Dermal Safety of Tapinarof Cream 1%: Results From 4 Phase 1 Trials.

BACKGROUND: Tapinarof (VTAMA®; Dermavant Sciences, Inc.) is a novel, non-steroidal, topical, aryl hydrocarbon receptor agonist, FDA approved for psoriasis treatment and under investigation for atopic dermatitis treatment as a 1% cream formulation for once-daily (QD) application. OBJECTIVE: Evaluate cumulative skin irritation, sensitization, and photoallergic and phototoxic potential of tapinarof cream 1% across a range of dosing frequencies and conditions. METHODS: We conducted 4 randomized, controlled, phase 1 trials of topical tapinarof cream 1% vs vehicle or other appropriate controls in healthy adults. Cumulative skin irritation was assessed following QD application for 21 days under fully occlusive patch conditions. Contact sensitization, photoallergenicity, and phototoxicity were assessed under semi-occlusive patch conditions. The contact sensitization and photoallergenicity trials used an induction phase of repeated applications followed by a 2-week rest period and a 1-time challenge, with rechallenge if responses indicated sensitization/photosensitization; the phototoxicity trial comprised a single application. Ultraviolet A and B irradiation was used to assess photoallergenicity/toxicity. RESULTS: 376 participants were randomized across the 4 trials. In the cumulative irritation trial, tapinarof cream 1% QD was classified as having a slight potential for very mild cumulative irritation under the exaggerated test conditions of repeated dosing for 21 days. There was no evidence of sensitization, photosensitization, or phototoxicity. Tapinarof was well tolerated and there was a low discontinuation rate across all trials. CONCLUSIONS: Tapinarof cream 1% was well tolerated, non-sensitizing, non-phototoxic, and non-photoallergic, with no evidence of clinically meaningful cumulative skin irritation in 4 dermal safety trials in healthy adults. TRIAL REGISTRATION: IND 104601 J Drugs Dermatol. 2022;21(10):1084-1090. doi:10.36849/JDD.6627R1.

Photodermatoses in skin of colour.

Photodermatoses represent a heterogeneous collection of disorders unified by the characteristic of being provoked through exposure to ultraviolet radiation. Generally, these conditions are classified into the following categories: immunologically mediated photodermatoses, chemical- and drug-induced photosensitivity, photoaggravated dermatoses and photosensitivity associated with defective DNA repair mechanisms or chromosomal instabilities. The list of photodermatoses is extensive, and each individual photodermatosis is understood to a different extent. Regardless, there exists a paucity of information with regards to the clinical presentation among those with skin of colour. With ever-changing global demographics, recognition of photosensitive disorders in a diverse population is essential for accurate diagnoses and therapeutic guidance. The scope of this article seeks to review the epidemiology and clinical variability in presentation of such photodermatoses in patients with skin of colour.

Voriconazole phototoxicity in children: a retrospective review.

BACKGROUND: Voriconazole, an antifungal agent, is associated with various cutaneous reactions, including phototoxicity, accelerated photoaging, and skin cancer. Incidence and risk factors for these reactions in children have not been well described. OBJECTIVE: We sought to determine the incidence of and factors associated with phototoxic reactions and nonmelanoma skin cancer in pediatric patients treated with voriconazole. METHODS: This was a retrospective analysis of 430 pediatric patients treated with voriconazole between 2003 and 2013 at Boston Children's Hospital. RESULTS: Incidence of phototoxicity was 20% in all children treated with voriconazole and 47% in children treated for 6 months or longer. Factors associated with phototoxicity included white race, cystic fibrosis, cumulative treatment time, and cumulative dose. Four patients (1%) had nonmelanoma skin cancer; all experienced a phototoxic reaction during voriconazole treatment. Of those with phototoxicity, 5% were discontinued on voriconazole, 6% were referred to dermatology, and 26% received counseling about sun protection from their primary physician. LIMITATIONS: Our study is limited by its retrospective design and potential referral bias associated with a tertiary-care center. CONCLUSIONS: Voriconazole-associated phototoxicity is relatively common in children and may lead to nonmelanoma skin cancer. However, those with phototoxic reactions are often continued on therapy, rarely referred to dermatology, and infrequently counseled on sun protection.

A multistep voriconazole-related phototoxic pathway may lead to skin carcinoma: results from a French nationwide study.

BACKGROUND: Voriconazole long-term therapy is suspected to induce cutaneous squamous cell carcinoma (SCC), as suggested by 18 case reports worldwide and 3 retrospective studies. METHODS: To better characterize the natural history of these potentially voriconazole-associated tumors, a nationwide call for notification of skin cancers and other skin lesions observed between 2002 and 2012 in patients treated by voriconazole was launched in France. A multidisciplinary committee evaluated voriconazole involvement in each case. RESULTS: Nineteen SCCs were reported. The committee determined the likelihood of voriconazole involvement to be high in 15 cases, intermediate in 2, and low in 2. In the 17 patients with high/intermediate likelihood of voriconazole involvement, the mean time between voriconazole initiation and SCC diagnosis was 39 ± 18 months (range, 28-84 months), and was shorter in transplant recipients (35 vs 45 months, P < .05). Cumulative mean duration of voriconazole therapy at SCC diagnosis was 35 months (range, 7-63 months). A multistep process was noted in 14 of 17 patients: acute phototoxicity during the first year of voriconazole therapy (mean time, 6 months [range, 0-18 months]), actinic keratosis (AK) of the same sun-exposed skin area in the second/third year (mean, 30 months [range, 11-57 months]), followed by SCC during the third year or later. Five cases of AK without SCC and 37 cases of other skin lesions were also reported. CONCLUSIONS: Our results suggest that long-term voriconazole prescription may be associated with a multistep phototoxic process involving acute skin lesions followed by AK then by SCC. Discontinuation of voriconazole should be strongly considered in patients experiencing chronic phototoxicity.

Ciprofloxacin-induced phototoxicity in an adult cystic fibrosis population.

The incidence of phototoxicity as a side effect of ciprofloxacin appears to be increased in patients with cystic fibrosis compared to the general population (approximately 2.4%). We used an interview-based questionnaire to determine the incidence of such phototoxic skin reactions in cystic fibrosis patients. Results from 105 respondents revealed the incidence of ciprofloxacin-induced phototoxicity in the adult cystic fibrosis population in Northern Ireland to be 48.4% with only 66% of the patients recalling being given sun care information beforehand. We concluded that the incidence of phototoxicity is increased in patients with cystic fibrosis and that it is important for all to receive good sun care information prior to taking ciprofloxacin given the high risk of developing phototoxic rash.

Chronic phototoxicity and aggressive squamous cell carcinoma of the skin in children and adults during treatment with voriconazole.

BACKGROUND: Voriconazole is a broad-spectrum antifungal agent associated with photosensitivity and accelerated photoaging. A possible link with aggressive squamous cell carcinoma (SCC) has also been reported. OBJECTIVE: We sought to determine the incidence and frequency of cutaneous SCC among patients undergoing long-term treatment with voriconazole who also manifest features of chronic phototoxicity. METHODS: We conducted a retrospective review of patients who developed one or more squamous cell neoplasms during long-term treatment with voriconazole at 3 academic dermatology centers. RESULTS: A total of 51 cutaneous SCC were identified in 8 patients (median age 34.5 years, range 9-54) treated with chronic voriconazole (median duration 46.5 months, range 13-60). Underlying diagnoses included graft-versus-host disease, HIV, and Wegener granulomatosis. Signs of chronic phototoxicity and accelerated photoaging included erythema, actinic keratoses, and lentigo formation. LIMITATIONS: The retrospective nature of the study cannot determine the true population risk of SCC associated with voriconazole therapy. A prospective cohort study is needed. CONCLUSION: A high index of suspicion for photosensitivity and SCC may be warranted with chronic voriconazole use when used in the setting of concurrent immunosuppression.

Topical minocycline foam 4%: Results of four phase 1 studies evaluating the potential for phototoxicity, photoallergy, sensitization, and cumulative irritation.

FMX101 4% contains 4% micronized minocycline (as an HCl) formulated in a lipophilic foam vehicle for topical administration. FMX101 4% has been shown to be an effective and well-tolerated treatment for moderate-to-severe acne in three Phase 3 pivotal studies, however, skin sensitization and toxicity potential remains to be fully evaluated. Four single-center, randomized, controlled, within-subject comparison studies were conducted to evaluate the potential for phototoxicity, photoallergy, skin sensitization, and cumulative skin irritation with topical administration of FMX101 4% and the corresponding vehicle. Across the four studies, healthy male and non-pregnant female volunteers (age ≥18 years) were randomized to FMX101 4%, vehicle, or other controls. In the phototoxicity study, treated skin was irradiated at 3 and 24 hr post-application, and local tolerability was assessed pre- and post-irradiation. In the photoallergy study, the skin was treated and irradiated (post-24 hr) twice weekly for 3 wk (induction phase), rested for 10-17 d, and naive skin sites were treated and irradiated (challenge phase); skin reactions were assessed after patch removal and post-irradiation. In the sensitization study, the skin was treated for 3 wk (induction phase), then rested for 10-14 d, and naive skin sites were treated for 48 hr (challenge phase); contact sensitization was assessed for both phases. In the cumulative irritation study, treatment and vehicle were applied daily for 21 d; skin irritation was assessed after each application. In all studies, standard safety assessments were conducted. A total of 32, 56, 233, and 42 subjects were enrolled in the phototoxicity, photoallergy, sensitization, and skin irritation studies, respectively. There was no evidence of phototoxicity, photoallergy, skin sensitization, or skin irritation potential with FMX101 4%. Few adverse events, mostly mild to moderate, were reported. In conclusion, FMX101 4% appeared to be well tolerated and non-irritating, and was considered to be non-sensitizing, non-phototoxic, and non-photoallergic.

Photopatch tests: an Italian multicentre study from 2004 to 2006.

BACKGROUND: Evaluation of possible photoallergic contact dermatitis in at-risk populations is often not undertaken, and an agreed methodology for investigation is uncommonly used. OBJECTIVES: We conducted a retrospective multicentre study to determine the prevalence of photoallergic contact dermatitis in Italy. METHODS: A total of 1082 patients with histories and clinical features suggestive of photoallergic contact dermatitis were evaluated. All the patients had undergone photopatch testing with allergens proposed for Italy as well as other substances suggested by each patient's personal history. RESULTS: 234 patients (21.6%) were positive to at least one test substance of the standard photopatch testing series or to added substances. 234 patients (21.6%) were positive to at least one substance with a total of 290 reactions. 204 of the reactions were typically photoallergic; 68 reactions were allergic and within this group 10 were photoaugmented reactions; 18 reactions were considered to be phototoxic. CONCLUSION: The predominant group of photoallergens was drugs, followed by organic UV filters and antimicrobial agents.

Phytophotodermatitis in Rijeka region, Croatia.

Contact with plants can cause phototoxic or rarely photoallergic reactions. Phototoxic dermatitis (photophytodermatitis) occurs after contact or ingestion of plants containing furocumarins i.e. psoralens and followed by sun exposure. Skin lesions develop usually after 24-48 hours with erythema, bulla formation, itch or pain, followed by a long lasting hyperpigmentation. Furocumarins can be linear i.e. psoralens (5-MOP, 8-MOP), or angular like angelicin and pimpinellin. Their binding to DNA causes cellular damage. This can happen in florists, gardeners, farmers, horticulturists, food handlers, and botanists. The plants causing phototoxic reaction can vary with the local flora but are commonly a member of the family apiaceae (formerly umbelliferae), family rutaceae, leguminosae and moraceae. The authors give special consideration to the phytophotodermatitis that appeared in their region in spring and summer during a three year period.

Phase 1 studies to assess the safety, tolerability and pharmacokinetics of JTE-052 (a novel Janus kinase inhibitor) ointment in Japanese healthy volunteers and patients with atopic dermatitis.

The purpose of the present two phase 1 studies was to assess the safety, tolerability and pharmacokinetics for topical application of a novel Janus kinase (JAK) inhibitor, JTE-052, in Japanese healthy adult male volunteers and Japanese adult patients with atopic dermatitis (AD). Additionally, exploratory investigation was performed on the efficacy for disease severity and pruritus score in AD patients. In the QBX1-1 study, the cutaneous safety of JTE-052 ointment by a patch test and a photo patch test was assessed in an intra-individual comparative study using placebo ointment, white petrolatum and non-application as comparators. The study demonstrated that JTE-052 ointment would be associated with a low potential for phototoxicity but had no potential for skin irritation or photoallergy. In the QBX1-2 study, it was revealed that the systemic exposure to JTE-052 in both healthy volunteers with normal skin and AD patients with inflamed skin was low in application of not only 1% but also 3% JTE-052 ointment. JTE-052 ointments of 1% and 3% were generally safe and well tolerated in both populations. In a repeated twice-daily application for 7 days, the efficacy of JTE-052 ointment to AD patients was observed with both 1% and 3% ointments in the exploratory investigations evaluated by Eczema Area and Severity Index, Investigator's Global Assessment and Numeric Rating Scale assessments. The mean scores for each assessment declined from the baseline throughout the study. These results suggest that the treatment of JTE-052 ointment is generally safe and effective in AD patients, although further large confirmatory studies are needed.

Molecular mechanisms of drug photodegradation and photosensitization.

Drug-induced photosensitivity of the skin is drawing increasing attention. In past few decades, photosensitivity has been reported with an array of drugs, and is now recognized as a noteworthy medical problem by clinicians, regulatory authorities and pharmaceutical industry. The photosensitivity is of two types i.e., phototoxicity and photoallergy. Phototoxic disorders have a high incidence, whereas photoallergic reactions are much less frequent in human population. Several hundred substances, chemicals, or drugs may invoke phototoxic and photoallergic reactions. In order to avoid photosensitive reactions, it is essential to understand the mechanism behind the photosensitizing properties of such substances before these drugs are introduced in clinical settings. Photosensitization is inter-related to photochemical reaction, through the knowledge of which the photosensitivity of a drug can be anticipated. This review highlights the current research status on photosensitizing drugs and its correlation to phototoxicity. Different mechanisms of photodegradation of photolabile drugs have also been discussed.

Voriconazole-associated phototoxic dermatoses and skin cancer.

Voriconazole's antifungal spectrum, oral bioavailability, and proven efficacy in treatment of invasive mycoses have led to its widespread off-label use for antifungal prophylaxis. There is an increasing recognition that long-term voriconazole use is associated with accelerated sun-induced skin changes that include acute phototoxicity reactions, photoaging, actinic keratosis and esp. among immunocompromised patients, skin cancers. The mechanisms underlying these dermatologic adverse events are not clearly understood. Population-risks of long-term voriconazole use need to be prospectively investigated. This review aims to provide an in-depth assessment of published literature and highlight salient findings from retrospective studies and case series. A broad practical guideline for assessment and management of these patients is provided.

Invasive giant hogweeds in Poland: Risk of burns among forestry workers and plant distribution.

The Caucasian giant hogweeds (Heracleum sosnowskyi Manden. and Heracleum mantegazzianum Sommier et Lever) are aggressive invaders that are successfully spreading in different parts of the world. Exposure of human skin to these plants may lead to phototoxicity and even chemical burns manifested by cutaneous, full-thickness, and long-lasting dermatitis, and in extreme cases, massive skin necrosis. Forestry workers are a group with potentially increased risk of exposure to these plants because of the outdoor nature of their work and their active involvement in managing invasive species. Therefore, in this study, we aimed at investigating their level of awareness with regard to the giant hogweeds in Poland. The morphology of the plants, health threats, treatment, and control methods were all considered. We also evaluated the distribution of these plants within forest districts in Poland. For this reason, we surveyed 1563 employees (forest rangers, manual workers, and administration staff) of the State Forests National Forest Holding in Poland "State Forests," working in 367 different forest districts. It was initially found that the forestry workers were generally aware of the giant hogweeds' morphology and phototoxicity. More than 20% of the surveyed individuals had been exposed to these plants at least once in their lives, but only less than half of them were aware of proceeding afterward. At the same time, <35% of those surveyed had any knowledge of the control and management of these giant hogweeds. As demonstrated by our study, stands of these species are widely distributed within the Polish forest districts (reported in over 50%). Therefore, there is an urgent need to implement an efficient, multistrategic, and long-term approach to both control their spread and protect human health.

Photosensitive disorders of the skin with ocular involvement.

Patients with photosensitive disorders of the skin may present with ocular manifestations that are evident at birth or may be manifested later with progression of the disorder. Dermatologists should be able to recognize these and appropriately refer patients for further management. Ocular involvement associated with immunologically mediated photodermatoses, drug- and chemical-induced photosensitivity, photodermatoses associated with defective DNA repair/chromosome instability, and photoaggravated dermatoses are reviewed. Photodermatoses are commonly classified into four general groups: (1) immunologically mediated photodermatoses; (2) drug- and chemical-induced photosensitivity; (3) photodermatoses associated with defective DNA repair/chromosome instability; and (4) photoaggravated dermatoses. Photodermatoses in these groups with ocular involvement will be discussed. In addition, skin diseases associated with photophobia are also described.

Cutaneous consequences of photodynamic therapy.

Photodynamic therapy (PDT) has several cutaneous complications: photosensitivity is well known, but the other complications are rarely reported, Since late 1997, we have studied the dermatologic complications of using porfimer sodium PDT to treat either Barrett esophagus with high-grade dysplasia or gastroesophageal cancer in 72 consecutive patients. Cutaneous complications of PDT included serious phototoxicity requiring oral corticosteroid treatment (22 patients; 31%), herpes zoster (HZ) requiring hospitalization and intravenous antiviral treatment (1 patient; 1%), and erythema multiforme drug reaction related to porfimer sodium (1 patient; 1%). PDT-associated dermatologic complications were common and were not related to cutaneous photosensitivity.

Voriconazole-induced phototoxicity in children.

Voriconazole is used in antifungal prophylaxis. We performed a retrospective review of immunocompromised children receiving prophylaxis with voriconazole during major hospital renovation, who developed phototoxic skin reactions. The overall incidence of phototoxic skin reactions was 33%. A voriconazole dose of ≥6 mg/kg of body weight per dose twice daily was associated with a significantly greater risk to develop phototoxic skin reactions compared with lower doses.

The link between sunshine and phototoxicity of sparfloxacin.

AIMS: To test the association between reporting rates for sparfloxacin-induced phototoxicity and sunlight u.v. exposure, and the effects of regulatory action. METHODS: The reporting rates for phototoxicity with sparfloxacin to the French Pharmacovigilance System or to the Drug Manufacturer were compared with concurrent national mean u.v. exposure obtained from Météo-France, before and after the regulatory restrictions and warnings. RESULTS: There were 371 severe phototoxic reaction reports during the first 9 months of marketing (reporting rate of 0.4 per thousand treated patients), approximately four to 25 times that reported for other fluoroquinolones. The reporting rate correlated highly (r = 0.873, P < 0.001) with the mean monthly u.v. exposure from sunlight (from Météo-France). Regulatory action including warnings for physicians, and restricted indications dramatically decreased the number of reports, but not the reporting rate. CONCLUSIONS: This is the first demonstration of a strong association between sunlight exposure in a population and drug-induced phototoxicity. Regulatory action had no effect on the reporting rate (individual exposed patient risk), though it solved the public health issue.

Results of evaluation of 203 patients for photosensitivity in a 7.3-year period.

BACKGROUND: Although photosensitivity disorders have been well described, their incidence in a referral institution had not been studied. OBJECTIVE: The purpose of this study was to evaluate the incidence of photosensitivity disorders, including photocontact dermatitis, in an academic medical center. METHODS: The results of the assessment of 203 consecutive patients, all of whom had phototests, referred for the evaluation of photosensitivity disorders during a 7.3-year period were reviewed. RESULTS: The mean age was 50 years, and 63% of the patients were women. The most frequent diagnoses were polymorphous light eruption (26% of the total patient population), chronic actinic dermatitis (17%), photoallergic contact dermatitis (8%), systemic phototoxicity to therapeutic agents (7%), and solar urticaria (4%). Positive photopatch reactions, patch test reactions, or both were observed in 40 (29%) of the 138 tested patients. The frequencies of the positive photopatch test reactions were sunscreens (57%), fragrances (18%), and antimicrobial agents (13%). Of the positive patch test responses, fragrances elicited 47% of the total positive reactions, followed by sunscreens (39%) and antimicrobial agents (7%). CONCLUSION: Polymorphous light eruption, chronic actinic dermatitis, and photoallergic contact dermatitis were the most frequently made diagnoses. Sunscreens, fragrances, and antimicrobial agents were the most common clinically relevant photoallergens and allergens.

PUVA-induced phototoxicity: incidence and causes.

BACKGROUND: Phototoxicity is the most significant short-term adverse effect of PUVA therapy. OBJECTIVE: We attempted to determine the incidence and possible causes of phototoxicity of sufficient degree to cause interruption of treatment. METHODS: A retrospective study was conducted of 16,506 PUVA treatments given to 414 patients in two treatment centers. RESULTS: Phototoxicity occurred in 10.9% of patients and was an adverse effect in 0.3% of treatments. Problems with the treatment protocol were the main cause. CONCLUSION: Phototoxicity is a common adverse effect, and patients should be warned of this potential occurrence. Awareness of the causes may help to reduce the incidence of this problem.

Incidence and clinical relevance of the interactions and side effects of Hypericum preparations.

Observational studies with preparations of St. John's wort have recorded an incidence of adverse events (AE) among those treated of between 1 and 3%. This is some ten times less than with synthetic antidepressants. The most common adverse events (1 per 300000 treated cases) among the spontaneous reports in the official register concern reactions of the skin exposed to light. Investigations in volunteers have shown that the threshold dose for an increased risk of photosensitisation is about 2-4 g/day of a usual commercial extract (equivalent to approximately 5-10 mg of the hypericin that causes the phenomenon). In view of the newly observed side effects and interactions, the following additional restrictions on use appear justified: as with all preparations in this group of indications, hypericum preparations must not be taken at the same time as other antidepressants. If co-medication with coumarin-type anticoagulants is unavoidable, it must only be undertaken provided the physician closely monitors clotting parameters. Co-medication with ciclosporin and indinavir, and for the time being, other protease inhibitors used in anti-HIV treatment, is absolutely contraindicated. Without exception, all preparations of St. John's wort must only be available through pharmacies.