after 
8 weeks, were randomised to another treatment course with Picato or vehicle. Patients in whom the 
first treatment course led to complete clearance were seen at 26 and 44 weeks and randomised to a 
second treatment course if they had a recurrence in the field. In all patients, assessment of efficacy was 
8 weeks after the randomisation. The first treatment course, given open label, resulted in a complete 
clearance rate of 62% (277/450). The results of the randomised and blinded second treatment course 
are presented in table 6. 
 
Table 6 Complete clearancea of the field 8 weeks after randomisation and Month 12 

 
Field recalcitrantc Field recurrentd 

Picato 
150 mcg/g 
gel (n= 92) 

Vehicle 
(n=49) 

Picato 
150 mcg/g 
gel (n=42) 

Vehicle 
(n=20) 

8 weeks after randomisation  47% (43) (p=0.001b) 18% (9) 
60% (25) 

(p=0.013b) 25% (5) 

Month 12 18% (17) (p=0.016b) 4% (2) 
31% (13) 
(p=0.10b) 15% (3) 

a Complete clearance rate is defined as the proportion of patients with no (zero) clinically visible actinic 
keratosis lesions in the treatment area. 
b Cochran-Mantel-Haenszel test of Picato® gel 150 mcg/g compared to vehicle adjusted for anatomical 
location (face/scalp) and country. 
c Patients, in whom the first treatment course did not lead to complete clearance of all AKs in the treatment 
area. 
d Patients in whom the first treatment course did lead to complete clearance and who had a recurrence in the 
treatment area at either week 26 or 44. 

 
Actinic Keratosis of the Face and Scalp, sequential use after cryotherapy 
In a two-arm study, 329 adult patients with AK on the face or scalp were randomised to treatment with 
Picato gel, 150 mcg/g or vehicle 3 weeks after cryotherapy of all visible lesions in the treatment area. 
The study enrolled patients with 4 to 8 clinically typical, visible, discrete non-hypertrophic and non-
hyperkeratotic AK lesions within a 25 cm2 contiguous treatment area.  

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Eleven weeks after baseline which is 8 weeks after Picato gel or vehicle, the complete clearance rate 
was 61% among patients randomised to Picato gel, and 49% among patients randomised to vehicle. At 
12 months, the complete clearance rates in these groups were 31% and 19% respectively. The percent 
reduction of the AK count in the Picato group was 83% at 11 weeks and 57% at 12 months, where in 
the vehicle group it was 78% at 11 weeks and 42% at 12 months. The mean number of AKs in the 
Picato group was 5.7 at baseline, 0.8 at week 11, and 0.9 at month 12 as opposed to 5.8, 1.0 and 1.2 in 
the vehicle group at these time points. 
Safety results from the study were comparable to the safety profile of Picato gel, 150 mcg/g as 
monotherapy 
 
Experience with treatment of a larger area 
In a double-blind, vehicle-controlled study to evaluate systemic exposure, Picato 500 mcg/g, from 4 
tubes, was applied to a 100 cm2 contiguous treatment area daily for 2 consecutive days. Results 
demonstrated no systemic absorption.  
Picato 500 mcg/g was well tolerated when applied to a contiguous treatment area of 100 cm2 on the 
trunk and extremities. 
 
In a double-blind, vehicle-controlled study in patients with AK on trunk and extremities, an 
investigational product with ingenol mebutate gel 600 mcg/g was applied once daily for 2, 3, or 4 days 
to a skin area of 250 cm2. The trial included a large group of severely sun-damaged patients. 12/163 
subjects treated with an investigational product of ingenol mebutate reported 16 skin tumour events 
inside the treatment area (1 SCC, 1 Bowen's disease and 14 keratoacanthoma following centralised 
pathology review) compared to 0/61 in the vehicle group. 
 
Paediatric population 
The European Medicines Agency has waived the obligation to submit the results of studies with Picato 
in all subsets of the paediatric population in actinic keratosis (see section 4.2 for information on 
paediatric use). 
 
Elderly population 
Of the 1,165 patients treated with Picato in the actinic keratosis clinical studies conducted with ingenol 
mebutate gel, 656 patients (56%) were 65 years and older, while 241 patients (21%) were 75 years and 
older. No overall differences in safety or efficacy were observed between younger and older patients. 
 
5.2 Pharmacokinetic properties 
 
The systemic pharmacokinetic profile of ingenol mebutate and its metabolites has not been 
characterised in humans due to the absence of quantifiable whole blood levels following cutaneous 
administration.   
 
Absorption 
No systemic absorption was detected at or above the lower limit of detection (0.1 ng/mL) when Picato 
500 mcg/g from 4 tubes was applied to an area of 100 cm2 on the dorsal forearm in actinic keratosis 
patients once daily for 2 consecutive days. 
 
In vitro study results demonstrate that ingenol mebutate does not inhibit or induce human cytochrome 
P450 isoforms.   
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated-dose toxicity and genotoxicity. 
 
The non-clinical safety studies demonstrate that cutaneous administration of ingenol mebutate gel is 
well tolerated with any skin irritation being reversible and a negligible risk of systemic toxicity under 
the recommended conditions of use. 

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In rats, ingenol mebutate was not associated with fetal developmental effects at IV doses up to 
5 mcg/kg/day (30 mcg/m2/day). In rabbits there were no major abnormalities. Minor fetal 
abnormalities or variants were observed in the fetuses of treated dams at doses of 1 mcg/kg/day 
(12 mcg/m2/day). 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Isopropyl alcohol 
Hydroxyethylcellulose 
Citric acid monohydrate 
Sodium citrate  
Benzyl alcohol 
Purified water 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2ºC-8ºC). 
Tubes should be discarded after first opening. 
 
6.5 Nature and contents of container 
 
Single-dose laminate tubes with inner layer of High Density Polyethylene (HDPE) and aluminium as 
the barrier layer. Caps of HDPE. 
 
Picato 150 mcg/g gel is available in a carton containing 3 tubes with 0.47 g of gel each.  
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
LEO Laboratories Ltd. 
285 Cashel Road 
Crumlin, Dublin 12 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/12/796/001 
 
 

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9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 15 November 2012 
Date of latest renewal: 13 July 2017 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 

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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Picato 500 micrograms/gram gel 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each gram of gel contains 500 mcg of ingenol mebutate. Each tube contains 235 mcg of ingenol 
mebutate in 0.47 g of gel. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Gel. 
Clear colourless gel. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Picato is indicated for the cutaneous treatment of non-hyperkeratotic, non-hypertrophic actinic 
keratosis in adults. 
 
4.2 Posology and method of administration 
 
Posology 
 
Actinic keratosis on the trunk and extremities in adults 
One tube of Picato 500 mcg/g gel (containing 235 mcg ingenol mebutate) should be applied once daily 
to the affected area for 2 consecutive days. 
 
Optimal therapeutic effect can be assessed approximately 8 weeks after treatment. 
 
A repeat treatment course of Picato can be given if an incomplete response is seen at a follow-up 
examination after 8 weeks or if lesions that are cleared at this examination recur in subsequent 
examinations. 
 
Paediatric population 
There is no relevant use of Picato in the paediatric population.  
 
Elderly population 
No dose adjustment is required (see section 5.1). 
 
Immunocompromised patients 
Clinical data on treatment in immunocompromised patients is not available, but systemic risks are not 
expected since ingenol mebutate is not absorbed systemically. 
 
Method of administration  
 

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The content of one tube covers a treatment area of 25 cm2 (e.g. 5 cm x 5 cm). The tube is for single 
use only and should be discarded after use (see section 6.6). 
 
The gel from the tube should be squeezed onto a fingertip and spread evenly over the entire treatment 
area, allowing it to dry for 15 minutes. The content of one tube should be used for one treatment area 
of 25 cm2.  
For single use only. 
 
For treatment of the neck:  
If more than half of the treatment area is located in the upper part of the neck, Picato 150 mcg/g gel 
should be used at the posology for face and scalp. If more than half of the treatment area is located in 
the lower part of the neck, Picato 500 mcg/g gel should be used at the posology for trunk and 
extremities. 
 
If an area on the face or scalp and another area on the trunk or extremities are simultaneously treated, 
then patients should be advised to ensure they use the appropriate strengths. Care should be exercised 
not to apply the Picato 500 mcg/g gel on the face or scalp as this could lead to a higher incidence of 
local skin responses. 
 
Patients should be instructed to wash their hands with soap and water, immediately after applying 
Picato, and between topical applications if two different areas require different strengths. If treating 
the hands, only the fingertip which is used for applying the gel should be washed. 
Washing and touching the treated area should be avoided for a period of 6 hours after application of 
Picato. After this period, the treatment area may be washed using mild soap and water. 
 
Picato should not be applied immediately after taking a shower or less than 2 hours before bedtime. 
 
The treated area should not be covered with occlusive bandages after Picato is applied. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
4.4 Special warnings and precautions for use 
 
Eye exposure 
Contact with the eyes can cause chemical conjunctivitis and corneal burns. Patients should wash their 
hands thoroughly after applying the gel and following any contact with the treated area, to avoid 
inadvertent transfer of the gel to the eyes. If accidental exposure occurs, the eyes should be flushed 
immediately with large amounts of water, and the patient should seek medical care as soon as possible. 
Eye disorders such as eye pain, eyelid oedema and periorbital oedema should be expected to occur 
after accidental eye exposure of Picato (see section 4.8). 
 
Ingestion 
Picato must not be ingested. If accidental ingestion occurs the patient should drink plenty of water and 
seek medical care.  
 
General 
Administration of Picato is not recommended until the skin is healed from treatment with any previous 
medicinal product or surgical treatment and should not be applied to open wounds or damaged skin 
where the skin barrier is compromised. 
Picato should not be used near the eyes, on the inside of the nostrils, on the inside of the ears or on the 
lips. 
 
Local skin responses 
Local skin responses such as erythema, flaking/scaling, and crusting should be expected to occur after 
cutaneous application of Picato (see section 4.8). Localised skin responses are transient and typically 

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occur within 1 day of treatment initiation and peak in intensity up to 1 week following completion of 
treatment. Localised skin responses typically resolve within 2 weeks of treatment initiation when 
treating areas on the face and scalp and within 4 weeks of treatment initiation when treating areas on 
the trunk and extremities. Treatment effect may not be adequately assessed until resolution of local 
skin responses. 
 
Sun exposure 
Studies have been conducted to assess the effects of UV irradiation of the skin following single and 
multiple applications of ingenol mebutate gel, 100 mcg/g. Ingenol mebutate gel did not demonstrate 
any potential for photo irritation or photo allergic effects. However, due to the nature of the disease, 
excessive exposure to sunlight (including sunlamps and tanning beds) should be avoided or 
minimised.  
 
Keratoacanthoma, basal cell carcinoma, Bowen’s disease, squamous cell carcinoma 
Reports of keratoacanthoma, basal cell carcinoma, Bowen’s disease, squamous cell carcinoma 
occurring within the treatment area with a time to onset ranging from weeks to months following use 
of ingenol mebutate gel have been received from a post-authorisation clinical trial (see section 5.1) 
and post-marketing. Ingenol mebutate should be used with caution in patients with a history of 
cutaneous malignancy. Health care professionals should advise patients to be vigilant for any lesions 
developing within the treatment area and to seek medical advice immediately should any occur. 
 
Management of actinic keratosis 
Lesions clinically atypical for actinic keratosis or suspicious for malignancy should be biopsied to 
determine appropriate treatment. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed. Interactions with systemically absorbed medicinal 
products are considered unlikely as Picato is not absorbed systemically. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
There are no data from the use of ingenol mebutate in pregnant women. Animal studies showed slight 
embryo-fetal toxicity (see section 5.3). Risks to humans receiving cutaneous treatment with ingenol 
mebutate are considered unlikely as Picato is not absorbed systemically. As a precautionary measure, 
it is preferable to avoid the use of Picato during pregnancy.  
 
Breast-feeding 
No effects on the breastfed newborn/infant are anticipated as Picato is not absorbed systemically. The 
nursing mother should be instructed that physical contact between her newborn/infant and the treated 
area should be avoided for a period of 6 hours after application of Picato.  
 
Fertility 
No fertility studies have been performed with ingenol mebutate. 
 
4.7 Effects on ability to drive and use machines 
 
Picato has no or negligible influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
The most frequently reported adverse reactions are local skin responses including erythema, 
flaking/scaling, crusting, swelling, vesiculation/pustulation and erosion/ulceration at the application 
site of ingenol mebutate gel, see table 1 for MedDRA terms. Following the application of ingenol 

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mebutate, most patients (>95%) experienced one or more local skin response(s). Infection at the 
application site has been reported when treating face and scalp.  
 
Tabulated list of adverse reactions 
Table 1 reflects exposure to Picato 150 mcg/g or 500 mcg/g in 499 patients with actinic keratosis 
treated in four vehicle controlled phase 3 studies enrolling a total of 1,002 patients and post-marketing 
reports. Patients received field treatment (area of 25 cm2) with Picato at concentrations of 150 mcg/g 
or 500 mcg/g or vehicle once daily for 3 or 2 consecutive days respectively. 
 
The table below presents adverse reactions by MedDRA system organ class and anatomical location. 
 
Frequencies have been defined according to the following convention:  
Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 
to <1/1,000); very rare (<1/10,000) and not known (cannot be estimated from the available data). 
 
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 
 
Table 1 Adverse reactions by MedDRA System Organ Classification 
 Frequency 
System Organ Class Face and scalp Trunk and extremities 
Infections and infestations 
Application site pustules  Very common  Very common 
Application site infection Common  
Immune system disorders 
Hypersensitivity (including 
angioedema) 

Uncommon Uncommon 

Nervous system disorders 
Headache Common   
Eye disorders* 
Eye lid oedema Common   
Periorbital oedema  Common  
Chemical conjunctivitis, corneal 
burn** 

Uncommon Uncommon 

Eye pain Uncommon  
General disorders and administration site conditions 
Application site erosion Very common  Very common 
Application site vesicles  Very common Very common 
Application site swelling  Very common Very common 
Application site exfoliation Very common  Very common 
Application site scab  Very common Very common  
Application site erythema Very common  Very common 
Application site pain*** Very common  Common  
Application site pruritus  Common  Common  
Application site irritation  Common  Common 
Application site discharge Uncommon  
Application site paraesthesia  Uncommon  Uncommon 
Application site ulcer  Uncommon Uncommon 

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Application site pigmentation 
changes 

Uncommon Uncommon 

Application site warmth   Uncommon 
Application site scarring Rare Rare 
*: Application site swelling on the face or scalp may gravitate to the eye area 
**: Accidental eye exposure: Post-marketing reports of chemical conjunctivitis and corneal burn in 
connection with accidental eye exposure have been received (see sections 4.2 and 4.4 for prevention of 
eye exposure) 
***: Including application site burning. 
 
Description of selected adverse reactions 
The incidence of local skin responses that occurred at an incidence >1% in both the ‘face/scalp’ and 
the ‘trunk/extremities’, respectively are: application site erythema (94% and 92%), application site 
exfoliation (85% and 90%), application site scab (80% and 74%), application site swelling (79% and 
64%), application site vesicles (13% and 20%), application site pustules (43% and 23%) and 
application site erosion (31% and 25%). 
 
Severe local skin responses occurred with an incidence of 29% on the face and scalp and with an 
incidence of 17% on the trunk and extremities. The incidence of severe local skin responses that 
occurred at an incidence >1% in both the ‘face/scalp’ and the ‘trunk/extremities’, respectively are: 
application site erythema (24% and 15%), application site exfoliation (9% and 8%), application site 
scab (6% and 4%), application site swelling (5% and 3%) and application site pustules (5% and 1%). 
 
Long-term follow up 
A total of 198 patients with complete clearance at day 57 (184 treated with Picato and 14 treated with 
vehicle) were followed for additionally 12 months. In another study, 329 patients who were initially 
treated with cryotherapy on the face/scalp were randomised after three weeks to either Picato 
150 mcg/g (n=158) or vehicle (n=150) for 3 days in the same area. 149 patients in the Picato group 
and 140 in the vehicle group were followed for 12 months. In a later study 450 patients were initially 
treated with Picato 150 mcg/g, of these 134 patients were randomised to a second treatment course of 
Picato 150 mcg/g and the patients followed for up to 12 months after the first treatment.  
These results did not change the safety profile of Picato (see section 5.1). 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Overdosing of Picato could result in an increased incidence of local skin responses. Management of 
overdose should consist of treatment of clinical symptoms. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antibiotics and chemotherapeutics for dermatological use, other 
chemotherapeutics, ATC code: D06BX02. 
 
Mechanism of action 
The mechanism of action of ingenol mebutate for use in actinic keratosis remains to be fully 
characterised. In vivo and in vitro models have shown a dual mechanism of action for the effects of 
ingenol mebutate: 1) induction of local lesion cell death and 2) promoting an inflammatory response 

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characterised by local production of proinflammatory cytokines and chemokines and infiltration of 
immunocompetent cells.  
 
Pharmacodynamic effects 
Results from two clinical studies on biological effects of ingenol mebutate have shown that topical 
administration induced epidermal necrosis and a profound inflammatory response in both epidermis 
and the upper dermis of the treated skin, dominated by infiltrating T cells, neutrophils and 
macrophages. Necrosis in the dermis was rarely observed.  
Gene expression profiles of skin biopsies from the treated areas is suggestive of inflammatory 
responses and response to wounding, which is consistent with the histology assessments. 
Non-invasive examination of the treated skin by reflectance confocal microscopy have shown that the 
skin changes induced by ingenol mebutate were reversible, with almost complete normalisation of all 
measured parameters on day 57 after treatment, which is supported also by clinical findings and 
studies in animals. 
 
Clinical efficacy and safety 
The efficacy and safety of Picato 150 mcg/g, administered on the face or scalp for 3 consecutive days 
was studied in two double-blind, vehicle-controlled, clinical studies including 547 adult patients. 
Likewise the efficacy and safety of Picato 500 mcg/g, administered on the trunk and extremities for 2 
consecutive days was studied in two double-blind, vehicle-controlled, clinical studies including 458 
adult patients. Patients continued in the studies for an 8 week follow-up period during which they 
returned for clinical observations and safety monitoring. Efficacy, measured as complete and partial 
clearance rate, as well as median percent reduction, was assessed at day 57 (see table 2). 
 
Patients had 4 to 8 clinically typical, visible, discrete, non-hyperkeratotic, non-hypertrophic, actinic 
keratosis lesions within a contiguous 25 cm2 treatment area on the face or scalp or on the trunk or 
extremities. On each scheduled dosing day, the study gel was applied to the entire treatment area. 
The compliance rate was high, with 98% of the patients completing these studies. 
Study patients ranged from 34 to 89 years of age (mean 64 and 66 years, respectively, for the two 
strengths) and 94% had Fitzpatrick skin type I, II, or III. 
 
At day 57, patients treated with Picato had higher complete and partial clearance rates than patients 
treated with vehicle gel (p<0.001). The median percent reduction in actinic keratosis lesions was 
higher in the group treated with ingenol mebutate compared to the vehicle group (see table 2).  
 
Table 2 Rates of subjects with complete and partial clearance and median percent (%) lesion 
reduction in actinic keratosis  
 Face and scalp Trunk and extremities 
 Picato  

150 mcg/g 
(n=277 ) 

Vehicle 
(n=270 ) 

Picato 
500 mcg/g 
(n=226 ) 

Vehicle 
(n=232 ) 

Complete Clearance Ratea 42.2%d 3.7% 34.1%d 4.7% 

Partial Clearance Rateb (≥ 75%) 63.9% d 7.4% 49.1% d 6.9% 

Median % Reductionc 83% 0% 75% 0% 

a Complete clearance rate was defined as the proportion of patients with no (zero) clinically visible actinic 
keratosis lesions in the treatment area.  
b Partial clearance rate was defined as the percentage of patients in whom 75% or more of the number of 
baseline actinic keratosis lesions were cleared.  
c Median percent (%) reduction in actinic keratosis lesions compared to baseline. 
d p<0.001; compared to vehicle by logistic regression with treatment, study and anatomical location. 
 
The level of efficacy varied between the individual anatomical locations. Within each location the 
complete and partial clearance rates were higher in the group treated with ingenol mebutate compared 
to the vehicle group (see table 3 and 4).  

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Table 3 Number and percent (95% CI) of subjects achieving complete and partial clearance at 
day 57 by anatomical location face and scalp 

 

Complete Clearance Partial Clearance( ≥ 75%) 

Picato 150 mcg/g 
(n=277 ) 

Vehicle 
(n=270 ) 

Picato 150 mcg/g 
(n=277) 

Vehicle 
(n=270) 

Face 104/220 47% (41-54%) 
9/220 

4% (2-8%) 
157/220 

71% (65-77%) 
18/220 

8% (5-13%) 

Scalp 13/57 23% (13-36%) 
1/50 

2% (0-11%) 
20/57 

35% (23-49%) 
2/50 

4% (1-14%) 
 
Table 4 Number and percent (95% CI) of subjects achieving complete and partial clearance at 
day 57 by anatomical location trunk and extremities 

 

Complete clearance Partial clearance ( ≥ 75%) 

Picato 500 mcg/g 
(n=226) 

Vehicle 
(n=232) 

Picato 500 mcg/g 
(n=226) 

Vehicle 
(n=232) 

Arm 49/142 35% (27-43%) 
7/149 

5% (2-9%) 
75/142 

53% (44-61%) 
11/149 

7% (4-13%) 

Back of Hand 10/54 19% (9-31%) 
0/56 

0% (0-6%) 
16/54 

30% (18-44%) 
1/56 

2% (0-10%) 

Chest 11/14 79% (49-95%) 
2/11 

18% (2-52%) 
12/14 

86% (57-98%) 
2/11 

18% (2-52%) 

Othera 7/16 44% (20-70%) 
2/16 

13% (2-38%) 
8/16 

50% (25-75%) 
2/16 

13% (2-38%) 
 aOther includes shoulder, back, leg. 

 
Safety of Picato 150 mcg/g treatment for 3 days or Picato 500 mcg/g treatment for 2 days was assessed 
up to day 57, the majority of the reported adverse reactions and local skin responses were mild to 
moderate in intensity and all resolved without sequelae. 
 
Statistically significant differences in patient reported outcomes were observed in favour of patients 
receiving Picato compared to those receiving vehicle gel. Higher mean patient global satisfaction 
scores, indicating a higher level of overall satisfaction, were seen in the ingenol mebutate groups 
compared to the vehicle groups (p<0.001) as measured by the Treatment Satisfaction Questionnaire 
for Medication (TSQM). 
 
Long term efficacy  
Three prospective, observational long term 1 year follow-up studies were conducted to evaluate 
sustained efficacy by recurrence of actinic keratosis lesions in the treatment field, and safety in 
patients who had received treatment with Picato. One study included patients treated with Picato 
150 mcg/g on the face or scalp for 3 days and two studies included patients treated with Picato 
500 mcg/g on the trunk or extremities for 2 days. Only those patients who achieved complete 
clearance in the treated area at the end of the phase 3 studies (day 57) were eligible for long term 
follow-up. Patients were followed every 3 months for 12 months (see table 5). 
 
Table 5 Rate of recurrence of actinic keratosis lesions  
 Picato 

150 mcg/g gel 
Face and scalp 

Picato  
500 mcg/g gel 

Trunk and extremities 

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(n=108 ) (n=76c ) 
Recurrence Rate 12 months 
KM estimate (95% CI)a 

53.9% (44.6-63.7) 56.0% (45.1-67.6) 

Lesion Based Recurrence Rateb 12 months 
Mean (SD) 

12.8% (19.1) 13.2% (23.0) 

a The recurrence rate is the Kaplan-Meier (KM) estimate at the target study date of the visit expressed as a 
percentage (95% CI). Recurrence was defined as any identified actinic keratosis lesion in the previously 
treated area for patients who achieved complete clearance at day 57 in the previous phase 3 studies. 
b The lesion-based recurrence rate for each patient defined as the ratio of the number of actinic keratosis 
lesions at 12 months to the number of lesions at baseline in the previous phase 3 studies. 
c Of these, 38 subjects were previously treated in a vehicle controlled phase 3 study and 38 subjects were 
previously treated in an uncontrolled phase 3 study. 
 
Risk of progression to squamous cell carcinoma 
At end of study (day 57), the rate of squamous cell carcinoma (SCC) reported in the treatment area 
was comparable in patients treated with ingenol mebutate gel (0.3%, 3 of 1,165 patients) and in 
vehicle treated patients (0.3%, 2 of 632 patients) in the actinic keratosis clinical studies conducted 
with ingenol mebutate gel.  
 
SCC in the treatment area was reported in no patients (0 of 184 patients previously treated with 
ingenol mebutate gel) in the three prospective, observational long term 1 year follow-up studies.  
 
Experience with more than one treatment course 
In a double blind, vehicle-controlled study, up to two treatment courses of Picato 150 mcg/g were 
administered to 450 patients with 4-8 AKs in a 25 cm2 treatment area on the face or scalp. Patients, in 
whom a first treatment course did not lead to complete clearance of all AKs in the treatment area after 
8 weeks, were randomised to another treatment course with Picato or vehicle. Patients in whom the 
first treatment course led to complete clearance were seen at 26 and 44 weeks and randomised to a 
second treatment course if they had a recurrence in the field. In all patients, assessment of efficacy was 
8 weeks after the randomisation. The first treatment course, given open label, resulted in a complete 
clearance rate of 62% (277/450). The results of the randomised and blinded second treatment course 
are presented in table 6. 
 
Table 6 Complete clearancea of the field 8 weeks after randomisation and Month 12 

 

Field recalcitrantc Field recurrentd 
Picato 

150 mcg/g 
gel (n= 92) 

Vehicle 
(n=49) 

Picato 
150 mcg/g 
gel (n=42) 

Vehicle 
(n=20) 

8 weeks after randomisation  47% (43) (p=0.001b) 18% (9) 
60% (25) 

(p=0.013b) 25% (5) 

Month 12 18% (17) (p=0.016b) 4% (2) 
31% (13) 
(p=0.10b) 15% (3) 

a Complete clearance rate is defined as the proportion of patients with no (zero) clinically visible actinic 
keratosis lesions in the treatment area. 
b Cochran-Mantel-Haenszel test of Picato® gel 150 mcg/g compared to vehicle adjusted for anatomical 
location (face/scalp) and country. 
c Patients, in whom the first treatment course did not lead to complete clearance of all AKs in the treatment 
area. 
d Patients in whom the first treatment course did lead to complete clearance and who had a recurrence in the 
treatment area at either week 26 or 44. 

 
Actinic Keratosis of the Face and Scalp, sequential use after cryotherapy 
In a two-arm study, 329 adult patients with AK on the face or scalp were randomised to treatment with 
Picato gel, 150 mcg/g or vehicle 3 weeks after cryotherapy of all visible lesions in the treatment area. 
The study enrolled patients with 4 to 8 clinically typical, visible, discrete non-hypertrophic and non-
hyperkeratotic AK lesions within a 25 cm2 contiguous treatment area.  

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Eleven weeks after baseline which is 8 weeks after Picato gel or vehicle, the complete clearance rate 
was 61% among patients randomised to Picato gel, and 49% among patients randomised to vehicle. At 
12 months, the complete clearance rates in these groups were 31% and 19% respectively. The percent 
reduction of the AK count in the Picato group was 83% at 11 weeks and 57% at 12 months, where in 
the vehicle group it was 78% at 11 weeks and 42% at 12 months. The mean number of AKs in the 
Picato group was 5.7 at baseline, 0.8 at week 11, and 0.9 at month 12 as opposed to 5.8, 1.0 and 1.2 in 
the vehicle group at these time points. 
Safety results from the study were comparable to the safety profile of Picato gel, 150 mcg/g as 
monotherapy 
 
Experience with treatment of a larger area 
In a double-blind, vehicle-controlled study to evaluate systemic exposure, Picato 500 mcg/g, from 4 
tubes, was applied to a 100 cm2 contiguous treatment area daily for 2 consecutive days. Results 
demonstrated no systemic absorption.  
Picato 500 mcg/g was well tolerated when applied to a contiguous treatment area of 100 cm2 on the 
trunk and extremities. 
 
In a double-blind, vehicle-controlled study in patients with AK on trunk and extremities, an 
investigational product with ingenol mebutate gel 600 mcg/g was applied once daily for 2, 3, or 4 days 
to a skin area of 250 cm2. The trial included a large group of severely sun-damaged patients. 12/163 
subjects treated with an investigational product of ingenol mebutate reported 16 skin tumour events 
inside the treatment area (1 SCC, 1 Bowen's disease and 14 keratoacanthoma following centralised 
pathology review) compared to 0/61 in the vehicle group. 
 
Paediatric population 
The European Medicines Agency has waived the obligation to submit the results of studies with Picato 
in all subsets of the paediatric population in actinic keratosis (see section 4.2 for information on 
paediatric use). 
 
Elderly population 
Of the 1,165 patients treated with Picato in the actinic keratosis clinical studies conducted with ingenol 
mebutate gel, 656 patients (56%) were 65 years and older, while 241 patients (21%) were 75 years and 
older. No overall differences in safety or efficacy were observed between younger and older patients. 
 
5.2 Pharmacokinetic properties 
 
The systemic pharmacokinetic profile of ingenol mebutate and its metabolites has not been 
characterised in humans due to the absence of quantifiable whole blood levels following cutaneous 
administration.   
 
Absorption 
No systemic absorption was detected at or above the lower limit of detection (0.1 ng/mL) when Picato 
500 mcg/g from 4 tubes was applied to an area of 100 cm2 on the dorsal forearm in actinic keratosis 
patients once daily for 2 consecutive days. 
 
In vitro study results demonstrate that ingenol mebutate does not inhibit or induce human cytochrome 
P450 isoforms.   
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated-dose toxicity and genotoxicity. 
 
The non-clinical safety studies demonstrate that cutaneous administration of ingenol mebutate gel is 
well tolerated with any skin irritation being reversible and a negligible risk of systemic toxicity under 
the recommended conditions of use. 

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In rats, ingenol mebutate was not associated with fetal developmental effects at IV doses up to 
5 mcg/kg/day (30 mcg/m2/day). In rabbits there were no major abnormalities. Minor fetal 
abnormalities or variants were observed in the fetuses of treated dams at doses of 1 mcg/kg/day 
(12 mcg/m2/day). 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Isopropyl alcohol 
Hydroxyethylcellulose 
Citric acid monohydrate 
Sodium citrate  
Benzyl alcohol 
Purified water 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2ºC-8ºC). 
Tubes should be discarded after first opening. 
 
6.5 Nature and contents of container  
 
Single-dose laminate tubes with inner layer of High Density Polyethylene (HDPE) and aluminium as 
the barrier layer. Caps of HDPE. 
 
Picato 500 mcg/g gel is available in a carton containing 2 tubes with 0.47 g of gel each.  
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
LEO Laboratories Ltd. 
285 Cashel Road 
Crumlin, Dublin 12 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/12/796/002 
 
 

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9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 15 November 2012 
Date of latest renewal: 13 July 2017 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu/ 

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24 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE  
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 

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25 

  
A.  MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
LEO Laboratories Ltd. 
285 Cashel Road 
Crumlin, Dublin 12 
Ireland 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to medical prescription. 
 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  
 
• Periodic Safety Update Reports 

 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
 
D.  CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT  
 
•  Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile or 
as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached. 

 
•  Obligation to conduct post-authorisation measures 
 
The MAH shall complete, within the stated timeframe, the below measures: 
 
Description Due date 
Post-Authorisation safety study:  
In order to further investigate the incidence of treatment area skin malignancy, 
particularly squamous cell carcinoma, the MAH should conduct and submit the 
results of a randomised, double-blind, trial in patients treated with ingenol 
mebutate compared with vehicle control, over at least 18 months of follow-up. 
The study should be based on an agreed protocol. 
 
The final study report shall be submitted: 
 

 
 
 
 
 
 
 
31 December 
2024 

Non-interventional Post-Authorisation safety study:  
In order to investigate the rate of skin malignancies (squamous cell carcinoma, 

 
 

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Bowen’s disease, basal cell carcinoma, keratoacanthoma, malignant melanoma) in 
patients with actinic keratosis treated with ingenol mebutate, the MAH should 
conduct and submit the results of a cohort study comparing patients treated with 
ingenol mebutate with patients exposed to other actinic keratosis treatments.  
 
The final study report shall be submitted: 
 

 
 
 
 
 
31 December 
2020 

 
 

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27 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 

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A. LABELLING 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON OF 150 mcg/g GEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Picato 150 micrograms/g gel  
ingenol mebutate 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each gram of gel contains 150 micrograms of ingenol mebutate. Each tube contains 70 micrograms of 
ingenol mebutate in 0.47 g of gel. 
 
 
3. LIST OF EXCIPIENTS 
 
Isopropyl alcohol 
Hydroxyethylcellulose 
Citric acid monohydrate 
Sodium citrate  
Benzyl alcohol 
Purified water 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
gel  
3 tubes 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For single use only  
Read the package leaflet before use. 
Cutaneous use 
 
To be printed on the inside of the carton lid: 
 

 

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6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
LEO Laboratories Ltd. 
285 Cashel Road 
Crumlin, Dublin 12 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/12/796/001  
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Picato 150 mcg/g 
 

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31 

 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: {number} 
SN: {number} 
NN: {number} 
 
 
 

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32 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON OF 500 mcg/g GEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Picato 500 micrograms/g gel  
ingenol mebutate 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each gram of gel contains 500 micrograms of ingenol mebutate. Each tube contains 235 micrograms 
of ingenol mebutate in 0.47 g of gel. 
 
 
3. LIST OF EXCIPIENTS 
 
Isopropyl alcohol 
Hydroxyethylcellulose 
Citric acid monohydrate 
Sodium citrate  
Benzyl alcohol 
Purified water 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
gel 
2 tubes 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For single use only 
Read the package leaflet before use. 
Cutaneous use 
 
To be printed on the inside of the carton lid: 
 

 

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33 

 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
LEO Laboratories Ltd. 
285 Cashel Road 
Crumlin, Dublin 12 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/12/796/002  
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Picato 500 mcg/g 
 

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17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: {number} 
SN: {number} 
NN: {number} 
 
 
 

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35 

 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
TUBE 150 mcg/g GEL  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Picato 150 mcg/g gel  
ingenol mebutate  
Cutaneous use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.47 g 
 
 
6. OTHER 
 
 

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36 

 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
TUBE 500 mcg/g GEL  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Picato 500 mcg/g gel 
ingenol mebutate  
Cutaneous use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.47 g 
 
 
6. OTHER 
 
 

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B. PACKAGE LEAFLET 

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38 

 
Package leaflet: Information for the patient 

 
Picato 150 micrograms/gram gel 

ingenol mebutate 
 

This medicine is subject to additional monitoring. This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What Picato is and what it is used for 
2. What you need to know before you use Picato 
3. How to use Picato  
4. Possible side effects 
5. How to store Picato  
6. Contents of the pack and other information 
 
 
1. What Picato is and what it is used for 
 
Picato contains the active substance ingenol mebutate. 
This medicine is used for topical (on the skin) treatment of actinic keratosis, also called solar keratosis, 
in adults. Actinic keratoses are rough areas of skin found in people who have been exposed to too 
much sunshine over the course of their lifetime. Picato 150 micrograms/gram gel is used for actinic 
keratosis on the face and scalp. 
 
 
2. What you need to know before you use Picato  
 
Do not use Picato   
- If you are allergic to ingenol mebutate or any of the other ingredients of this medicine (listed in 

section 6). 
 
Warnings and precautions 
Talk to your doctor or pharmacist before using Picato. 
- Do not get Picato in your eyes. Wash your hands thoroughly after you have applied the gel. 

Wash your hands again if you happen to touch the area where you applied the gel. Take care not 
to transfer gel from the treatment area into your eyes. In the event of accidental contact, remove 
the gel by rinsing with plenty of water and seek medical assistance as soon as possible. 

- Do not swallow this medicine. Drink plenty of water if you accidentally swallow this medicine 
and seek medical assistance. 

- Make sure that your skin has healed from any other treatments or surgery before using this 
medicine. Do not apply Picato on open-wounds or damaged skin. 

- Do not apply this medicine internally, to the area near the eyes, to the inside of the nostrils, the 
inside of the ear or on the lips. 

- Avoid sunlight as much as possible (including sunlamps and tanning beds). 

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39 

- Be vigilant for any new scaly red patches, open sores, elevated or warty growths within the 
treatment area. Should any occur, talk to your doctor immediately. 

- This medicine is intended to treat one area of 25 cm2 for three days. 
- Do not apply more gel than your doctor has advised. 
- You should expect to get local skin reactions, such as reddening and swelling, after treatment 

with this medicine (see section 4). Contact your doctor if these local skin reactions get severe. 
 
Children and adolescents 
Actinic keratosis does not occur in children, and this medicine must not be used in children and 
adolescents under 18 years of age. 
 
Other medicines and Picato 
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. 
 
If you have previously used Picato or other similar medicines tell your doctor before starting the 
treatment.  
 
Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before using this medicine. You should avoid the use of Picato if you are 
pregnant. 
If you are breast-feeding, avoid physical contact between the baby and the treated area for 6 hours 
after application of this medicine. 
 
Driving and using machines 
This medicine does not have any effect on your ability to drive or to use machines.  
 
 
3. How to use Picato 
 
Always use this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if 
you are not sure. 
 
If you have been prescribed two different strengths for treatment of two different areas you should 
make sure that you use the prescribed strength on the correct area. Do not apply the 500 mcg/g gel on 
the face or scalp as this could lead to intense local skin responses. 
 
- Treatment of actinic keratosis on the face and scalp is one tube of Picato 150 micrograms/g gel 

(containing 70 micrograms of ingenol mebutate) once a day for 3 days in a row. 
 
Instructions for use: 
- Open a new tube each time you use this medicine. Remove the cap from the tube just before 

use. 
- Squeeze the gel from one tube onto a fingertip. 
- Apply the content of one tube to one area of 25 cm2 (e.g. 5 cm x 5 cm). 
- Gently rub the gel onto the treatment area. 
- Allow the area to dry for 15 minutes. Avoid touching the treatment area for 6 hours after 

applying your medicine. 
- Wash your hands with soap and water immediately after applying the gel, and also in between 

administrations if prescribed two different strengths for two different areas.  
- Do not apply this medicine immediately after taking a shower or less than 2 hours before 

bedtime. 
- Do not wash the areas where you applied the gel for at least 6 hours after you apply it. 
- Do not touch the treatment area yourself or allow anyone or any pets to touch the treatment area 

for a period of 6 hours after applying the gel. 
- Do not cover the treated area with air- or water-tight bandages after you have applied this 

medicine. 

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40 

- The full effect of Picato can be evaluated approximately 8 weeks after treatment. 
 

 
 
If you use Picato for treatment of the neck 
If more than half of the treatment area is located in the upper part of the neck: 
- Use Picato 150 mcg/g gel (face and scalp) 
If more than half of the treatment area is located in the lower part of the neck: 
- Use Picato 500 mcg/g gel (trunk and extremities) 
 
If you use more Picato than you should 
Wash the area with soap and water. Please contact your doctor or pharmacist if you experience severe 
skin reactions. 
 
If you forget to use Picato 
Please contact your doctor or pharmacist if you forget to use Picato. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them.  
 
Seek medical attention right away if you experience an allergic reaction that may include swelling of 
the mouth, tongue or throat when using this medicine. This side effect is uncommon. 
 
After using this medicine the skin where you apply it is likely to get red, peel and have scabs. These 
side effects most often occur within one day after applying this medicine. The side effects may get 
worse for up to 1 week after you have stopped using this medicine. They will usually get better within 
2 weeks from when you started the treatment.  
 
Infection of the skin in the treatment area can occur (has been reported as a common side effect, which 
may affect up to 1 in 10 people, when treating the face and scalp).  
 
Swelling of the application site is very common (has been reported in more than 1 in 10 people). 
Application site swelling on the face or scalp may gravitate to the eye area. 
 
Should the symptoms described above intensify beyond the first week after you have stopped using 
this medicine, or if there is discharge of pus, you might have an infection and should contact your 
doctor or pharmacist. 
 
The most frequently occurring side effects when treating the face and scalp: 
 
Very common side effects on the treatment area, may affect more than 1 in 10 people: 
On the treatment area:  

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- Some of the outer layer of your skin may wear away (erosion)  
- Blisters (vesicles, pustules) 
- Peeling (exfoliation) 
- Scabs 
- Redness due to widening of the small blood vessels (erythema) 
- Pain (including application site burning) 
 
The most frequently occurring side effects when treating the trunk and extremities: 
 
Very common side effects on the treatment area, may affect more than 1 in 10 people: 
On the treatment area:  
- Some of the outer layer of your skin may wear away (erosion)  
- Blisters (vesicles, pustules) 
- Peeling (exfoliation) 
- Scabs 
- Redness due to widening of the small blood vessels (erythema) 
 
Other possible side effects when treating the face and scalp: 
 
Common side effects, may affect up to 1 in 10 people: 
On the treatment area: 
- Itching (pruritus) 
- Irritation 
 
Other side effects: 
- Swelling of the area around the eye (periorbital oedema)  
- Swelling (oedema) of your eye lid 
- Headache  
 
Uncommon side effects, may affect up to 1 in 100 people: 
On the treatment area: 
- Tingling or numbness (paraesthesia) 
- Open sores (ulcer) 
- Discharge (secretion) of fluid 
- Change in skin colour (pigmentation change) 
 
Other side effects: 
- Eye pain 
- Injury or irritation to the surface of the eye (cornea, conjunctiva) following accidental exposure 
 
Rare side effects, may affect up to 1 in 1000 people: 
On the treatment area: 
- Scarring 
 
Other possible side effects when treating the trunk and extremities: 
 
Common side effects, may affect up to 1 in 10 people: 
On the treatment area: 
- Itching (pruritus) 
- Irritation 
- Pain (including application site burning) 
 
Uncommon side effects, may affect up to 1 in 100 people: 
On the treatment area: 
- Tingling or numbness (paraesthesia) 
- Open sores (ulcer) 
- Change in skin colour (pigmentation change) 

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42 

- Warmth 
 
Other side effects: 
- Injury or irritation to the surface of the eye (cornea, conjunctiva) following accidental exposure 
 
Rare side effects, may affect up to 1 in 1000 people: 
On the treatment area: 
- Scarring 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Picato  
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and tube after EXP. The 
expiry date refers to the last day of that month. 
 
Store in a refrigerator (2°C-8°C). 
 
For single use only. Do not re-use the tubes once opened.  
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Picato contains  
- The active substance is ingenol mebutate. Each gram of gel contains 150 micrograms of ingenol 

mebutate. Each tube contains 70 micrograms of ingenol mebutate in 0.47 g of gel.  
 
- The other ingredients are isopropyl alcohol, hydroxyethylcellulose, citric acid monohydrate, 

sodium citrate, benzyl alcohol, purified water. 
 
What Picato looks like and contents of the pack 
Picato 150 micrograms/g gel is clear and colourless and each carton contains 3 tubes with 0.47 g of gel 
each.  
 
Marketing Authorisation Holder 
LEO Laboratories Ltd. 
285 Cashel Road 
Crumlin, Dublin 12 
Ireland 
 
Manufacturer 
LEO Laboratories Ltd. 
285 Cashel Road, Crumlin, Dublin 12 
Ireland 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 

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http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


43 

 
België/Belgique/Belgien 
LEO Pharma N.V./S.A 
Tél/Tel: +32 3 740 7868 
 

Lietuva 
LEO Pharma A/S 
Tel: +45 44 94 58 88 
 

България 
Borola Ltd 
Teл.: +359 2 9156 136 
 

Luxembourg/Luxemburg 
LEO Pharma N.V./S.A 
Tél/Tel: +32 3 740 7868 
 

Česká republika 
LEO Pharma s.r.o. 
Tel: +420 225 992 272 
 

Magyarország 
LEO Pharma  
Tel: +36 1 888 0525 
 

Danmark 
LEO Pharma AB 
Tlf: +45 70 22 49 11 
 

Malta 
PHARMA-COS LTD 
Tel: +356 2144 1870 
 

Deutschland 
LEO Pharma GmbH 
Tel: +49 6102 2010 
 

Nederland 
LEO Pharma B.V.   
Tel: +31 205104141 
 

Eesti 
LEO Pharma A/S 
Tel: +45 44 94 58 88 
 

Norge 
LEO Pharma AS 
Tlf: +47 22514900 
 

Ελλάδα 
LEO Pharmaceutical Hellas S.A. 
Τηλ: +30 210 68 34322 
 

Österreich 
LEO Pharma GmbH 
Tel: +43 1 503 6979 
 

España 
Laboratorios LEO Pharma, S.A. 
Tel: +34 93 221 3366 
 

Polska 
LEO Pharma Sp. z o.o. 
Tel.: +48 22 244 18 40 
 

France 
LEO Pharma  
Tél: +33 1 3014 4000 
 
Hrvatska 
Remedia d.o.o 
Tel: +385 1 3778 770 
 

Portugal 
LEO Farmacêuticos Lda.  
Tel: +351 21 711 0760 
 
România 
LEO Pharma Romania 
Tel: +40 213121963 
 

Ireland 
LEO Laboratories Ltd 
Tel: +353 (0) 1 490 8924 
 

Slovenija 
PHARMAGAN d.o.o. 
Tel: +386 4 2366 700 
 

Ísland 
Vistor hf. 
Sími: +354 535 7000 
 

Slovenská republika 
LEO Pharma s.r.o. 
Tel: +421 2 5939 6236 
 

Italia 
LEO Pharma S.p.A 
Tel: +39 06 52625500 
 

Suomi/Finland 
LEO Pharma Oy 
Puh/Tel: +358 20 721 8440 
 

Κύπρος 
The Star Medicines Importers Co. Ltd. 
Τηλ: +357 2537 1056  
 

Sverige 
LEO Pharma AB 
Tel: +46 40 3522 00 
 

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Latvija 
LEO Pharma A/S 
Tel: +45 44 94 58 88 
 

United Kingdom 
LEO Laboratories Ltd 
Tel: +44 (0) 1844 347333 
 

  
 
This leaflet was last revised in.  
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/  
------------------------------------------------------------------------------------------------------------------------- 

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http://www.ema.europa.eu/


45 

Package leaflet: Information for the patient 
 

Picato 500 micrograms/gram gel 
ingenol mebutate 

 
This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What Picato is and what it is used for 
2. What you need to know before you use Picato 
3. How to use Picato  
4. Possible side effects 
5. How to store Picato  
6. Contents of the pack and other information 
 
 
1. What Picato is and what it is used for 
 
Picato contains the active substance ingenol mebutate. 
This medicine is used for topical (on the skin) treatment of actinic keratosis, also called solar keratosis, 
in adults. Actinic keratoses are rough areas of skin found in people who have been exposed to too 
much sunshine over the course of their lifetime. Picato 500 micrograms/gram gel is used for actinic 
keratosis on the body, arms, hands and legs. 
 
 
2. What you need to know before you use Picato  
 
Do not use Picato   
- If you are allergic to ingenol mebutate or any of the other ingredients of this medicine (listed in 

section 6). 
 
Warnings and precautions 
Talk to your doctor or pharmacist before using Picato. 
- Do not get Picato in your eyes. Wash your hands thoroughly after you have applied the gel. 

Wash your hands again if you happen to touch the area where you applied the gel. Take care not 
to transfer gel from the treatment area into your eyes. In the event of accidental contact, remove 
the gel by rinsing with plenty of water and seek medical assistance as soon as possible. 

- Do not swallow this medicine. Drink plenty of water if you accidentally swallow this medicine 
and seek medical assistance. 

- Make sure that your skin has healed from any other treatments or surgery before using this 
medicine. Do not apply Picato on open-wounds or damaged skin. 

- Do not apply this medicine internally, to the area near the eyes, to the inside of the nostrils, the 
inside of the ear or on the lips. 

- Avoid sunlight as much as possible (including sunlamps and tanning beds). 
- Be vigilant for any new scaly red patches, open sores, elevated or warty growths within the 

treatment area. Should any occur, talk to your doctor immediately. 

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- This medicine is intended to treat one area of 25 cm2 for two days. 
- Do not apply more gel than your doctor has advised. 
- You should expect to get local skin reactions, such as reddening and swelling, after treatment 

with this medicine (see section 4). Contact your doctor if these local skin reactions get severe. 
 
Children and adolescents 
Actinic keratosis does not occur in children, and this medicine must not be used in children and 
adolescents under 18 years of age. 
 
Other medicines and Picato 
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. 
 
If you have previously used Picato or other similar medicines tell your doctor before starting the 
treatment.  
 
Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before using this medicine. You should avoid the use of Picato if you are 
pregnant. 
If you are breast-feeding, avoid physical contact between the baby and the treated area for 6 hours 
after application of this medicine. 
 
Driving and using machines 
This medicine does not have any effect on your ability to drive or to use machines.  
 
 
3. How to use Picato 
 
Always use this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if 
you are not sure.  
 
If you have been prescribed two different strengths for treatment of two different areas you should 
make sure that you use the prescribed strength on the correct area. Do not apply the 500 mcg/g gel on 
the face or scalp as this could lead to intense local skin responses. 
 
-  Treatment of actinic keratosis on the body, arms, hands and legs is one tube of Picato 

500 micrograms/g gel (containing 235 micrograms of ingenol mebutate) once a day for 2 days 
in a row. 

 
Instructions for use: 
- Open a new tube each time you use this medicine. Remove the cap from the tube just before 

use. 
- Squeeze the gel from one tube onto a fingertip. 
- Apply the content of one tube to one area of 25 cm2 (e.g. 5 cm x 5 cm). 
- Gently rub the gel onto the treatment area. 
- Allow the area to dry for 15 minutes. Avoid touching the treatment area for 6 hours after 

applying your medicine. 
- Wash your hands with soap and water immediately after applying the gel, and also in between 

administrations if prescribed two different strengths for two different areas. If you are treating 
your hands you should only wash the fingertip which you used for applying the gel. 

- Do not apply this medicine immediately after taking a shower or less than 2 hours before 
bedtime. 

- Do not wash the areas where you applied the gel for at least 6 hours after you apply it. 
- Do not touch the treatment area yourself or allow anyone or any pets to touch the treatment area 

for a period of 6 hours after applying the gel. 
- Do not cover the treated area with air- or water-tight bandages after you have applied this 

medicine. 

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47 

- The full effect of Picato can be evaluated approximately 8 weeks after treatment. 
 

 
 
If you use Picato for treatment of the neck 
If more than half of the treatment area is located in the upper part of the neck: 
- Use Picato 150 mcg/g gel (face and scalp) 
If more than half of the treatment area is located in the lower part of the neck: 
- Use Picato 500 mcg/g gel (trunk and extremities) 
 
If you use more Picato than you should 
Wash the area with soap and water. Please contact your doctor or pharmacist if you experience severe 
skin reactions. 
 
If you forget to use Picato 
Please contact your doctor or pharmacist if you forget to use Picato. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them.  
 
Seek medical attention right away if you experience an allergic reaction that may include swelling of 
the mouth, tongue or throat when using this medicine. This side effect is uncommon. 
 
After using this medicine the skin where you apply it is likely to get red, peel and have scabs. These 
side effects most often occur within one day after applying this medicine. The side effects may get 
worse for up to 1 week after you have stopped using this medicine. They will usually get better within 
4 weeks from when you started the treatment. 
 
Infection of the skin in the treatment area can occur (has been reported as a common side effect, which 
may affect up to 1 in 10 people, when treating the face and scalp).  
 
Swelling of the application site is very common (has been reported in more than 1 in 10 people). 
Application site swelling on the face or scalp may gravitate to the eye area. 
 
Should the symptoms described above intensify beyond the first week after you have stopped using 
this medicine, or if there is discharge of pus, you might have an infection and should contact your 
doctor or pharmacist. 
 
The most frequently occurring side effects when treating the face and scalp: 
 
Very common side effects on the treatment area, may affect more than 1 in 10 people: 
On the treatment area:  

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48 

- Some of the outer layer of your skin may wear away (erosion)  
- Blisters (vesicles, pustules) 
- Peeling (exfoliation) 
- Scabs 
- Redness due to widening of the small blood vessels (erythema) 
- Pain (including application site burning) 
 
The most frequently occurring side effects when treating the trunk and extremities: 
 
Very common side effects on the treatment area, may affect more than 1 in 10 people: 
On the treatment area:  
- Some of the outer layer of your skin may wear away (erosion)  
- Blisters (vesicles, pustules) 
- Peeling (exfoliation) 
- Scabs 
- Redness due to widening of the small blood vessels (erythema) 
 
Other possible side effects when treating the face and scalp: 
 
Common side effects, may affect up to 1 in 10 people: 
On the treatment area: 
- Itching (pruritus) 
- Irritation 
 
Other side effects: 
- Swelling of the area around the eye (periorbital oedema)  
- Swelling (oedema) of your eye lid 
- Headache  
 
Uncommon side effects, may affect up to 1 in 100 people: 
On the treatment area: 
- Tingling or numbness (paraesthesia) 
- Open sores (ulcer) 
- Discharge (secretion) of fluid 
- Change in skin colour (pigmentation change) 
 
Other side effects: 
- Eye pain 
- Injury or irritation to the surface of the eye (cornea, conjunctiva) following accidental exposure 
 
Rare side effects, may affect up to 1 in 1000 people: 
On the treatment area: 
- Scarring 
 
Other possible side effects when treating the trunk and extremities: 
 
Common side effects, may affect up to 1 in 10 people: 
On the treatment area: 
- Itching (pruritus) 
- Irritation 
- Pain (including application site burning) 
 
Uncommon side effects, may affect up to 1 in 100 people: 
On the treatment area: 
- Tingling or numbness (paraesthesia) 
- Open sores (ulcer) 
- Change in skin colour (pigmentation change) 

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49 

- Warmth 
 
Other side effects: 
- Injury or irritation to the surface of the eye (cornea, conjunctiva) following accidental exposure. 
 
Rare side effects, may affect up to 1 in 1000 people: 
On the treatment area: 
- Scarring 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Picato  
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and tube after EXP. The 
expiry date refers to the last day of that month. 
 
Store in a refrigerator (2°C-8°C). 
 
For single use only. Do not re-use the tubes once opened.  
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Picato contains  
- The active substance is ingenol mebutate. Each gram of gel contains 500 micrograms of ingenol 

mebutate. Each tube contains 235 micrograms of ingenol mebutate in 0.47 g of gel. 
 
- The other ingredients are isopropyl alcohol, hydroxyethylcellulose, citric acid monohydrate, 

sodium citrate, benzyl alcohol, purified water. 
 
What Picato looks like and contents of the pack 
Picato 500 micrograms/g gel is clear and colourless and each carton contains 2 tubes with 0.47 g of gel 
each.  
 
Marketing Authorisation Holder 
LEO Laboratories Ltd. 
285 Cashel Road 
Crumlin, Dublin 12 
Ireland 
 
Manufacturer 
LEO Laboratories Ltd. 
285 Cashel Road, Crumlin, Dublin 12 
Ireland 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 

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http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


50 

 
België/Belgique/Belgien 
LEO Pharma N.V./S.A 
Tél/Tel: +32 3 740 7868 
 

Lietuva 
LEO Pharma A/S 
Tel: +45 44 94 58 88 
 

България 
Borola Ltd 
Teл.: +359 2 9156 136 
 

Luxembourg/Luxemburg 
LEO Pharma N.V./S.A 
Tél/Tel: +32 3 740 7868 
 

Česká republika 
LEO Pharma s.r.o. 
Tel: +420 225 992 272 
 

Magyarország 
LEO Pharma  
Tel: +36 1 888 0525 
 

Danmark 
LEO Pharma AB 
Tlf: +45 70 22 49 11 
 

Malta 
PHARMA-COS LTD 
Tel: +356 2144 1870 
 

Deutschland 
LEO Pharma GmbH 
Tel: +49 6102 2010 

Nederland 
LEO Pharma B.V. 
Tel: +31 205104141 
 

Eesti 
LEO Pharma A/S 
Tel: +45 44 94 58 88 
 

Norge 
LEO Pharma AS 
Tlf: +47 22514900 
 

Ελλάδα 
LEO Pharmaceutical Hellas S.A. 
Τηλ: +30 210 68 34322 
 

Österreich 
LEO Pharma GmbH 
Tel: +43 1 503 6979 
 

España 
Laboratorios LEO Pharma, S.A. 
Tel: +34 93 221 3366 
 

Polska 
LEO Pharma Sp. z o.o. 
Tel.: +48 22 244 18 40 
 

France 
LEO Pharma  
Tél: +33 1 3014 4000 
 

Portugal 
LEO Farmacêuticos Lda.  
Tel: +351 21 711 0760 
 

Hrvatska 
Remedia d.o.o 
Tel: +385 1 3778 770 
 

România 
LEO Pharma Romania 
Tel: +40 213121963 
 

Ireland 
LEO Laboratories Ltd 
Tel: +353 (0) 1 490 8924 
 

Slovenija 
PHARMAGAN d.o.o. 
Tel: +386 4 2366 700 
 

Ísland 
Vistor hf. 
Sími: +354 535 7000 
 

Slovenská republika 
LEO Pharma s.r.o. 
Tel: +421 2 5939 6236 
 

Italia 
LEO Pharma S.p.A 
Tel: +39 06 52625500 
 

Suomi/Finland 
LEO Pharma Oy 
Puh/Tel: +358 20 721 8440 
 

Κύπρος 
The Star Medicines Importers Co. Ltd. 
Τηλ: +357 2537 1056  
 

Sverige 
LEO Pharma AB 
Tel: +46 40 3522 00 
 

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51 

Latvija 
LEO Pharma A/S 
Tel: +45 44 94 58 88 
 

United Kingdom 
LEO Laboratories Ltd 
Tel: +44 (0) 1844 347333 
 

  
 
This leaflet was last revised in. 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/  
------------------------------------------------------------------------------------------------------------------------- 

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http://www.ema.europa.eu/


52 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 

 
ANNEX IV 

 
SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS 

OF THE MARKETING AUTHORISATION(S) 

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53 

Scientific conclusions 

Taking into account the PRAC Assessment Report on the PSUR(s) for ingenol mebutate, the 
scientific conclusions of CHMP are as follows:  

Taking into account the treatment purpose for actinic keratosis, which is prevention of skin 
malignancy, and considering the number of skin tumour cases reported to ingenol mebutate in 
clinical trials and post-marketing, the PRAC has serious concerns about the impact of the risk of skin 
tumours on the benefit risk balance of Picato. The PRAC is of the opinion that a thorough review is 
needed of the impact of all available data related to skin malignancies, including the results of study 
LP0041-63, on the benefit risk balance of Picato. Additionally, the product information should be 
varied concerning ingenol mebutate use and the risk of skin malignancy. The PRAC also agreed that 
a DHPC is needed in order to mitigate this risk. 

 
The CHMP agrees with the scientific conclusions made by the PRAC. 

 

Grounds for the variation to the terms of the marketing authorisation(s) 

On the basis of the scientific conclusions for ingenol mebutate the CHMP is of the opinion that the 
benefit-risk balance of the medicinal product(s) containing ingenol mebutate is unchanged subject 
to the proposed changes to the product information 

The CHMP recommends that the terms of the marketing authorisation(s) should be varied. 

 

 
 

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	SUMMARY OF PRODUCT CHARACTERISTICS
	A.  MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION 
	D.  CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 
	A. LABELLING
	B. PACKAGE LEAFLET