Botulinum Toxin Update

On February 1, the US Food and Drug Administration (FDA) gave clearance for another botulinum toxin – prabotulinumtoxinA (DWP-450) to be sold in the US as Jeuveau.1 This had been preceded by approval in Canada in August 2018.2 With the possible approval of more toxins in future, it may be prudent to consider the ‘new’ toxins and review developments in this field. One of the confusing issues is that the same toxin may appear with different names and be distributed by different companies with alliances with other companies. This article will summarise the current status of these developments, without going into the minutiae regarding the pharmacology of these drugs. ‘New’ toxins? There are several botulinum toxins already on the market internationally. Jeuveau is not ‘new’; as with most of the toxins coming through, it is manufactured in South Korea. The South Korean manufacturer is Daewoong Pharmaceuticals and this particular toxin has been available in Korea since 2014 and is known in other international markets as Nabota.3 Daewoong distributes the toxin in Asia, South America and Central America; Evolus has the distribution rights for Canada, US, Europe, Japan, South Africa, Australia and Russia.4 The toxin has undergone safety and efficacy trials,5,6 which do not appear to indicate inferiority to that of Botox. Comparative studies have also suggested that there appears to be a 1:1 equipotential dosage between the two.7,8 The next toxin that will probably apply for FDA approval in 2020 will be from Revance Therapeutics, known as Daxi – daxibotulinumtoxinA (RT002).9 This was initially developed as a ‘topical toxin’, however after many years of research and investment this has been abandoned (see later for topical toxins). Revance, a US-based company, has developed this toxin to include a unique stabilising positively charged peptide (5Kd); the studies often quoted are the Belmont,10 SAKURA 1 and SAKURA 2.11 In summary, the data appears to indicate that 7174% of the treated subjects had a response rate at 120 days.11 These results have been presented as evidence for a superior longevity of this particular toxin; however, the study compared 40 units of Daxi to 20 units of Botox. Other comparative trials of 120 units of abobotulinumtoxinA (Azzalure) and 40 units onabotulinumtoxinA (Botox) both showed similar responses to 40 units of Daxi. An interesting aspect of this is that 20 units of Botox has 0.17ng of botulinum toxin, whereas 40 units of Daxi has 0.18ng botulinum toxin.12 This difference in molecular content may be an indication of different molecular bioavailability and response between the two toxin formulations. We await further clarification on this new toxin. Another South Korean toxin that is expected to submit approval in the latter part of 2020 following the Phase III trials is letibotulinumtoxinA, currently available as Botulax.13 It is already approved in several Asian countries and is also marketed as Zentox.14 This toxin is produced by Hugel, and in Europe and the US it will be distributed by Croma.15 Studies on letibotulinumtoxinA are in progress and further information is awaited.

Consultant plastic, reconstructive and aesthetic surgeon Mr Dalvi Humzah outlines Other toxins There are several other toxins produced in countries the development of new and existing toxins to supply local medical needs, however these have not penetrated the wider aesthetic market (Figure 1). ChinaTox and Relatox appear to have gelatin as excipients, which have been reported to cause localised allergic reactions.16,17 Another South Korean toxin with a Phase III trial in progress is produced by Huons Global – called Hutox.18 It is already available in Asia and awaiting further public information. One of the main toxin producers in South Korea is Medytox; a company that produces three different botulinum toxin A formulations:19 • Neuronox: already available in Asia, with approval in Brazil and Mexico • Innotox (nivobotulinumtoxinA): the first liquid botulinum toxin (see later) • Coretox: a pure botulinum toxin similar to incobotulinumtoxinA (Bocouture) In an interesting strategic move in 2013, Allergan licensed the rights to Medytox’s toxin development programme, which granted Allergan exclusive rights, worldwide outside of Korea, to develop and, if approved, commercialise neurotoxin product candidates in development, including the liquid-injectable product.20 How this will be introduced into Europe and the US awaits to be seen. Country Name Other names China ChinaTox • Prosigne – Brasil • Redux – Peru • Lantox – Russia • Lanzox – Indonesia Russia Relatox India Botogenie Iran Masport Figure 1: Locally-manufactured botulinum toxin. Table courtesy of Professor Andy Pickett.

Liquid injectable botulinum toxin (LIBT) The first liquid injectable toxin, which consists of a liquid formulation as opposed to powder, was Myobloc (rimabotulinumtoxinB), which is generally used medically and is rarely used in the aesthetic arena.21 Innotox, mentioned above, was developed by Medytox and is commercially available in Asia. In September 2018 Allergan confirmed it would begin phase III clinical trials of the LIBT it licensed from Medytox, with hopes to get US marketing approval in 2022.22 Galderma has made an investment and built a factory to synthesise their own LIBT, currently known as QM114. A phase II trial was initiated in 2014 and further developments are awaited.23,24 How the medical aesthetic practitioner will view these formulations and what benefit they will confer to clinical practice awaits evaluation. Ease of use and not having to dissolve the toxin may be regarded as a time-saving benefit.

Topical toxins The term ‘topical toxin’ is actually a misnomer – the technology is dependent on a transdermal delivery system to allow a botulinum toxin molecule to be carried through the skin. Revance was the leading company trying to develop its system (RT001), however, after several years the company has now abandoned its work on a topical application and is concentrating on its own botulinum toxin A, as discussed previously. In 2016, Allergan announced that it acquired Anterios Inc., which was also developing a next generation delivery system and botulinum toxin. Through this acquisition Allergan acquired the potential development and commercialisation related to NDS, Anterios’ proprietary platform delivery technology that enables local, targeted delivery of neurotoxins through the skin without the need for injections. In addition to NDS, Allergan also acquired global rights to ANT-1207; an investigational botulinum toxin type A.25 A UK-based company, Malvern Cosmeceutics, and another US-based company, Transdermal Corp based in Birmingham, Michigan, have also not reported any progress beyond pre-clinical studies on their transdermal delivery systems at the time of publication.26,27 Although attractive to patients and practitioners, as this may negate the use of injection delivery, the technology and control of delivery is still not yet confirmed, despite years of development. Future developments in nano-technology may deliver this possibility, however it has not been achieved yet, according to public knowledge.

New technology Currently, botulinum toxin is derived from the fermentation of clostridium botulinum – a spore-producing bacterium. Following purification, the botulinum toxin subtype is derived in the laboratory. Using recombinant gene technology, researchers in Ipsen have now modified the genes in E. coli. 28 This produces the single serotype A toxin through this process without contamination from the mixed toxin produced by the clostridium strains. Further details on how and when this product will be available are awaited.

Toxin serotypes Pharmacologically, there are at least 51 different serotypes of botulinum toxin. Type A and B that are available, or in development, have been discussed above. Recently there has been interest in botulinum toxin type E, as it is reported to have a short duration of effect of a few weeks. However, it may require activation and larger doses may be required to have a clinical effect.29 The type E toxin also cleaves SNAP25, however this occurs at a different point to that of type A toxin.29 In September 2018, Allergan acquired the global rights to biotechnology company Bonti’s development programme, consisting of two botulinum neurotoxin serotype E (BoNT/E) programmes currently in Phase II development, EB-001A (aesthetic) and EB-001T (therapeutic). The active ingredient in both programmes, EB-001, is a novel botulinum neurotoxin serotype E (BoNT/E) with a unique clinical profile, characterised by a rapid onset of action within 24 hours and a two-to-four week duration of effect.30 Bonti recently announced results of the first clinical study of EB-001 in glabellar frown lines. The study both suggested the safety and efficacy of the differentiated profile. The company is expected to launch this in 2024.31 Ipsen has also reported that a development programme for its own botulinum toxin E is in the pipeline.32 The clinical aesthetic use and acceptance of these short duration serotypes remains to be clarified.

Aesthetic treatment Currently, approved aesthetic use of botulinum toxins include upper facial lines (glabellar/forehead/crow’s feet), while other areas remain off-label. Phase II trials are ongoing on the use of Botox for the treatment of masseter hypertrophy and initial results were reported at a recent toxin conference in Copenhagen.33 Masseter volume and hypertrophy were significantly reduced at 90 days and maintained for six months after two treatments. Allergan is also conducting a phase II trial in the treatment of platysmal hypertonicity, which is ongoing with preliminary results expected this year.34 Studies on the established toxins are looking closely at the effects of dosage, dilution volumes and number of injection factors, as well as individual genetic variation in receptor activity. Outcomes of these studies will enable the practitioner to tailor the treatment to their patients.

Practicalities for the medical practitioner With these new developments, and the possible approval of other toxins, what will it mean to the clinician? In my opinion, from a clinical standpoint, studies indicate very little difference between the different manufactured botulinum toxin as

In my opinion, from a clinical standpoint, studies indicate very little difference between the different manufactured botulinum toxins

they all suggest that they act in the same way and cleave SNAP25 at the same position.35 The clinical effect of onset and duration appears to be related to the bioavailability of that particular toxin. The units used by different manufacturers are not necessarily interchangeable. This makes comparisons more difficult and the molecular potency of these toxins will be more important than the stated units.35 Certainly, there will be a choice of several different distributors/ manufacturers on the market; it may also lead to greater competition between products available in the sector. Evolus has already stated that its aim in the US market is to be at least 25% lower in its price profile than the established toxin distributors.36 In Asia, Medytox has plans to enter the Chinese market in the latter half of 2019 with its Neuronox product.37 According to Dr Patrick Huang, who has analysed and researched the worldwide toxin market, it has a low-price strategy to enter into active competition within the Chinese market. At a presentation on a review of the emerging toxins in Asia at IMCAS 2019, he suggested Nueronox would enter the Chinese market at a significantly reduced cost to that of Botox and BTXA (Chinese toxin).38 Would such a strategy have any effect on the market structure?

According to Dr Huang, there will certainly be competition which, he explained at his IMCAS presentation, has already been evident in the Korean market.38 Whether potential lower prices attract clinicians to switch from their established toxins and if such cost savings will be passed on to the end user (the patient) remains to be seen. In my opinion, how the European and UK market will react to this strategy will lead to interesting and exciting times ahead for manufacturers, distributors, clinicians and patients alike.

Acknowledgement: Many thanks to all my colleagues who have discussed different aspects of this update; in particular, Professor Andy Pickett, for constantly updating me, and Dr Patrick Huang, for sharing his data.

Mr Dalvi Humzah is a consultant plastic surgeon and delivers his clinical practice through PD Surgery in the West Midlands and The London Welbeck Hospital. He is also director of the award-winning Dalvi Humzah Aesthetic Training and clinical director of Derma-Seal Ltd. He has wide experience in teaching and training nationally and internationally.

REFERENCES

1. FDA, Research C for DE and. Drug Approvals and Databases – Drug Trials Snapshot: Jeuveau (US: FDA, 2019) <https://www.fda.gov/Drugs/InformationOnDrugs/ucm630567.htm> 2. Pulse, US FDA resumes review of Daewoong Pharm’s botox Nabota, decide by Feb (Korea: Pulse, 2018) <https://pulsenews.co.kr/view.php?year=2018&no=549378> 3. Pulse, Daewoong Pharma’s Nabota gets US FDA approval for frown lines treatment (Korea: Pulse, 2019) <https://pulsenews.co.kr/view.php?year=2019&no=71047> 4. Equities, Evolus files for IPO ahead of potential 2018 approval for Botox alternative (US: Equities, 2018) <https://www.equities.com/news/evolus-files-for-ipo-ahead-of-potential-2018-approval-forbotox-alternative> 5. Evolus, A phase III study to demonstrate the safety and efficacy of DWP-450 to treat glabellar lines – EV001, February 2019 <https://clinicaltrials.gov/ct2/show/study/NCT02334423> 6. Evolus, A phase III study to demonstrate the safety and efficacy of DWP-450 to treat glabellar lines – EV002, February 2019 <https://clinicaltrials.gov/ct2/show/NCT02334436> 7. Daewoong Pharmaceuticals, Safety and Efficacy of NABOTA in Treatment of Essential

Blepharospasm, October 2016 <ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02947815> 8. Rungsima Wanitphakdeedecha, Chanida Ungaksornpairote, Arisa Kaewkes, Angkana

Sathaworawong, Nittaya Lektrakul & Woraphong Manuskiatti, ‘The efficacy of two formulations of botulinum toxin type A for masseter reduction: a split-face comparison study’, Journal of

Dermatological Treatment, Volume 28, 2017, Issue 5, <https://www.tandfonline.com/doi/full/10.1080/ 09546634.2016.1263382> 9. Modern Medicine Network, Update on pipeline neuromodulator for daxibotulinumtoxinA (US:

The Aesthetics Channel, 2018) <https://www.aestheticchannel.com/neurotoxins-facial-aesthetics/ update-pipeline-neuromodulator-daxibotulinumtoxina> 10. Carruthers J, Solish N, Humphrey S, et al., ‘Injectable DaxibotulinumtoxinA for the Treatment of

Glabellar Lines’, Dermatologic Surg. 2017;43(11), pp.1321-1331. 11. Solish, Nowell MD; Bertucci, Vince MD; Humphrey, Shannon MD et al., ‘Two phase 3, randomized, double-blind, placebo-controlled, multicenter trials to evaluate the efficacy and safety of daxibotulinumtoxinA for injection to treat moderate to severe glabellar lines (SAKURA 1 and 2)’,

Journal of the American Academy of Dermatology, 79(3) Supplement 1:AB306, September 2018. 12. Gary Monheit, Sakura 1 & 2, IMCAS, February 2018 <http://www.revance.com/pdfs/Sakura_1_2_

TLR_Presentation_at_IMCAS_3_Feb_18_Gary_Monheit.pdf> 13. Hugel, Evaluate the safety and efficacy of Botulax as compared to Botox in subject with moderate to severe crow’s feet lines, January 2018 <https://clinicaltrials.gov/ct2/show/

NCT03408236?intr=botulax&rank=3> 14. Drugs.com, Botulinum toxin A (US: Drugs.com, 2019) <https://www.drugs.com/international/ botulinum-a-toxin.html> 15. Croma, New global brand campaign by Croma (Canada: Croma, 2017) <https://at.croma.at/homeen-ca/news-and-events/news/> 16. Frevert J, Ahn KY, Park MY, Sunga O., ‘Comparison of botulinum neurotoxin type A formulations in

Asia’, Clin Cosmet Investig Dermatol. (2018)11, pp.327-331. 17. Pickett A, Mewies M, ‘Serious issues relating to the clinical use of unlicensed botulinum toxin products’, Journal of the American Academy of Dermatology <https://www.jaad.org/article/S01909622(09)00025-5/fulltext> 18. Huons, The Safety and Efficacy Study of Hutox Versus Botox® in Subject With

Moderate to Severe Glabellar Lines, April 2018 <https://clinicaltrials.gov/ct2/ results?cond=&term=hutox&cntry=&state=&city=&dist> 19. Medytox, Botulinum toxin product (South Korea, Medytox, 2019) <http://www.medytox.com/page/ meditoxin_en?site_id=en> 20. Business Wire, Allergan Inc and Medytox Inc to enter licensing agreement (US: Business Wire, 2013) <https://www.businesswire.com/news/home/20130925006570/en/Allergan-Medytox-Enter-

Licensing-Agreement> 21. Myobloc, Turn to a brighter future (US: Myobloc, 2018) <https://www.myobloc.com> 22. Seo KK. Innotox®: “Botulinum toxin endorsed by BOTOX®” In: Seo KK, editor. Botulinum Toxin for Asians. 1st ed. Singapore: Springer Science+Business Media; 2017. p. 19. https://www. thepharmaletter.com/article/allergan-closes-65-million-deal-with-medytox 23. Aesthetics, Galderma begin trials for liquid form of botulinum toxin (UK: Aesthetics, 20140 https:// aestheticsjournal.com/news/galderma-begin-trials-for-liquid-form-of-botulinum-toxin 24. Stated by Lin, Xiaoming, Product analysis – toxins: roundtable with the participation of Galderma (IMCAS, 2019) <https://www.imcas.com/en/attend/imcas-world-congress-2019/program/ session/50505> 25. Allergan, Allergan acquires medical dermatology and aesthetic medicine company Anterios to expand neurotoxin pipeline (US: Allergan, 2016) <https://www.allergan.com/news/news/thomsonreuters/allergan-acquires-medical-dermatology-and-aestheti> 26. Malvern Cosmeceutics, Development pipeline (UK: Malvern Cosmeceutics, 2015) <http:// malverncosmeceutics.com/development_pipeline.html> 27. Transdermal Corp, Intellectual Property (US: Transdermal Corp, 2016) <https://www. transdermalcorp.com/patents> 28. Fonfria E, Maignel J, Lezmi S, et al., ‘The expanding therapeutic utility of botulinum neurotoxins’,

Toxins (Basel). 2018; 10(5), pp.1-27. 29. Duff JT, Wright GG, Yarinsky A, ‘Activation of Clostridium botulinum type E toxin by trypsin, J

Bacteriol, (1956), pp.455-460. 30. PharmaTimes, Allergan snaps up Bonti (US: Pharma Times, 2018) <http://www.pharmatimes.com/ news/allergan_snaps_up_bonti_1252557> 31. Dermatology Times, Two pipeline neurotoxins make strides (US: Dermatology Times, 2018) <https://www.dermatologytimes.com/fda/two-pipeline-neurotoxins-make-strides> 32. Elena Fonfria, Jacquie Maignel, Stephane Lezmi, ‘The Expanding Therapeutic Utility of Botulinum

Neurotoxins’, Toxins 2018, 10(5), 208 <https://doi.org/10.3390/toxins10050208> 33. International Neurotoxin Association, TOXINS 2019: Basic Science and Clinical Aspects of

Botulinum and Other Neurotoxins, 16-19 January, 2019, Copenhagen, Denmark. 34. Allergan, Allergan highlights key growth drivers for medical aesthetics, (US: Allergan, 2018) <https://www.allergan.com/news/news/thomson-reuters/allergan-highlights-key-growth-drivers-formedical> 35. Dover JS, Monheit G, Greener M, Pickett A., ‘Botulinum Toxin in Aesthetic Medicine: Myths and

Realities’, Dermatol Surg. 2018;44(2), pp.249-260. 36. Reuters, FDA approves cheaper Botox rival to treat frown lines (US: Reuters, 2019) <https:// www.reuters.com/article/us-evolus-fda/fda-approves-cheaper-botox-rival-to-treat-frown-linesidUSKCN1PQ5WK> 37. Jae-hyeon SO, Medytox in final stage to sell facial filler in China, (South Korea: Korea Biomedical

Review, 2018) 38. Stated by Huang, Patrick, ‘A review of the emerging toxins in Asia (Chinese, Korea & others from

Asia) (IMCAS, 2019) <https://www.imcas.com/en/attend/imcas-world-congress-2019/program/ session/50713>

A PARTNERSHIP YOU CAN COUNT ON

CELEBRATING OUR 10TH ANNIVERSARY IN AESTHETIC TREATMENTS

Azzalure is made in the UK and has been used for 20 million glabellar lines treatments in Europe alone.1,2 Here’s to another decade of natural-looking results and high patient satisfaction.3

Prescribing information can be found overleaf

References: 1. Azzalure SPC 2018. 2. Data on File MA-39613. 3. Molina B et al. J Eur Acad Dermatol Venereol 2015;29(7):1382–8.

Presentation: Botulinum toxin type A (Clostridium botulinum toxin A haemagglutinin complex) 125 Speywood units of reconstituted solution (powder for solution for injection) Indications: Temporary improvement in appearance of moderate to severe: • Glabellar lines seen at maximum frown, and/or • lateral canthal lines (crow’s feet lines) seen at maximum smile in adult patients under 65 years, when severity of these lines has an important psychological impact on the patient. Dosage & Administration: Azzalure should only be administered by physicians with appropriate qualifications and expertise in this treatment and having the required equipment. Botulinum toxin units are different depending on the medicinal products. Speywood units are specific to this preparation and are not interchangeable with other botulinum toxins. Reconstitute prior to injection. Intramuscular injections should be performed using a sterile suitable gauge needle. Glabellar lines: recommended dose is 50 Speywood units divided equally into 5 injection sites, 10 Speywood units to be administered intramuscularly, at right angles to the skin; 2 injections into each corrugator muscle and one into the procerus muscle near the nasofrontal angle. Lateral canthal lines: recommended dose per side is 30 Speywood units divided into 3 injection sites; 10 Speywood units to be administered intramuscularly into each injection point, injected lateral (20 - 30° angle) to the skin and very superficial. All injection points should be at the external part of the orbicularis oculi muscle and sufficiently far from the orbital rim (approximately 1 - 2 cm); (See summary of product characteristics for full technique). Treatment interval should not be more frequent than every three months. The efficacy and safety of repeat injections of Azzalure has been evaluated in Glabellar lines up to 24 months and up to 8 repeat treatment cycles and for Lateral Canthal lines up to 12 months and up to 5 repeat treatment cycles. Not recommended for use in individuals under 18 years of age. Contraindications: In individuals with hypersensitivity to botulinum toxin A or to any of the excipients. In the presence of infection at the proposed injection sites, myasthenia gravis, Eaton Lambert Syndrome or amyotrophic lateral sclerosis. Special warnings and precautions for use: Care should be taken to ensure that Azzalure is not injected into a blood vessel. Use with caution in patients with a risk of, or clinical evidence of, marked defective neuro-muscular transmission, in the presence of inflammation at the proposed injection site(s) or when the targeted muscle shows excessive weakness or atrophy. Patients treated with therapeutic doses may experience exaggerated muscle weakness. Not recommended in patients with history of dysphagia, aspiration or with prolonged bleeding time. Seek immediate medical care if swallowing, speech or respiratory difficulties arise. Facial asymmetry, ptosis, excessive dermatochalasis, scarring and any alterations to facial anatomy, as a result of previous surgical interventions should be taken into consideration prior to injection. Injections at more frequent intervals/higher doses can increase the risk of antibody formation. Avoid administering different botulinum neurotoxins during the course of treatment with Azzalure. To be used for one single patient treatment only during a single session. There is a potential risk of localised muscle weakness or visual disturbances linked with the use of this medicinal product which may temporarily impair the ability to drive or operate machinery. Interactions: Concomitant treatment with aminoglycosides or other agents interfering with neuromuscular transmission (e.g. curare-like agents) may potentiate effect of botulinum toxin. Pregnancy, Lactation & Fertility: Not to be used during pregnancy or lactation. There are no clinical data from the use of Azzalure on fertility. There is no evidence of direct effect of Azzalure on fertility in animal studies Side Effects: Most frequently occurring related reactions are headache and injection site reactions for glabellar lines and; headache, injection site reactions and eyelid oedema for lateral canthal lines. Generally treatment/injection technique related reactions occur within first week following injection and are transient. Undesirable effects may be related to the active substance, the injection procedure, or a combination of both. For glabellar lines: Very Common (≥ 1/10): Headache, Injection site reactions (e.g. erythema, oedema, irritation, rash, pruritus, paraesthesia, pain, discomfort, stinging and haematoma). Common (≥ 1/100 to < 1/10): Temporary facial paresis (due to temporary paresis of facial muscles proximal to injection sites, predominantly describes brow paresis), Asthenopia, Eyelid ptosis, Eyelid oedema, Lacrimation increase, Dry eye, Muscle twitching (twitching of muscles around the eyes). Uncommon (≥ 1/1,000 to <1/100): Dizziness, Visual impairment, Vision blurred, Diplopia, Pruritus, Rash, Hypersensitivity, Eye movement disorder. Rare (≥ 1/10,000 to < 1/1,000): Urticaria. For lateral canthal lines: Common (≥ 1/100 to < 1/10): Headache, Temporary facial paresis (due to temporary paresis of facial muscles proximal to injection sites), Eyelid ptosis, Eyelid oedema and Injection site disorders (e.g. haematoma, pruritus and oedema). Uncommon (≥ 1/1,000 to <1/100): Dry eye. Adverse reactions resulting from distribution of the effects of the toxin to sites remote from the site of injection have been very rarely reported with botulinum toxin (excessive muscle weakness, dysphagia, aspiration pneumonia with fatal outcome in some cases). Prescribers should consult the summary of product characteristics in relation to other side effects. Packaging Quantities & Cost: UK 1 Vial Pack (1 x 125u) £64.00 (RRP), 2 Vial Pack (2 x 125u) £128.00 (RRP), IRE 1 Vial Pack (1 x 125u) €93.50, 2 Vial Pack (2 x 125u) €187.05 (RRP) Marketing Authorisation Number: PL 06958/0031 (UK), PA 1613/001/001 (IRE) Legal Category: POM Further Information is Available From: Galderma (UK) Limited, Meridien House, 69-71 Clarendon Road, Watford, Herts. WD17 1DS, UK. Tel: +44 (0) 1923 208950 Fax: +44 (0) 1923 208998 Date of Revision: September 2018

Adverse events should be reported. For the UK, Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. For Ireland, Suspected adverse events can be reported via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie. Adverse events should also be reported to Galderma (UK) Ltd.

AZZALURE® IS A TRADEMARK BELONGING TO NESTLE SKIN HEALTH S.A.

AZZALURE IS SOLD AS A PRESCRIPTION MEDICINAL PRODUCT IN THE EUROPEAN UNION. PLEASE REFER TO THE PRESCRIBING INFORMATION AVAILABLE UPON REQUEST TO GALDERMA.