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Expert Opinion on Drug Safety Volume 14, 2015 - Issue 12

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Drug Safety Evaluation

Safety and tolerability of ingenol mebutate in the treatment of actinic keratosis

Brian BermanCenter for Clinical and Cosmetic Research, Aventura, FL, USA;Center for Clinical and Cosmetic Research, 2925 Aventura Boulevard, Suite 205, Aventura, FL33180, USA;Correspondence[email protected]

, MD PhD

Pages 1969-1978 | Published online: 02 Nov 2015

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https://doi.org/10.1517/14740338.2015.1108962
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Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.
Google Scholar
Berman B. New developments in the treatment of actinic keratosis: focus on ingenol mebutate gel. Clin Cosmet Investig Dermatol. 2012;5:111–122.
PubMedGoogle Scholar

• Overview of ingenol mebutate.

Perera E, McGuigan S, Sinclair R. Cost for the treatment of actinic keratosis on the rise in Australia. F1000Res. 2014;3:184.
PubMedGoogle Scholar
Flohil SC, van der Leest RJ, Dowlatshahi EA, et al. Prevalence of actinic keratosis and its risk factors in the general population: the Rotterdam study. J Invest Dermatol. 2013;133:1971–1978.
PubMed Web of Science ®Google Scholar
Eder J, Prillinger K, Korn A, et al. Prevalence of actinic keratosis among dermatology outpatients in Austria. Br J Dermatol. 2014;171:1415–1421.
PubMed Web of Science ®Google Scholar
Landis ET, Davis SA, Taheri A, et al. Top dermatologic diagnoses by age. Dermatol Online J. 2014;20:22368.
PubMedGoogle Scholar
Criscione VD, Weinstock MA, Naylor MF, et al. Actinic keratoses. Cancer. 2009;115:2523–2530.
PubMed Web of Science ®Google Scholar
Krawtchenko N, Roewert-Huber J, Ulrich M, et al. A randomised study of topical 5% imiquimod vs. topical 5-fluorouracil vs. cryosurgery in immunocompetent patients with actinic keratoses: a comparison of clinical and histological outcomes including 1-year follow-up. Br J Dermatol. 2007;157(Suppl 2):34–40.
PubMed Web of Science ®Google Scholar
Simon JC, Dominicus R, Karl L, et al. A prospective randomized exploratory study comparing the efficacy of once-daily topical 0.5% 5-fluorouracil in combination with 10.0% salicylic acid (5-FU/SA) vs. cryosurgery for the treatment of hyperkeratotic actinic keratosis. J Eur Acad Dermatol Venereol. 2015;29:881–889.
PubMed Web of Science ®Google Scholar
Gupta AK, Paquet M, Villanueva E, et al. Interventions for actinic keratoses. Cochrane Database Syst Rev. 2012;12:CD004415.
PubMed Web of Science ®Google Scholar
LEO Pharma. Picato^® (ingenol mebutate) gel, 0.015%, 0.05% [Internet]. Prescribing information; [cited 2015 Aug 10]. Available from: http://www.picato.com/_pdf/PrescribingInformation.pdf
Google Scholar
Gupta AK, Paquet M. Ingenol mebutate: a promising treatment for actinic keratoses and nonmelanoma skin cancers. J Cutan Med Surg. 2013;17:173–179.
PubMed Web of Science ®Google Scholar
Martin G, Swanson N. Clinical findings using ingenol mebutate gel to treat actinic keratoses. J Am Acad Dermatol. 2013;68:S39–48.
PubMed Web of Science ®Google Scholar
Tzogani K, Nagercoil N, Hemmings RJ, et al. The European medicines agency approval of ingenol mebutate (Picato) for the cutaneous treatment of non-hyperkeratotic, non-hypertrophic actinic keratosis in adults: summary of the scientific assessment of the committee for medicinal products for human use (CHMP). Eur J Dermatol. 2014;24:457–463.
PubMed Web of Science ®Google Scholar

• Overview of the data leading to European approval of ingenol mebutate.

Anderson L, Schmieder GJ, Werschler WP, et al. 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;60:934–943.
PubMed Web of Science ®Google Scholar
Anderson L, Jarrett M, Schmieder G, et al. Tolerability and pharmacokinetics of ingenol mebutate 0.05% gel applied to treatment areas up to 100 cm2 on the forearm(s) of patients with actinic keratosis. J Clin Aesthet Dermatol. 2014;7:19–29.
PubMedGoogle Scholar

•• Study highlighting the lack of systemic bioavailability of ingenol mebutate.

Berman B, Goldenberg G, Hanke W, et al. Efficacy and safety of ingenol mebutate 0.015% gel 3 weeks after cryosurgery of actinic keratosis: 11-week results. J Drugs Dermatol. 2014;13:154–160.
PubMed Web of Science ®Google Scholar
Berman B, Nestor MS, Newburger J, et al. Treatment of facial actinic keratoses with aminolevulinic acid photodynamic therapy (ALA-PDT) or ingenol mebutate 0.015% gel with and without prior treatment with ALA-PDT. J Drugs Dermatol. 2014;13:1353–1356.
PubMed Web of Science ®Google Scholar
Bettencourt MS. Use of ingenol mebutate gel for actinic keratosis in patients in a community dermatology practice. J Drugs Dermatol. 2014;13:269–273.
PubMed Web of Science ®Google Scholar
Dosik JS, Damstra M, Udell C, et al. Evaluation of the skin sensitization, photoirritation, and photoallergic potential of ingenol mebutate gel in healthy volunteers. J Clin Aesthet Dermatol. 2014;7:35–42.
PubMedGoogle Scholar
Garbe C, Basset-Seguin N, Poulin Y, et al. Safety of follow-up field application of ingenol mebutate 0.015% gel for actinic keratoses on face and scalp. J Am Acad Dermatol. 2015;72(Suppl 1):AB191.
Google Scholar

• Study investigating repeat dosing with ingenol mebutate.

Goldenberg G, Berman B. Assessment of local skin reactions with a sequential regimen of cryosurgery followed by ingenol mebutate gel, 0.015%, in patients with actinic keratosis. Clin Cosmet Investig Dermatol. 2015;8:1–8.
PubMed Web of Science ®Google Scholar
Lebwohl M, Swanson N, Anderson LL, et al. Ingenol mebutate gel for actinic keratosis. N Engl J Med. 2012;366:1010–1019.
PubMed Web of Science ®Google Scholar

•• Pivotal Phase 3 study of ingenol mebutate in patients with actinic keratosis (AK).

Pellacani G, Peris K, Guillen C, et al. A randomized trial comparing simultaneous versus sequential field treatment of actinic keratosis with ingenol mebutate on two separate areas of the head and body. J Eur Acad Dermatol Venereol. 2015; epub ahead of print. DOI:10.1111/jdv.13211.
Web of Science ®Google Scholar

• Study comparing simultaneous dosing versus sequential dosing for lesions in different anatomical locations.

Samorano LP, Torezan LA, Sanches JA. Evaluation of the tolerability and safety of a 0.015% ingenol mebutate gel compared to 5% 5-fluorouracil cream for the treatment of facial actinic keratosis: a prospective randomized trial. J Eur Acad Dermatol Venereol. 2015;29:1822–1827.
PubMed Web of Science ®Google Scholar

•• Study comparing ingenol mebutate and 5-fluorouracil for the treatment of AK.

Siller G, Gebauer K, Welburn P, et al. PEP005 (ingenol mebutate) gel, a novel agent for the treatment of actinic keratosis: results of a randomized, double-blind, vehicle-controlled, multicentre, phase IIa study. Australas J Dermatol. 2009;50:16–22.
PubMed Web of Science ®Google Scholar
Gillespie SK, Zhang XD, Hersey P. Ingenol 3-angelate induces dual modes of cell death and differentially regulates tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in melanoma cells. Mol Cancer Ther. 2004;3:1651–1658.
PubMed Web of Science ®Google Scholar
Ogbourne SM, Suhrbier A, Jones B, et al. Antitumor activity of 3-ingenyl angelate: plasma membrane and mitochondrial disruption and necrotic cell death. Cancer Res. 2004;64:2833–2839.
PubMed Web of Science ®Google Scholar

• Description of the novel mechanism of action of ingenol mebutate.

Challacombe JM, Suhrbier A, Parsons PG, et al. Neutrophils are a key component of the antitumor efficacy of topical chemotherapy with ingenol-3-angelate. J Immunol. 2006;177:8123–8132.
PubMed Web of Science ®Google Scholar
Kedei N, Lundberg DJ, Toth A, et al. Characterization of the interaction of ingenol 3-angelate with protein kinase C. Cancer Res. 2004;64:3243–3255.
PubMed Web of Science ®Google Scholar
Hampson P, Chahal H, Khanim F, et al. PEP005, a selective small-molecule activator of protein kinase C, has potent antileukemic activity mediated via the delta isoform of PKC. Blood. 2005;106:1362–1368.
PubMed Web of Science ®Google Scholar
Hampson P, Kavanagh D, Smith E, et al. The anti-tumor agent, ingenol-3-angelate (PEP005), promotes the recruitment of cytotoxic neutrophils by activation of vascular endothelial cells in a PKC-delta dependent manner. Cancer Immunol Immunother. 2008;57:1241–1251.
PubMed Web of Science ®Google Scholar
Cozzi SJ, Ogbourne SM, James C, et al. Ingenol mebutate field-directed treatment of UVB-damaged skin reduces lesion formation and removes mutant p53 patches. J Invest Dermatol. 2012;132:1263–1271.
PubMed Web of Science ®Google Scholar
Li L, Shukla S, Lee A, et al. The skin cancer chemotherapeutic agent ingenol-3-angelate (PEP005) is a substrate for the epidermal multidrug transporter (ABCB1) and targets tumor vasculature. Cancer Res. 2010;70:4509–4519.
PubMed Web of Science ®Google Scholar
3M Health Care Limited. Aldara (Imiquimod): highlights of prescribing information [Internet]. [cited 2015 Aug 10]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/020723s020lbl.pdf
Google Scholar
Allergan Inc. Fluoroplex (fluorouracil) 1% topical cream [Internet]. Prescribing information; [cited 2013 Apr 26]. Available from: http://www.allergan.com/assets/pdf/fluoroplex_pi.pdf
Google Scholar
Almirall Ltd. Solaraze. Summary of product characteristics [Internet]. [cited 2015 Aug 10]. Available from: http://www.medicines.org.uk/emc/medicine/21229/SPC
Google Scholar
Electronic Medicines Consortium (eMC). Solaraze SmPC [Internet]. [cited 2015 July 15]. Available from: http://www.medicines.org.uk/emc/medicine/21229/SPC
Google Scholar
Graceway Pharmaceuticals. Aldara (imiquimod) cream, 5%. Prescribing information [Internet]. [cited 2015 July 16]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020723s022lbl.pdf
Google Scholar
Pharmaderm. Solaraze gel. Prescribing information [Internet]. [cited 2015 Aug 10]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021005s013lbl.pdf
Google Scholar
Food and Drug Administration (FDA). Zyclara (imiquimod) cream, 3.75%. Prescribing information, Graceway Pharmaceuticals [Internet]. [cited 2015 July 27]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/201153s000,022483s001lbl.pdf
Google Scholar
Rosen R, Marmur E, Anderson L, et al. A new, objective, quantitative scale for measuring local skin responses following topical actinic keratosis therapy with ingenol mebutate. Dermatol Ther (Heidelb). 2014;4:207–219.
PubMedGoogle Scholar
Lebwohl M, Shumack S, Stein Gold L, et al. Long-term follow-up study of ingenol mebutate gel for the treatment of actinic keratoses. JAMA Dermatol. 2013;149:666–670.
PubMed Web of Science ®Google Scholar
Berman B, Goldenberg G, Hanke CW, et al. Efficacy and safety of ingenol mebutate 0.015% gel after cryosurgery of actinic keratosis: 12-month results. J Drugs Dermatol. 2014;13:741–747.
PubMed Web of Science ®Google Scholar
European Medicines Agency. Picato: EPAR—public assessment report; [cited 2015 July 10]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002275/human_med_001600.jsp&mid=WC0b01ac058001d124.
Google Scholar
Dodds A, Chia A, Shumack S. Actinic keratosis: rationale and management. Dermatol Ther (Heidelb). 2014;4:11–31.
PubMedGoogle Scholar
Chen K, Yap LM, Marks R, et al. Short-course therapy with imiquimod 5% cream for solar keratoses: a randomized controlled trial. Australas J Dermatol. 2003;44:250–255.
PubMedGoogle Scholar
Lebwohl M, Dinehart S, Whiting D, et al. Imiquimod 5% cream for the treatment of actinic keratosis: results from two phase III, randomized, double-blind, parallel group, vehicle-controlled trials. J Am Acad Dermatol. 2004;50:714–721.
PubMed Web of Science ®Google Scholar
Salasche SJ, Levine N, Morrison L. Cycle therapy of actinic keratoses of the face and scalp with 5% topical imiquimod cream: an open-label trial. J Am Acad Dermatol. 2002;47:571–577.
PubMed Web of Science ®Google Scholar
Gupta AK, Cooper EA, Abramovits W. Zyclara (imiquimod) cream, 3.75%. Skinmed. 2010;8:227–229.
PubMedGoogle Scholar
Chetty P, Choi F, Mitchell T. Primary care review of actinic keratosis and its therapeutic options: a global perspective. Dermatol Ther (Heidelb). 2015;5:19–35.
PubMed Web of Science ®Google Scholar
Li W, Xin H, Ge L, et al. Induction of vitiligo after imiquimod treatment of condylomata acuminata. BMC Infect Dis. 2014;14:329.
PubMed Web of Science ®Google Scholar
Mashiah J, Brenner S. Possible mechanisms in the induction of vitiligo-like hypopigmentation by topical imiquimod. Clin Exp Dermatol. 2008;33:74–76.
PubMed Web of Science ®Google Scholar
Serra MC, Menicanti C, Pennacchioli E, et al. Vulvar vitiligo-like depigmentation and multiple halos of hypomelanosis at the trunk following treatment with imiquimod 5% cream for vulvar condylomata: casual or related events? An Bras Dermatol. 2014;89:806–807.
PubMed Web of Science ®Google Scholar
Cantisani C, Lazic T, Richetta AG, et al. Imiquimod 5% cream use in dermatology, side effects and recent patents. Recent Pat Inflamm Allergy Drug Discov. 2012;6:65–69.
PubMedGoogle Scholar
Micali G, Lacarrubba F, Nasca MR, et al. Topical pharmacotherapy for skin cancer: part I. Pharmacology. J Am Acad Dermatol. 2014;70:965 e1-12; quiz 77-8.
Web of Science ®Google Scholar
Johnson MR, Hageboutros A, Wang K, et al. Life-threatening toxicity in a dihydropyrimidine dehydrogenase-deficient patient after treatment with topical 5-fluorouracil. Clin Cancer Res. 1999;5:2006–2011.
PubMed Web of Science ®Google Scholar
Braathen LR, Morton CA, Basset-Seguin N, et al. Photodynamic therapy for skin field cancerization: an international consensus. International society for photodynamic therapy in dermatology. J Eur Acad Dermatol Venereol. 2012;26:1063–1066.
PubMed Web of Science ®Google Scholar
Dreno B, Amici JM, Basset-Seguin N, et al. Management of actinic keratosis: a practical report and treatment algorithm from AKTeam expert clinicians. J Eur Acad Dermatol Venereol. 2014;28:1141–1149.
PubMed Web of Science ®Google Scholar
Braathen LR, Paredes BE, Saksela O, et al. Short incubation with methyl aminolevulinate for photodynamic therapy of actinic keratoses. J Eur Acad Dermatol Venereol. 2009;23:550–555.
PubMed Web of Science ®Google Scholar
Wiegell SR, Wulf HC, Szeimies RM, et al. Daylight photodynamic therapy for actinic keratosis: an international consensus: International Society for Photodynamic Therapy in Dermatology. J Eur Acad Dermatol Venereol. 2012;26:673–679.
PubMed Web of Science ®Google Scholar
Augustin M, Tu JH, Knudsen KM, et al. Ingenol mebutate gel for actinic keratosis: the link between quality of life, treatment satisfaction, and clinical outcomes. J Am Acad Dermatol. 2015;72:816–821.
PubMed Web of Science ®Google Scholar

• Study highlighting patient satisfaction and quality of life with ingenol mebutate treatment.

Stockfleth E, Peris K, Guillen C, et al. A consensus approach to improving patient adherence and persistence with topical treatment for actinic keratosis. Int J Dermatol. 2015;54:509–515.
PubMed Web of Science ®Google Scholar

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Safety and tolerability of ingenol mebutate in the treatment of actinic keratosis

Bibliography

• Overview of ingenol mebutate.

• Overview of the data leading to European approval of ingenol mebutate.

•• Study highlighting the lack of systemic bioavailability of ingenol mebutate.

• Study investigating repeat dosing with ingenol mebutate.

•• Pivotal Phase 3 study of ingenol mebutate in patients with actinic keratosis (AK).

• Study comparing simultaneous dosing versus sequential dosing for lesions in different anatomical locations.

•• Study comparing ingenol mebutate and 5-fluorouracil for the treatment of AK.

• Description of the novel mechanism of action of ingenol mebutate.

• Study highlighting patient satisfaction and quality of life with ingenol mebutate treatment.

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Safety and tolerability of ingenol mebutate in the treatment of actinic keratosis

Bibliography

• Overview of ingenol mebutate.

• Overview of the data leading to European approval of ingenol mebutate.

•• Study highlighting the lack of systemic bioavailability of ingenol mebutate.

• Study investigating repeat dosing with ingenol mebutate.

•• Pivotal Phase 3 study of ingenol mebutate in patients with actinic keratosis (AK).

• Study comparing simultaneous dosing versus sequential dosing for lesions in different anatomical locations.

•• Study comparing ingenol mebutate and 5-fluorouracil for the treatment of AK.

• Description of the novel mechanism of action of ingenol mebutate.

• Study highlighting patient satisfaction and quality of life with ingenol mebutate treatment.

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