Ingenol mebutate

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 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.

There are no data from the use of ingenol mebutate in pregnant women. Animal studies showed slight embryo-fetal toxicity. Risks to humans receiving cutaneous treatment with ingenol mebutate are considered unlikely as ingenol mebutate is not absorbed systemically. As a precautionary measure, it is preferable to avoid the use of ingenol mebutate during pregnancy.

No effects on the breastfed newborn/infant are anticipated as ingenol mebutate 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 ingenol mebutate.

Fertility

No fertility studies have been performed with ingenol mebutate.

Ingenol mebutate has no or negligible influence on the ability to drive and use machines.

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 the list below 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.

List of adverse reactions

The following list reflects exposure to ingenol mebutate 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 ingenol mebutate at concentrations of 150 mcg/g or 500 mcg/g or vehicle once daily for 3 or 2 consecutive days respectively.

The list 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.

Adverse reactions by MedDRA System Organ Classification:

* 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
*** 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 ingenol mebutate 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 ingenol mebutate 150 mcg/g (n=158) or vehicle (n=150) for 3 days in the same area. 149 patients in the ingenol mebutate group and 140 in the vehicle group were followed for 12 months. In a later study 450 patients were initially treated with ingenol mebutate 150 mcg/g, of these 134 patients were randomised to a second treatment course of ingenol mebutate 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 ingenol mebutate.