Ingenol mebutate

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Structural formula
Structure of ingenol mebutate
General
Non-proprietary name Ingenol mebutate
other names
  • (1a R , 2 S , 5 R , 5a S , 6S, 8a S , 9 R , 10a R ) -5,5a-dihydroxy-4- (hydroxymethyl) -1,1,7,9-tetramethyl-11-oxo -1a, 2,5,5a, 6,9,10,10a-octahydro-1 H -2,8a-methanocyclopenta [ a ] cyclpropa [ e ] [10] annulene-6-yl (2 Z ) -2-methylbut -2-enoate
  • 3-angeloylin enol
  • Ingenol-3-angelat
  • I3A
  • PEP005
Molecular formula C 25 H 34 O 6
Brief description

amorphous substance

External identifiers / databases
CAS number 75567-37-2
EC number 688-125-2
ECHA InfoCard 100.214.695
PubChem 6918670
ChemSpider 21171549
DrugBank DB05013
Wikidata Q426386
Drug information
ATC code

D06 BX02

Drug class

Antineoplastic

properties
Molar mass 430.53 g · mol -1
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
no GHS pictograms
H and P phrases H: no H-phrases
P: no P-phrases
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Ingenol mebutate is a substance from the chemical group of diterpenes that occurs in the garden spurge ( Euphorbia peplus ) . It can be used as a medicinal substance for the topical treatment of actinic keratosis , a skin disease and precancerous condition caused by intensive exposure to UV radiation . A gel containing ingenol mebutate has been approved in the USA since January 2012. In the European Union, it was approved from November 2012 to February 2020. Due to an increased risk of skin cancer, the risk-benefit ratio is assessed as negative.

Occurrence and effect

Ingenol mebutate is a substance found in the aerial parts of garden milkweed .

Ingenol mebutate belongs to the esters of a group of diterpenes (Ingenane, Tigliane, Daphnane) which play an important role in the etiology of tumor development.

Ingenol mebutate is applied once to the affected skin areas on two (trunk, extremities) or three (face, scalp) consecutive days, where it leads to epidermal necrosis . The exact mechanism of action is not known. In-vivo and in-vitro experiments indicate a dual mechanism: on the one hand, a direct cytotoxic effect and, on the other hand, the promotion of an inflammatory reaction through the localized production of proinflammatory cytokines and chemokines and through immigration of immunocompetent cells. The undesirable effects observed very frequently (i.e. in more than 10 percent of those treated) were local, including severe, skin reactions at the application site, such as erythema , exfoliation , scabs, swellings and pustules.

Early benefit assessment

In Germany, since 2011, newly approved drugs with new active ingredients have to undergo an " early benefit assessment " by the Federal Joint Committee (G-BA) based on Section 35a SGB ​​V ( AMNOG ) . The additional benefit compared to an “appropriate” comparator therapy is assessed in a process specified in the procedural rules. The G-BA then determines the degree of additional benefit in a resolution. Based on this, pharmaceutical entrepreneurs and the central association of statutory health insurance companies negotiate the drug price. This also applies to ingenol mebutate. An initial assessment by the Institute for Quality and Efficiency in Health Care (IQWiG) took place in April 2013, the G-BA passed a resolution in July 2013, as well as the agreement of a reimbursement amount that was valid for health insurance companies in Germany from January 15, 2014 . Ingenol mebutate gel is "the first preparation for topical use that has undergone the early benefit assessment procedure and the subsequent reimbursement negotiations."

Security aspects

In 2015, the FDA warned of the potential for severe allergic reactions and herpes zoster, highlighting the need for careful and appropriate use to minimize unwanted skin reactions.

In September 2019, the European Medicines Agency (EMA) initiated a safety review of ingenol mebutate. The investigation was initiated at the request of the European Commission (EC) after data from several studies showed an increased number of skin cancer cases, including cases of squamous cell carcinoma , in patients using Picato . In January 2020, the manufacturer announced that the approval had been suspended, which the European Commission had ordered as a precautionary measure to initially continue the review of the skin cancer risk. At the request of the previous authorization holder, the authorization to place Picato on the European Union was revoked on February 11, 2020 .

On April 20, 2020, the European Medicines Agency finished its review of Picato, with a conclusion that the risks of the medicine outweigh the benefits. Accordingly, compared to imiquimod (another drug against actinic keratosis) ingenol mebutate shows an increased incidence of skin cancer, especially squamous cell carcinoma, in the treated skin areas. Furthermore, there is no permanent therapeutic effect. There are also other treatment options available for actinic keratosis.

No such action has been taken in the United States as of January 2020.

Trade names

Picato (USA, EU), Ingenol Mebutate Perrigo (USA)

Web links

Individual evidence

  1. ↑ a b c data sheet Ingenol-3-angelate, ≥98% (HPLC), amorphous from Sigma-Aldrich , accessed on August 11, 2011 ( PDF ).
  2. ↑ Press release: LEO Pharma announces that Picato® (ingenol mebutate) gel has been approved by US FDA for once-daily, 2 or 3 day treatment of actinic keratoses ( Memento from February 22, 2017 in the Internet Archive ), from January 26, 2012 , accessed February 21, 2017.
  3. ↑ T. Dingermann, K. Hiller, G. Schneider, I. Zündorf: Schneider drug drugs. 5th edition, Elsevier 2004, ISBN 3-8274-1481-4 . P. 22.
  4. ↑ LEO Laboratories Ltd: Technical Information Picato , as of November 15, 2019.
  5. ↑ Additional benefit of ingenol mebutate is not proven IQWiG press release from April 15, 2013, accessed on April 16, 2013.
  6. ↑ Benefit assessment procedure for the active ingredient ingenol mebutate , July 4, 2013.
  7. ↑ Announcement of a resolution of the Federal Joint Committee on an amendment to the Drugs Directive (AM-RL): Annex XII - Resolutions on the benefit assessment of drugs with new active ingredients according to Section 35a of the fifth book of the Social Code (SGB V) - Ingenolmebutat dated: 04.07.2013 Federal Ministry of Health BAnz AT 08/01/2013 B5
  8. ↑ First reimbursement amount for topical drug (Picato®) agreed , joint press release from GKV-Spitzenverband and LEO Pharma GmbH, Berlin, January 15, 2014.
  9. ↑ FDA Safety Announcement , August 21, 2015.
  10. ↑ Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 2-5 September 2019 , EMA dated September 6, 2019, accessed on September 11, 2019
  11. ↑ Rote-Hand-Brief : Picato (ingenol mebutate) - Caution when treating patients with a history of skin cancer , on September 17, 2019 on the BfArM website.
  12. ↑ Picato (ingenol mebutate): The approvals are suspended as a precautionary measure, the review of the skin cancer risk will continue , on January 20, 2020 on the BfArM website.
  13. ↑ Rote-Hand-Brief: Picato (ingenol mebutate): Approvals are suspended due to the risk of malignant skin changes , on January 27, 2020 on the BfArM website.
  14. ↑ Risk assessment method - Picato® (ingenol mebutate): Assessment of the risk-benefit ratio. Federal Institute for Drugs and Medical Devices, April 20, 2020, accessed on April 21, 2020 .
  15. ↑ European marketing of Picato suspended while skin cancer risk reviewed , the pharmaletter, January 17, 2020 (English).