Picato(r) 0.015% gel should be applied to the affected area once daily for 3 consecutive days.

Picato(r) 0.05% gel should be applied to the affected area once daily for 2 consecutive days.

Picato(r) should be applied to the treatment area as defined by the treating physician. Each tube contains enough gel to cover an area of approximately 25 cm2 (e.g. 5 cm x 5 cm).

The gel from the single dose tube should be squeezed onto a fingertip and spread evenly over the entire treatment area, allowing it to dry for 15 minutes. One single dose tube should be used for the treatment area. Patients should be instructed to wash their hands immediately after applying Picato(r). 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(r).

Contraindications

Special Warnings and Precautions for Use

Avoid contact with 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. Picato(r) must not be ingested. If accidental ingestion occurs the patient should drink plenty of water. Local skin responses such as erythema, flaking/scaling, and crusting can occur after topical application of Picato(r) (see section 4.8). These local skin responses have been shown to be associated with the clinical efficacy. Localised skin responses are transient and typically 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. Administration of Picato(r) is not recommended until the skin is healed from treatment with any previous medicinal product or surgical treatment. Clinical data on treatment for more that one treatment course of 2 to 3 consecutive days are not available. Studies have been conducted to assess the effects of UV irradiation of the skin following single and multiple applications of ingenol mebutate gel, 0.01%. 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.

Interaction with other Medicinal Products and Other Forms of Interaction

No interaction studies have been performed. Interactions with systemically absorbed medicinal products are considered minimal as Picato(r) is not absorbed systemically.

Fertility, Pregnancy and Lactation

There are no data from the use of ingenol mebutate in pregnant women. Animal studies do not indicate harmful effects with respect to reproductive toxicity (see section 5.3). Risks to humans receiving topical treatment with Picato(r) are considered unlikely as ingenol mebutate gel is not absorbed systemically. As a precautionary measure, it is preferable to avoid the use of Picato(r) during pregnancy.

No effects on the breastfed newborn/infant are anticipated as ingenol mebutate gel is not absorbed systemically. The nursing mother should be instructed that the newborn/infant avoid physical contact with the treated area for a period of 6 hours after application of Picato(r).

Effects on ability to drive and use machines

Undesirable Effects

Summary of the safety profile

The most frequently reported adverse reactions assessed by investigators 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 mebutate, most patients (>95%) experienced one or more local skin response(s). The local skin responses are transient and typically occur within 1 day of treatment initiation and peak in intensity up to 1 week following completion of treatment. These effects typically resolve within 2 weeks of treatment initiation for areas treated on the face and scalp and within 4 weeks of treatment initiation for areas treated on the trunk and extremities.

Tabulated summary of adverse reactions

Table 1 reflects exposure to Picato(r) (0.015% or 0.05%) in 499 patients with solar (actinic) keratoses treated in four vehicle controlled phase 3 studies enrolling a total of 1002 patients. Patients received field treatment (area of 25 cm2) with Picato(r) at concentrations of 0.015% or 0.05%or vehicle once daily for 3 or 2 consecutive days respectively. The table below presents adverse reactions by MedDRA system organ class. 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)

v2.0

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1 Adverse reactions by MedDRA System Organ Class

System Organ Class	Frequency
Infections and Infestations
Application site pustules	Very common
Application site infection	Common
Nervous system disorders
Headache	Common
Eye Disorders
Periorbital oedema	Common
Eye lid oedema	Uncommon
General disorders and administration site conditions
Application site erosion Application site vesicles Application site swelling Application site exfoliation Application site scab Application site erythema	Very common
Application site pain Application site pruritus Application site irritation	Common
Application site paraesthesia Application site ulcer	Uncommon

Long-term follow up

A total of 198 patients (184 treated with Picato(r) and 14 treated with vehicle) were enrolled in long-term efficacy follow-up studies. Results from these studies did not change the safety profile of Picato(r) (see section 5.1).

Overdose

There has been no experience of overdose in clinical studies with Picato(r). In a clinical study 4 single dose tubes of Picato(r) 0.05% was applied daily for 2 consecutive days to a 100 cm2 area of skin for the treatment of solar (actinic) keratoses. The result demonstrated no change in the safety profile compared to the safety profile of Picato(r) 0.05% when 1 tube is applied to a 25 cm2 area for 2 consecutive days.

Pharmacodynamic properties

Pharmacotherapeutic group: ATC code: D06BX02 (other chemotherapeutics for topical use).

The mechanism of action in solar (actinic) keratoses is not fully understood. 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 characterised by infiltration of neutrophils and other immunocompetent cells.

Ingenol mebutate induces multiple mechanisms in tumour cells by exerting a direct cytotoxic effect and modulating Protein Kinase C (PKC) isoforms. At a high concentration (100 mcg/ml) in vitro and in vivo, ingenol mebutate induces mitochondrial swelling and loss of cell membrane integrity leading to cell death; at lower concentrations (10 to 100 ng/ml), ingenol mebutate stimulates PKC dependent activation of human endothelial cells to support neutrophil adhesion in vitro. Exposure of isolated human keratinocytes to lower concentrations of ingenol mebutate (10 to 100 ng/ml) in vitro, was shown to induce release of the cytokines IL-8 and TNF-alpha and specific PKC-mediated neutrophil activation. Both in vitro and in mice, ingenol mebutate induced IL-8 / murine IL-8 homologue MIP-2, TNF-alpha, and IL-1beta, all mediators of neutrophil recruitment and activation. In mouse squamous cell carcinoma and malign melanoma tumour models, topical ingenol mebutate removed tumours and prevented tumour recurrence by a dual mechanism of action: 1) induction of local lesional cell death, and 2) promoting an inflammatory response characterised by infiltration of neutrophils and other immunocompetent cells. Topical treatment with ingenol mebutate gel in the squamous cell carcinoma model resulted in a localised and transient application site inflammatory reaction, which peaked after few days, and resolved within 2 weeks followed by scar resolution after 2 to 3 months. After 3 weeks treatment ingenol mebutate treated mouse skin was similar to untreated skin in elasticity. With intratumoural injection of ingenol mebutate in syngeneic mouse tumour models, ingenol mebutate stimulated a tumour-specific CD8 + T cell response leading to anti-tumour activity against distant secondary tumours. The potential for off-target activity against various receptors and enzymes was investigated in in vitro assays. No off-target activity was observed.

The efficacy and safety of Picato(r) 0.015%, administered on the face or scalp for 3 consecutive days was studied in two double-blind, vehicle-controlled, clinical studies including 547 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, solar (actinic) keratoses lesions on the face or scalp within a contiguous 25 cm2 treatment area. 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 years) and 94% had Fitzpatrick skin type I, II, or III. At day 57, patients treated with Picato(r) had higher complete and partial clearance rates than patients treated with vehicle gel (p<0.001). The median percent reduction in solar (actinic) keratoses 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 percent (%) reduction on face and scalp

Safety of Picato(r) 0.015% gel treatment for 3 days was assessed up to day 57 and ingenol mebutate gel was found to be well tolerated. All adverse drug reactions and local skin responses resolved without sequelae. Statistically significant differences in patient reported outcomes were observed in favour of patients receiving Picato(r) 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).

The efficacy and safety of Picato(r) 0.05% gel, administered on the trunk or extremities (body) 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 3).

Patients had 4 to 8 clinically typical, visible, discrete, non-hyperkeratotic, non-hypertrophic solar (actinic) keratoses lesions on the trunk or extremities within a contiguous 25 cm2 treatment area. 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 66 years) and 94% had Fitzpatrick skin type I, II, or III. At day 57, patients treated with Picato(r) had higher complete and partial clearance rates than patients treated with vehicle gel (p<0.001). The median percent reduction in solar (actinic) keratoses lesions was higher in the group treated with ingenol mebutate compared to the vehicle group (see Table 3).

Table 3 Rates of subjects with complete and partial clearance and percent (%) reduction on body (trunk and extremities)

Safety of Picato(r) 0.05% gel treatment for 2 days was assessed up to day 57 and ingenol mebutate gel was found to be well-tolerated. All adverse drug reactions and local skin responses resolved without sequelae. Statistically significant differences in patient reported outcomes were observed in favour of patients receiving Picato(r) 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 TSQM.

Three prospective, observational long term 1 year follow-up studies were conducted to evaluate sustained efficacy by recurrence of solar (actinic) keratoses lesions in the treatment field, and safety in patients who had received treatment with Picato(r). One study included patients treated with Picato(r) 0.015% on the face or scalp for 3 days and two studies included

patients treated with Picato(r) 0.05% on the truck or extremities (body) 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 4 and 5).

Table 4 Rate of recurrence of solar (actinic) keratoses lesions on face and scalp

Table 5 Rate of recurrence of solar (actinic) keratoses lesions on trunk and extremities (body)

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 1165 patients) and in vehicle treated patients (0.3%, 2 of 632 patients) in the solar (actinic) keratoses clinical studies conducted with ingenol mebutate. 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.

In a double-blind, vehicle-controlled study to evaluate systemic exposure, ingenol mebutate 0.05% gel, from 4 single dose tubes, was applied to a 100 cm2 contiguous treatment area daily for 2 consecutive days. Results demonstrated no systemic absorption. Picato(r) 0.05% was well tolerated when applied to a contiguous treatment area of 100 cm2 on the trunk and extremities (body).

Of the 1165 patients treated with Picato(r) in the solar (actinic) keratoses 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.

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 topical administration. No systemic absorption was detected at or above the lower limit of detection (0.1 ng/ml) when Picato(r) 0.05% from 4 single dose tubes was applied to an area of 100 cm2 on the dorsal forearm in solar (actinic) keratoses patients once daily for 2 consecutive days. In vitro study results demonstrate that ingenol mebutate does not inhibit or induce human cytochrome P450 isoforms.

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 topical administration of ingenol mebutate gel is well tolerated with skin irritation potential and negligible risk of systemic toxicity under the recommended conditions of use. In rats, ingenol mebutate was not associated with foetal developmental effects at IV doses up to 5 mcg/kg/day (30 mcg/m2/day). In rabbits there were no major abnormalities. Minor foetal abnormalities or variants were observed in the foetuses of treated dams; however, the findings did not suggest a clear association with IV ingenol mebutate administration. The foetal NOAEL was 1 mcg/kg/day (12 mcg/m2/day).

List of Excipients

Shelf life

Special precautions for storage

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 0.015% gel for application to the face and scalp is available in a carton containing 3 single-dose tubes with 0.47 g of gel each. Picato 0.05% gel for application to the body is available in a carton containing 2 single-dose tubes with 0.47 g of gel each.

	Picato (r) 0.015% (n=277)	Vehicle (n=270)
Complete Clearance Rate a	42.2% d	3.7%
Partial Clearance Rate b (>=75%)	63.9% d	7.4%
Median % Reduction c	83%	0%
a Complete clearance rate was defined as the proportion of patients with no (zero) clinically visible solar (actinic) keratoses 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 solar (actinic) keratoses lesions were cleared. c Median percent (%) reduction in solar (actinic) keratoses lesions compared to baseline. d p<0.001; compared to vehicle by logistic regression with treatment, study and anatomical location.

	Picato (r) 0.05% (n=226)	Vehicle (n=232)
Complete Clearance Rate a	34.1% d	4.7%
Partial Clearance Rate b (>=75%)	49.1% d	6.9%
Median % Reduction c	75%	0%
a Complete clearance rate was defined as the proportion of patients with no (zero) clinically visible solar (actinic) keratoses lesions in the treatment area. b The partial clearance rate was defined as the percentage of patients in whom 75% or more of the number of baseline solar (actinic) keratoses lesions were cleared. c Median percent (%) reduction in number of solar (actinic) keratoses lesions compared to baseline. d p<0.001; compared to vehicle by logistic regression with treatment, study and anatomical location.

	Picato (r) 0.015% (n=108)
Recurrence Rate 12 months KM estimate (95% CI) a	53.9% (44.6-63.7)
Lesion Based Recurrence Rate b 12 months Mean (SD)	12.8% (19.1)
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 solar (actinic) keratoses 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 solar (actinic) keratoses lesions at 12 months to the number of lesions at baseline in the previous phase 3 studies.

	Picato (r) 0.05% (n=76 c )
Recurrence Rate 12 months KM estimate (95% CI) a	56.0% (45.1-67.6)
Lesion Based Recurrence Rate b 12 months Mean (SD)	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 solar (actinic) keratoses lesion in the previously treated area for patients who achieved complete clearance at day 57 in a previous phase 3 studies. b The lesion-based recurrence rate for each patient defined as the ratio of the number of solar (actinic) keratoses 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.

Therapeutic Indications

Posology and Method of Administration