Pharmacology Update

Ingenol Mebutate Gel (Picato)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD, Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationships relevant to this field of study.

A new topical agent is available for the treatment of actinic keratosis (AK). Ingenol mebutate is a macrocyclic diterpene ester found in the sap of Euphorbia peplus, a common plant found in Africa, Europe, and Asia. It is a novel agent with a postulated dual mechanism of action, rapid lesion necrosis followed by specific neutrophil-mediated antibody dependent cellular cytotoxicity.1 It is marketed as a topical gel by Leo Pharma as Picato.

Indications

Ingenol mebutate is indicated for the topical treatment of AK.1

Dosage

For AK of the face and scalp, the 0.015% gel is applied once daily for 3 consecutive days. For lesions on the trunk and extremities, the 0.05% gel is applied once daily for 2 consecutive days.

Ingenol mebutate is available as 0.015% and 0.05% gel for two or three unit dose tubes.

Potential Advantages

Ingenol mebutate treatment is for 2-3 days compared to prolonged treatment (14-60 days) required for current therapy (e.g., 5-FU, imiquimod, diclofenac). This reduces the duration of adverse reactions and likely improves adherence.

Potential Disadvantages

The most common local skin reactions (> 60%) were erythema, flaking/scaling, crusting, and swelling. Less frequently reported reactions include vesiculation/pustulation and erosion/ulceration (26-56%).2

Comments

The safety and efficacy of ingenol mebutate were evaluated in four double-blind, vehicle-controlled trials, two involving lesions on the face or scalp and two involving the trunk or extremities.2,3 Subjects with AK on the face or scalp were randomized to ingenol mebutate 0.015% (n = 277) or vehicle gel (n = 270) applied once daily for 3 consecutive days. Those with AK of the trunk or extremities were randomized to 0.05% (n = 226) or vehicle (n = 232) once daily for 2 consecutive days. The primary endpoint was complete clearance of all clinically visible AK in the treatment area; partial clearance was reduction of 75% on day 57. Pooled results for face and scalp were 42.2% complete and 63.9% partial clearance compared to 3.7% and 7.4%, respectively, for the vehicle. Complete and partial clearance were 34.1% and 49.1% for trunk and extremities, and 4.7% and 6.9% for the vehicle. The median reductions of lesions were 83% and 75% for face/scalp and trunk/extremities compared to 0% for the vehicle. For those with complete clearance, there was a roughly 50% recurrence in the previously treated area. There are currently no comparative studies with other topical agents. The magnitude of success appears similar to that reported for 5-fluorouracil, diclofenac gel, and imiquimod cream.4-6

Clinical Implications

AK is a premalignant lesion that can progress to squamous cell carcinoma. The prevalence of AK is estimated to be 27% in men and 10% in women. Currently recommended topical treatment by the American Academy of Dermatology includes 5-fluorouracil cream, diclofenac gel, imiquimond cream, and now ingenol mebutate gel.4 The latter offers a significantly shorter duration of treatment and appears to be comparable in effectiveness to the other agents. The wholesale acquisition cost of ingenol mebutate is $590, which is similar to diclofenac gel (Solaraze, $621) and imiquimod (Zyclara, $598), but more expensive than 5-fluorouracil (Efudex, Fluroplex) which is $230 and $350.

References

1. Rosen RH, et al. Dual mechanism of action of ingenol mebutate gel for topical treatment of actinic keratoses: Rapid lesion necrosis followed by lesion-specific immune response. J Am Acad Dermatol 2012;66:486-493.

2. Picato Prescribing Information. Parsippany, NJ: LEO Pharma, Inc.; February 2012.

3. Lebwohl M, et al. Ingenol mebutate gel for actinic keratosis. N Engl J Med 2012;366:1010-1019.

4. Rhavar M, et al. Randomized, vehicle-controlled trials of topical 5-fluorouracil therapy for actinic keratosis treatment: An overview. Immunotherapy 2012;4:939-945.

5. Aldara Prescribing Information. Bristol, TN: Graceway Pharmaceuticals; February 2007.

6. Solaraze Gel Prescribing Information. Florham Park, NJ: PharmaDerm.

7. http://www.aad.org/skin-conditions/dermatology-a-to-z/actinic-keratosis/diagnosis-treatment/actinic-keratosis-diagnosis-treatment-and-outcome. Accessed Dec. 23, 2012.