Ingenol mebutate gel

Author: Anoma Ranaweera B.V.Sc; PhD (Clinical Biochemistry, University of Liverpool, UK), 2012. Updated by Dr Amanda Oakley, 13 March 2014.


Ingenol mebutate (also called ingenol-3-angelate) is an extract of a common plant, petty spurge or milk weed (Euphorbia peplus). Ingenol mebutate is derived from a cultivar of Euphorbia peplus that is specifically grown in Queensland for this purpose.

It has been shown to be useful in the treatment of superficial skin cancers including actinic keratoses (actinic keratoses), which are scaly spots caused by long term sun exposure.

In January 2012, the US Food and Drug Administration (FDA) approved ingenol mebutate gel for the treatment for actinic keratoses on the face, scalp, trunk and extremities. Ingenol mebutate gel is available in concentrations of 0.015% and 0.05% and is manufactured by LEO Pharma with the trade name Picato®. Ingenol mebutate gel was registered as a prescription medicine by MedSafe for use in New Zealand in October 2013.

The two or three-day course of ingenol mebutate gel compares favourably to several weeks or months needed for other topical therapies used for actinic keratoses, such as 5-fluorouracil cream and imiquimod cream. Treatment can be repeated at a later date if required.

Ingenol mebutate gel

How is ingenol mebutate gel administered?

Administration of ingenol mebutate gel is not recommended until skin is healed from any previous drug or surgical treatment. It can be applied at any time of year.

Ingenol mebutate gel is applied to a sun-damaged area.The contents of a single-dose tube will cover about 5 cm x 5 cm of skin. The treatment varies according to the site of the keratoses.

  • The gel must be refrigerated.
  • Read the instructions in the box carefully.
  • On the face and scalp, ingenol mebutate gel 0.015% (150 mcg/g) is applied once daily for three days.
  • On the trunk and extremities, ingenol mebutate gel 0.05% (500 mcg/g) is applied once daily for two days.
  • Hands should be washed thoroughly after applying the gel, so it is not inadvertently spread to other sites.

The treated area is allowed to dry for 15 minutes after application and should not be washed or touched for 6 hours after treatment. The treated area can be gently washed after that. Activities that cause excessive sweating should be avoided.

Treated areas become inflamed, often crusted, and then heal over a few days. If blistering or ulceration occurs, the gel should not be reapplied to this site until the skin has fully healed. Moisturiser can be applied as required when the skin peels off.

Day 0 pretreatment Effects of ingenol mebutate gel on facial actinic keratoses Effects of ingenol mebutate gel on facial actinic keratoses Effects of ingenol mebutate gel on facial actinic keratoses Effects of ingenol mebutate gel on facial actinic keratoses
The worst day Effects of ingenol mebutate gel on facial actinic keratoses
Day 2
Effects of ingenol mebutate gel on facial actinic keratoses
Day 5
Effects of ingenol mebutate gel on facial actinic keratoses
Day 4
Effects of ingenol mebutate gel on facial actinic keratoses
Day 3
Follow-up Effects of ingenol mebutate gel on facial actinic keratoses
Day 6
Effects of ingenol mebutate gel on facial actinic keratoses
Day 13
Effects of ingenol mebutate gel on facial actinic keratoses
Day 7
Effects of ingenol mebutate gel on facial actinic keratoses
Day 7
Effects of ingenol mebutate gel on facial actinic keratoses

How does ingenol mebutate gel act?

How ingenol mebutate works on actinic keratoses is incompletely understood. It appears to have a dual mechanism of action:

  1. rapid lesion necrosis
  2. specific neutrophil-mediated, antibody-dependent cellular cytotoxicity.

Link to key clinical-trial evidence

Potential drug interactions with ingenol mebutate

Studies have shown that drug interactions are not likely to be of clinical importance.

  • Ingenol mebutate is metabolised by human liver cells.
  • Ingenol mebutate does not inhibit or induce CYP450 enzymes.

Adverse events due to ingenol mebutate gel

Ingenol mebutate gel commonly causes skin reactions at the site of application, such as:

  • pain
  • itch
  • irritation
  • infection
  • swelling.

Anaphylaxis and severe contact allergic dermatitis have rarely been reported. A few patients have complained of upper respiratory symptoms and headache.

The periocular area is unsuitable for ingenol mebutate gel because severe eye pain, swelling and drooping of the eyelid can occur if the gel contacts these sites. If accidental exposure occurs, flush eyes with water and seek medical care.

Symptoms from ingenol mebutate gel used for facial actinic keratoses

Use of ingenol mebutate gel in pregnancy

There are no adequate and well-controlled studies of ingenol mebutate gel in pregnant women. Ingenol mebutate gel should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Use of ingenol mebutate gel in children

The safety and effectiveness of ingenol mebutate gel have not been established in patients less than 18 years of age, but actinic keratoses are not generally seen in children.

Future considerations for ingenol mebutate gel

Topical ingenol mebutate is currently in phase II clinical trials for eradicating basal cell carcinoma and squamous cell carcinoma (SCC) in situ (also called intraepidermal SCC or Bowen disease).

Off label use

A case report described resolution of a keloid following treatment with 0.05% ingenol mebutate gel daily for 2 days.

Two of four patients treated for actinic cheilitis had clearance.

New Zealand approved datasheets are the official source of information for these prescription medicines, including approved uses and risk information. Check the individual New Zealand datasheet on the Medsafe website.

 

Related Information

References:

  • Anderson L, Melgaard A, Xu Z. Multicenter, randomized, parallel-group, double-blind, vehicle-controlled, phase 3 study to evaluate the efficacy and safety of PEP005 (ingenol mebutate) gel, 0.05% in patients with actinic keratoses on non-head locations (Study PEP005-028). Poster presented at: 22nd World Congress of Dermatology 2011 May 24-29 Seoul, Korea. Poster P2180.
  • Berman B, Melgaard A, Larsson T. Multicenter, randomized, parallel-group, double-blind, vehicle-controlled phase 3 study of the efficacy and safety of PEP005 (ingenol mebutate) gel, 0.015% in patients with actinic keratoses on the head (face or scalp) (Study PEP005-016). Poster presented at: 22nd World Congress of Dermatology 2011 May 24-29 Seoul, Korea. Poster P2179.
  • Lebwohl M, Melgaard A, Xu Z. Randomized, parallel-group, double-blind, vehicle-controlled, multicenter phase 3 study of the efficacy and safety of PEP005 (ingenol mebutate) gel, 0.015% in patients with actinic keratoses on the head (Study PEP005-025). Poster presented at: 22nd World Congress of Dermatology 2011 May 24-29 Seoul, Korea. Poster P2181.
  • Swanson N, Melgaard A, Larsson T. Multicenter, randomized, parallel-group, double-blind, vehicle-controlled phase 3 study to evaluate the efficacy and safety of PEP005 (ingenol mebutate) gel, 0.05% in patients with actinic keratoses on non-head locations (Study PEP005-014). . Poster presented at: 22nd World Congress of Dermatology 2011 May 24-29 Seoul, Korea. Poster P2182.
  • Anderson L, Schmieder GJ, Werschler WP, Tschen EH, Ling MR, Stough DB, Katsamas J. Randomized, double-blind, double-dummy, vehicle-controlled study of ingenol mebutate gel 0.025% and 0.05% for actinic keratosis. J Am Acad Dermatol. 2009 Jun; 60(6):934-43.
  • Ko CJ. Actinic keratosis: facts and controversies. Clin Dermatol 2010;28(3):249-53.
  • Stockfleth E, Kerl H. Guidelines for the management of actinic keratoses. Eur J Dermatol 2006;16(6):599-606.
  • De Felice B, Guida M, Boccia L, Nacca M. Ingenol mebutate treatment in keloids. BMC Res Notes. 2015 Sep 22;8(1):466. doi: 10.1186/s13104-015-1429-9. PubMed PMID: 26391582; PubMed Central PMCID: PMC4578559.

On DermNet NZ:

Other websites:

Books:

See the DermNet NZ bookstore