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Drugs in Dermatology: Ameluz (Aminolevulinic Acid Hydrochloride)

Eng, David J.; Grigsby, Phillip M.; Jacob, Sharon E.

Journal of the Dermatology Nurses' Association: November/December 2017 - Volume 9 - Issue 6 - p 319–322
doi: 10.1097/JDN.0000000000000349
DEPARTMENTS: Drugs in Dermatology

ABSTRACT A drug is a substance used to cause a physiological change in the human body. In dermatology, drugs that treat different disorders usually fall into three categories: oral, topical, and biologic medications. Topical drugs include antibacterial and antifungal creams, corticosteroids, and gels. This column will explore the mechanism of action of Ameluz as well as its efficacy, dosage, administration, adverse effects, and alternatives.

David J. Eng, BS, School of Medicine, Loma Linda University, Loma Linda, CA.

Phillip M. Grigsby, BA, School of Medicine, Loma Linda University, Loma Linda, CA

Sharon E. Jacob, MD, Loma Linda University, Loma Linda, CA.

Financial disclosure/conflict of interest: Phillip Grigsby and David Eng have no conflict of interest and no disclosures. Dr. Jacob is founder and CEO of the Dermatitis Academy, a free education portal on contact dermatitis. She served as a coordinating principal investigator on the PREA-1 and PREA-2 Trials supported by Smartpractice USA (Phoenix, AZ) and serves as a consultant to Johnson and Johnson, Inc.

Correspondence concerning this article should be addressed to Sharon E. Jacob, MD, Contact Dermatitis Clinic, Department of Dermatology, Loma Linda University, Faculty Medical Offices, 11370 Anderson Street, Suite 2600, Loma Linda, CA 92354. E-mail: sjacob@contactderm.net

Actinic keratoses (AKs) are premalignant skin lesions that result from abnormal keratinocyte growth in exposed areas due to prolonged exposure to ultraviolet (UV) radiation. They are especially common among light-skinned individuals consistent with Fitzpatrick Types I and II (Type I: always burn and never tan, Type II: burn but minimally tan; Roewert-Huber, Stockfleth, & Kerl, 2007). This common lesion is the reason for nearly a third of the visits to a dermatologist (Salasche, 2000). AKs progress to squamous cell carcinoma in 5%–20% of patients (Braathen et al., 2007).

The two principal methods for treating actinic AKs are lesion-specific destruction and field-directed therapy with topical medications and photodynamic therapy (PDT; Bobyr et al., 2016). Destructive measures include cryosurgery and curettage with electrodessication (Tzogani et al., 2014). Cryosurgery involves destruction of AKs by intense cold, usually by applying liquid nitrogen at a temperature of −5°C (23°F), which cryogenically destroys the cells (Goldberg, Kaplan, Vergilis-Kalner, & Landau, 2010). Curettage is a procedure performed in many different dermatology clinics and involves scraping the lesion to its base with a curette followed by electrodessication. Medical treatments for AKs include 5-fluorouracil cream, diclofenac gel, ingenol mebutate gel, and imiquimod cream (Tzogani et al., 2014). Another therapeutic class includes the photosensitizing drugs containing 5-aminolevulinic acid (5-ALA) that are to be used with phototherapy include ALA HCl, which is to be used with blue-light phototherapy, methyl aminolevulinate, and a 5-ALA patch (Hauschild et al., 2009). These therapies are summarized in Table 1 (Nelson, 2011). Herein, we explore the second-generation topical sensitizer, Ameluz (Leverkusen, Germany), including its mechanism of action, efficacy, dosage, administration, adverse effects, indications, and implications.

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MECHANISM OF ACTION

The main component of Ameluz is a synthetically derived 5-ALA analog, a compound found in eukaryotic cells important for the synthesis of porphyrin (Reinhold et al., 2016). Porphyrin is the main organic compound found in heme, the prosthetic group found in hemoproteins such as hemoglobin, myoglobin, and cytochromes (see Figure 1). These hemoproteins serve an important role in humans, especially as carriers of oxygen and electrons (Peng, Berg, Moan, Kongshaug, & Nesland, 1997).

Neoplastic cells such as the cells involved in AK have an altered metabolic state where they accumulate excess protoporphyrin IX, the immediate precursor to heme (Reinhold et al., 2016). They do this by converting 5-ALA, the main component of Ameluz, into protoporphyrin IX. Protoporphyrin IX is activated by red light of PDT at a wavelength of 630 nm. In the presence of oxygen, this results in the production of reactive oxygen species. This buildup of reactive oxygen species destroys the neoplastic cells, hence serving as an effective way of treating the AK (Tzogani et al., 2014).

FIGURE 1

FIGURE 1

TABLE 1

TABLE 1

Notably, 5-ALA, the main component of Ameluz, is hydrophilic and has difficulty penetrating the outer layer of the epidermis, the stratum corneum, upon application. Past therapies that utilized ALA include Levulan (DUSA Pharmeceuticals, Inc.), an ALA in aqueous solution formulation, and Alacare (Spirig Pharma AG, Egerkingen, Switzerland), a patch containing ALA. Ameluz, a second-generation topical sensitizer used in conjunction with PDT, has been shown to have improved stability in aqueous solution. It uses a lecithin microemulsion as a transdermal delivery system that comes in a gel, which increases penetration of the stratum corneum by increasing the fluidity of lipids in the skin. This microemulsion medium sets Ameluz apart from other ALA photodynamic therapies. It increases the absorption of the drug and allows it to both reach deeper lesions and be distributed more uniformly throughout the lesion (Maisch, Santarelli, Schreml, Babilas, & Szeimies, 2010).

Moreover, it has been shown to be superior to other photodynamic therapies that utilize metabolites of ALA, including methyl-5-aminolevulinate formulations. Dirschka et al. conducted a multicentered, randomized, Phase III trial comparing nanoemulsion/noncolloidal ALA with methyl-5-aminolevulinate and found that it cleared more AKs than the latter (clearance = 78.2% vs. 64.2%, respectively, p < .05; Dirschka et al., 2012).

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EFFICACY, DOSING, AND ADMINISTRATION

The results of the Phase III trial showed that Ameluz resulted in 90.9% complete clearance of AKs compared with the 21.9% clearance in the placebo group 12 weeks after the last PDT treatment. This showed that Ameluz was a statistically effective treatment (p < .0001). After only 12 weeks of the first PDT treatment, Ameluz treatment resulted in 61.8% clearance of AK compared with 9.4% for the placebo group. Most (90.7%) of the patients treated with Ameluz were satisfied with the treatment, and the number of patients with improved skin quality (measured by lack of roughness, dryness, and scales) increased from 14.8% before treatment to 63% after treatment (Reinhold et al., 2016).

Ameluz is applied topically only by a trained healthcare professional. First, the skin lesions need to be wiped with isopropanol or ethanol to decrease the normal lipid barrier of the skin allowing for better penetration and absorption of the medication. A 1-mm layer of Ameluz gel is then applied to the AK area with enough to cover a 5-mm border of surrounding skin. The Ameluz gel is applied to an area no larger than 20 mm2, and no more than 20 g of gel should be used for any one treatment area. Ameluz should not be applied to the eyes, mouth, nostrils, or inside of the ears (U.S. Food and Drug Administration [FDA], 2016).

The gel is then allowed to dry for 10 minutes before an occlusive dressing is applied to the application site. After 3 hours, the dressing is removed and the site is illuminated with red light around 635 nm from a BF-RhodoLED lamp. The lamp needs to deliver a radiation exposure dose of 37 J/cm2 to the skin at a distance of 5–8 cm from the skin surface for 10 minutes. The treated area should not be exposed to sunlight or UV light for 48 hours because Ameluz increases photosensitivity (FDA, 2016). Patients treated with Ameluz and phototherapy must be instructed to keep the treatment area covered with clothing or sunscreen and avoid UV light exposure for 48 hours.

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ADVERSE EFFECTS

During the Phase III trial, all patients given Ameluz reported at least one adverse effect. The adverse effects were all at the application site and included pruritus, erythema, exfoliation, scabs, vesicles, and pain. Most of these reactions were of mild intensity and resolved within 2 weeks (Reinhold et al., 2016). Other less common adverse reactions were headache and problems at the treatment site, including warmth, erosions, paresthesia, and hyperalgesia (Tzogani et al., 2014). Several methods have been developed to decrease the pain associated with this treatment. Although conventional topical anesthetics are used, newer techniques have also been developed, including cold air analgesia where a device that produces cold air cools the treatment area in PDT, such as a cold-air fan (Pagliaro, Elliot, Bulsara, King, & Vinciullo, 2004). Livopan (Linde Gas Therapeutics GmbH, Germany) is nitrous oxide/oxygen mixture that is used as an inhalation analgesia (Fink, Enk, & Gholam, 2015).

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INDICATIONS

Ameluz was approved for the treatment of AKs of mild to moderate intensity (Olsen grades 1–2) appearing on the face and scalp. Treatment with Ameluz is done in conjunction with PDT using a BF-RhodoLED lamp (FDA, 2016).

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CONTRAINDICATIONS

Patients who are sensitive to porphyrins or have a history of porphyria/pseudoporphyria (either from a genetic defect or immune dysregulation that leads to accumulation of porphyrins or pathway metabolites) should not use Ameluz. In addition, Ameluz should not be used on patients who are hypersensitive to any of the ingredients in Ameluz or who have photodermatoses. There are no available data for the risks of using Ameluz in association with pregnancy (FDA, 2016).

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IMPLICATIONS

As a healthcare provider, this therapy is important because it offers a convenient method for nursing staff to treat AKs in a few scheduled visits once a diagnosis and treatment plan has been established. A patient can simply check in and have the visit supervised by the nursing staff independently of a physician. This also offers benefits for patients who struggle with compliance with scheduled medications or AKs when treatment of the entire field is desired, such as topical creams. Patients can simply show up for a few visits and receive an equivalent treatment without the added stress of remembering when to apply their medications.

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CONCLUSION

Ameluz is a great option for patients who have had negative experiences with alternative treatments, such as liquid nitrogen, 5-fluorouracil cream, or the more invasive electrodessication and curettage. Moreover, it is an additional option for patients with difficulty following rigorous treatment regimens. Overall, it is a safe and effective FDA-approved method of treating AKs in conjunction with PDT.

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REFERENCES

Bobyr I., Campanati A., Consales V., Giuliodori K., Scalise A., Offidani A. (2016). Efficacy, safety and tolerability of field treatment of actinic keratosis with ingenol mebutate 0.015 % gel: A single center case series. SpringerPlus, 5, 627. doi:10.1186/s40064-016-2290-6
Braathen L. R., Szeimies R. M., Basset-Seguin N., Bissonnette R., Foley P., Pariser D., Morton C. A. (2007). Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: An international consensus. International Society for Photodynamic Therapy in Dermatology, 2005. Journal of the American Academy of Dermatology, 56, 125–143.
Dirschka T., Radny P., Dominicus R., Mensing H., Bruning H., Jenne L., … AK-CT002 Study Group. (2012). Photodynamic therapy with BF-200 ALA for the treatment of actinic keratosis: Results of a multicentre, randomized, observer-blind phase III study in comparison with a registered methyl-5-aminolaevulinate cream and placebo. British Journal of Dermatology, 166(1), 137–146.
Fink C., Enk A., Gholam P. (2015). Photodynamic therapy—Aspects of pain management. Journal of the German Society of Dermatology, 13(1), 15–22. doi:10.1111/ddg.12546
Goldberg L. H., Kaplan B., Vergilis-Kalner I., Landau J. (2010). Liquid nitrogen: Temperature control in the treatment of actinic keratosis. Dermatologic Surgery, 36(12), 1956–1961.
Hauschild A., Stockfleth E., Popp G., Borrosch F., Bruning H., Dominicus R., Szeimies R. M. (2009). Optimization of photodynamic therapy with a novel self-adhesive 5-aminolaevulinic acid patch: Results of two randomized controlled phase III studies. British Journal of Dermatology, 160(5), 1066–1074.
Maisch T., Santarelli F., Schreml S., Babilas P., Szeimies R. M. (2010). Fluorescence induction of protoporphyrin IX by a new 5-aminolevulinic acid nanoemulsion used for photodynamic therapy in a full-thickness ex vivo skin model. Experimental Dermatology, 19(8), e302–e305.
Nelson C. G. (2011). Diclofenac gel in the treatment of actinic keratoses. Therapeutics and Clinical Risk Management, 7, 207–211.
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Reinhold U., Dirschka T., Ostendorf R., Aschoff R., Berking C., Philipp-Dormston W. G., Szeimies R. M. (2016). A randomized, double-blind, phase III, multicentre study to evaluate the safety and efficacy of BF-200 ALA (Ameluz®) vs. placebo in the field-directed treatment of mild-to-moderate actinic keratosis with photodynamic therapy (PDT) when using the BF-RhodoLED® lamp. British Journal of Dermatology, 175(4), 696–705. doi:10.1111/bjd.14498
Roewert-Huber J., Stockfleth E., Kerl H. (2007). Pathology and pathobiology of actinic (solar) keratosis—An update. British Journal of Dermatology, 157(Suppl. 2), 18–20.
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Tzogani K., Straube M., Hoppe U., Kiely P., O’Dea G., Enzmann H., Pignatti F. (2014). The European Medicines Agency approval of 5-aminolaevulinic acid (Ameluz) for the treatment of actinic keratosis of mild to moderate intensity on the face and scalp: Summary of the scientific assessment of the Committee for Medicinal Products for Human Use. Journal of Dermatological Treatment, 25(5), 371–374.
U.S. Food and Drug Administration. (2016). Ameluz-FDA. Retrieved from http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208081s000lbl.pdf
Keywords:

Ameluz; Actinic Keratoses; 5-Aminolevulinic Acid; Photodynamic Therapy; Squamous Cell Carcinoma

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