Adverse reactions : תופעות לוואי

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 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      Uncommon                          Uncommon angioedema)
Nervous system disorders
Headache                         Common
Eye disorders*
Eye lid oedema                   Common
Periorbital oedema               Common
Chemical conjunctivitis,         Uncommon                          Uncommon corneal burn**
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 Application site pigmentation    Uncommon                          Uncommon changes
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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic @moh.gov.il