Guest guest Posted May 20, 2001 Report Share Posted May 20, 2001 This is from Medscape sorry if you can't read the charts Human Dermal Safety Studies with Eflornithine HCl 13.9% Cream (VaniqaTM), a Novel Treatment for Excessive Facial Hair Janet G. Hickman, Education and Research Foundation Inc., Lynchburg, VA 24501, USA; Ferdinand Huber and Palmisano, Bristol Myers Squibb, Princeton, NJ 08540, USA. [Current Medical Research and Opinion 16(4):235-244, 2001] Summary Eflornithine HCl 13.9% cream (VaniqaTM) is a novel treatment for the management of unwanted facial hair in women. This paper reports the results of four modified open-label, within-subject vehicle-controlled studies evaluating the dermal safety of this topical treatment. In a repeated insult patch test (230 subjects), erythema with oedema occurred in 38.9% of subjects treated with eflornithine HCl 13.9% cream and 4.8% of subjects treated with vehicle cream. Challenge applications at previously untested sites following the three-week induction period produced noticeable erythema or greater on only four sites treated with eflornithine HCl 13.9% cream and one vehicle-treated site. The erythema at these sites subsided substantially within 24 hours. In a three-week cumulative irritation study (30 subjects), the mean irritation score for sites treated with eflornithine HCl 13.9% cream was 1.33, compared with 0.76 at vehicle-treated sites and 3.09 at positive-control (sodium lauryl sulphate-treated) sites (p < 0.001 between all three groups). In a phototoxicity study (25 subjects), irradiated sites showed either no reaction (40% of both sites treated with eflornithine HCl 13.9% cream and vehicle-treated sites), or mild erythema subsiding in all cases but one within 24 hours. No reaction was seen at non-irradiated sites. In a photocontact allergy study (30 subjects), challenge with eflornithine HCl 13.9% cream or its vehicle alone produced either no reaction or mild erythema subsiding within 24 hours at both irradiated and non-irradiated sites. No serious adverse events were reported during the studies, and the only adverse events considered related to treatment were pruritus (three subjects) and dry skin at test site (one subject). These results demonstrate that eflornithine HCl 13.9% cream does not have contact sensitising, photocontact allergic or phototoxic properties. It can cause irritation under exaggerated conditions of use. Eflornithine HCl 13.9% cream, therefore, has a favourable dermal safety profile appropriate for a topical treatment to be applied routinely. Introduction Many women who suffer from unwanted facial hair regard this as a defect in their appearance. This can lead to psychosocial problems ranging from withdrawal from social situations to anxiety and depression.[1-3] Until recently, there has been no proven safe and effective topical medication for controlling facial hair growth. Popular methods for removing facial hair include shaving, plucking (tweezing), waxing, chemical depilation and electrolysis.[4-6] These methods are often painful, inconvenient or expensive. Therefore a treatment that reduces the need for hair removal would bring benefits to women with unwanted facial hair. Eflornithine HCl 13.9% cream (VaniqaTM) is a convenient topical treatment for reducing facial hair growth. Eflornithine is an irreversible inhibitor of ornithine decarboxylase, an enzyme responsible for the catalysis of ornithine to putrescine.[7] Putrescine and other polyamines play an important role in the regulation of cell growth and differentiation.[8] Ornithine decarboxylase is present in the hair follicle and studies in animal models have shown that eflornithine is a potent inhibitor of hair growth.[9] Clinical evaluation of eflornithine HCl 13.9% cream shows this topical agent to be effective in reducing facial hair growth in women (Wolf et al., manuscript in preparation). Extensive preclinical evaluations have shown eflornithine HCl 13.9% cream to have predictable pharmacokinetics and a favourable toxicological profile (Shander and , personal communication). Clinical studies in humans showed that eflornithine HCl 13.9% cream has a low percutaneous absorption (< 1%) under conditions of likely clinical use, and that any absorbed eflornithine is rapidly excreted in urine without being metabolised (Malhotra, manuscript in preparation). Dermal safety is an important consideration for a topical treatment that is to be used regularly. This paper reports the results of four dermatological studies in humans, which evaluated the potential of eflornithine HCl 13.9% cream and its vehicle to cause contact sensitisation, irritation, phototoxicity and photocontact allergy. The contact sensitisation and cumulative irritation studies both involved exaggerated use of eflornithine HCl 13.9% cream in that the cream was applied and maintained under occlusive dressings for 21 days. Contact Sensitisation Study Subjects and Methods In total, 230 healthy subjects were enrolled in a 37-day, modified, open-label, single-centre, within-subject vehicle-controlled study, to examine the contact sensitisation potential of topical treatment with eflornithine HCl 13.9% cream and its vehicle alone. The study consisted of a three-week induction period of exaggerated use under occlusive patches, followed two weeks later by a single-dose challenge given at a previously untested site (modified Draize skin sensitisation test). Skin responses to challenge were used to assess contact sensitisation.[10-12] Subjects were at least 18 years of age. Female subjects were sterile or had a negative pregnancy test on entry into the study and agreed to use contraception for the duration of the study. Subjects were not permitted to use medications such as anti-histamines, corticosteroids, analgesics and anti-inflammatories during the study. Exclusion criteria were concomitant skin pathologies, atopic dermatitis/eczema, psoriasis or asthma, a history of hypersensitivity to any component of the formulations, treatment with medications such as anti-histamines, corticosteroids, analgesics and anti-inflammatories in the week before the study, treatment with investigational medicines during the four weeks before the study, current pregnancy or nursing, a history of pregnancy while using contraception, and skin pigmentation likely to interfere with assessment of skin reactions. Eflornithine HCl (2-(difluoromethyl)-D,L-ornithine monohydrochloride 13.9% (w/w) cream, equivalent to 15% when expressed as the monohydrate) (VaniqaTM) (0.2 g) was applied using a Hill Top Chamber under occlusive patches to a site 1.8 cm in diameter on the upper back of each subject. Vehicle cream was applied to a second site in the same manner. Patch test sites were selected to avoid skin blemishes, moles, scars and the midline over the spine. During the three-week induction period, doses of eflornithine HCl 13.9% cream and vehicle were applied to the test site three times a week (Monday, Wednesday and Friday) and left in place until the next application. During the subsequent two-week rest period, no treatment was applied. This was followed by application of single 48-hour challenge doses made at previously untested skin sites. Skin reactions were evaluated five minutes after each induction patch was removed (three times a week for three weeks), and both five minutes and 24 hours after the challenge patches were removed, using a five-point ordinal scale: No sign of reaction Slight erythema Noticeable erythema with slight infiltration Erythema with marked oedema Erythema with oedema and blistering If the test product produced a severe reaction (Grades 3 or 4), applications were moved to a new skin site, or the subject was withdrawn from the study if necessary. Adverse events were recorded for the duration of the study for all subjects enrolled. Results The demographic characteristics of the enrolled subjects are shown in Table 1. Two-hundred and eight of the 230 subjects enrolled completed the study and 185 made all scheduled visits (22 subjects missed one scheduled visit and one subject missed two scheduled visits). All 208 subjects were included in the analysis. The remaining 22 subjects withdrew from the study prematurely for the following reasons: 14 left of their own volition, four were lost to follow-up, three missed two or more consecutive visits and one withdrew owing to an adverse event not considered to be related to the study therapy. During the three-week induction period with eflornithine HCl 13.9% cream, 81 sites (38.9%) had response scores of 3 or 4. Of subjects completing the study, five (2.4%) showed no evidence of reaction at test sites (Grade 0) during induction with eflornithine HCl 13.9% cream. During induction with vehicle cream alone, 203 sites (97.6%) had scores of 1 or greater on at least one occasion, but only 10 sites (4.8%) scored 3 or 4. Challenge with eflornithine HCl 13.9% cream produced either no reaction (score of 0) or slight erythema (score of 1) on 98.1% of test sites (204/208) (Table 2). Three sites had a score of 2 (noticeable erythema with slight infiltration) five minutes after patch removal, falling to 1 or 0 within 24 hours, and 1 had a score of 4 (erythema with oedema and blistering), which fell to 2 within 24 hours. After challenge with vehicle only, all sites had a score of 0 or 1, with the exception of one score of 2, which fell to 1 within 24 hours. No serious adverse events were reported during the contact sensitisation study. In total, 11 adverse events were reported in 10 subjects (4.3%): headache (three subjects), pruritus (two subjects), accidental injury (one subject), cyst (one subject), infection (one subject), back pain (one subject), cholelithiasis (one subject), and diarrhoea (one subject). Of these, only pruritus at patch sites (two subjects), occurring 10-15 days into the study was considered related to treatment. Cumulative Irritation Study Subjects and Methods In total, 30 healthy subjects were enrolled in an open-label, single-centre, within-subject vehicle- and positive-controlled study to evaluate the irritation potential of topical treatment with eflornithine HCl 13.9% cream, its vehicle alone and a known irritant - sodium lauryl sulphate (0.5%) in petrolatum. The study consisted of a three-week period of exaggerated use, during which skin responses were assessed daily.[10-13] Subjects were enrolled based on the same criteria as before. Each subject received eflornithine HCl 13.9% cream, vehicle alone and 0.5% (w/w) sodium lauryl sulphate in petrolatum (0.2 g of each), which were applied under separate occlusive patches as described before. Each patch was removed and fresh test materials were applied six days a week (Monday to Saturday) for three weeks. The final patch was removed 48 hours after application. Cumulative irritation was measured five minutes after patch removal using a five-point ordinal scale, as before. Once a score of 4 was observed, no further applications of that treatment were made to the subject and a score of 4 was assigned for the remainder of the study. Adverse events were recorded for the duration of the study. The statistical significance of the scores obtained was assessed using the Friedman test. An approximation to the Friedman test was employed using the procedure PROC GLM in SAS. This procedure was applied after a ranking was performed within subject on the treatment means (averaged over time) using the procedure PROC RANK in SAS. Tukey's Studentised Range test was employed for pairwise comparisons. Results The demographic characteristics of the enrolled subjects are shown in Table 1. In total, 28 of the 30 subjects completed the study, of whom 20 completed all scheduled visits and eight subjects missed one scheduled visit. One subject discontinued from the study owing to an adverse event unrelated to treatment and a second subject discontinued after missing two visits. All subjects were included in the analysis. Maximum scores at sites treated with eflornithine HCl 13.9% cream were greater than for vehicle-treated sites and less than at sodium lauryl sulphate-treated sites (Table 3). Cumulative irritation scores were 701 at sites treated with eflornithine 13.9% cream, 396 at vehicle cream-treated sites and 1625 at sodium lauryl sulphate-treated sites, out of a possible maximum of 2016 (Table 4). Tukey's Studentised Range test and Friedman's test showed that the mean scores for the three treatments were significantly different from each other (p < 0.001) (Table 4). One subject reported chest tightness and dizziness during the cumulative irritation study; these events were considered unrelated to the study treatments. One subject also complained of itchy dry skin unrelated to patch sites. No other adverse events were reported. Phototoxicity Study Subjects and Methods In total, 25 subjects were enrolled in an open-label, single-centre, within-subject vehicle-controlled study to evaluate the phototoxicity potential of eflornithine HCl 13.9% cream and its vehicle alone. The study consisted of a single application of each study material made to stripped skin sites followed by irradiation with ultraviolet light. Skin responses were assessed during the following two days[11, 14]. Healthy subjects were enrolled in the study based on the same criteria as before. Additionally, subjects with a recent tan, sunburn or cataracts, or taking medications suspected of causing photobiological reactions (e.g. tetracyclines and thiazides), were excluded. Three sites on the back of each subject were prepared by stripping the skin with cellophane tape. The skin was stripped to the glistening layer, or a maximum of 15 repetitions of the stripping process. Eflornithine HCl 13.9% cream (0.2 g) was applied to one 2.54 cm2 patch of stripped skin (i.e. 80 mg eflornithine HCl 13.9% cream per square centimetre) and vehicle cream alone was applied to a second patch, while the third site was left untreated. The creams were allowed to dry and a portion of each treated site was covered with an opaque material. All three sites were then exposed to filtered UVA light for an exposure time equal to 10 times the minimal erythema dose (MED), followed by an additional 0.5 MED of unfiltered UVA and UVB light, from a xenon lamp solar simulator. The MED of each subject had been determined previously using a 1000 W Oriel Solar Simulator (peak transmission 320-4000 nm, UVA output 45.5 mW/cm2, UVB output 6.0 mW/cm2). All sites were examined for signs of skin reaction using the same five-point ordinal scale as before, immediately after irradiation and 20 minutes, 3 hours, 24 hours and 48 hours thereafter. Adverse events were recorded for the duration of the study for all subjects enrolled. Results The demographic characteristics of the enrolled subjects are shown in Table 1. All 25 subjects completed the study. One subject missed the three-hour and 24-hour evaluations but was not excluded from the analyses. Following a single treatment with eflornithine HCl 13.9% cream and subsequent irradiation, 10 of 25 sites (40%) showed no sign of reaction (Table 5). The remaining 15 irradiated sites treated with eflornithine 13.9% cream had maximum scores of 1 (slight erythema), all but one falling to 0 within 24 hours. The same pattern of reaction was seen at vehicle cream-treated and untreated irradiated sites. No sign of reaction was detected at non-irradiated sites treated with eflornithine HCl 13.9% cream or vehicle alone (scores of 0). No adverse events were reported during the phototoxicity study. Photocontact Allergy Study Subjects and Methods In total, 30 subjects were enrolled in an open-label, single-centre, within-subject vehicle-controlled study to evaluate the photoallergic potential of eflornithine HCl 13.9% cream and vehicle alone. Subjects were enrolled using the same criteria as the phototoxicity study. Twice-weekly during a three-week induction period, eflornithine HCl 13.9% cream and vehicle alone (0.2 g of each) were applied in duplicate under occlusive patches to sites 1.8 cm in diameter on the subjects' backs. The patches were removed 24 hours after application and one of each pair of duplicate sites, plus an untreated site, were irradiated with 2 MEDs of unfiltered ultraviolet light (UVA and UVB) using a solar simulator. Following a two-week no-treatment period, a challenge application of study materials was made as before, to previously untreated sites. After 24 hours, one of each of the duplicate treated sites and an untreated site were irradiated with 10 MEDs of filtered ultraviolet light (UVA). All sites were examined for signs of skin reaction using the same five-point ordinal scale as before, five minutes, 20 minutes, 24 hours, 48 hours and 72 hours after irradiation. Adverse events were recorded for the duration of the study for all subjects enrolled. Results The demographic characteristics of the enrolled subjects are shown in Table 1. Of the 30 subjects enrolled, 28 completed the study and were included in the analysis. Two subjects left the study, of their own volition. During the induction period, all irradiated sites (treated with eflornithine HCl 13.9% cream, vehicle-treated and untreated) had at least one score of 1 and there were no scores greater than 1. During induction, most non-irradiated sites treated with eflornithine HCl 13.9% cream (85.7%) had a score of 0 throughout, three sites (10.7%) had single scores of 1 and one site (3.6%) had a single score of 2. During induction at vehicle-treated, non-irradiated sites, 12 sites (42.9%) had a score of 0 throughout and the remaining 16 sites (57.1%) had scores of 1 on one or two occasions. After challenge, there was no sign of reaction at over half of the irradiated sites (sites treated with eflornithine HCl 13.9%; cream 64.3%; vehicle-treated 57.1%; untreated 64.3%) and most of the non-irradiated sites (sites treated with eflornithine HCl 13.9%; cream 85.7%; vehicle-treated 85.7%) (Table 6). The remaining sites had signs of mild erythema five or 20 minutes after challenge, which disappeared within 24 hours. No serious adverse events were reported in this study. Four adverse events were reported in three subjects: dry skin at a site treated with eflornithine HCl 13.9% cream (considered related to study medication), itching at skin test sites during the third week of study (considered possibly related to study medication), bronchitis (considered unrelated to treatment) and stress (considered unrelated to treatment). Discussion In these studies, test conditions were created to assess the potential of eflornithine HCl 13.9% cream to provoke irritant, allergic, photoallergic and phototoxic dermal reactions. The results provide no evidence to suggest that either eflornithine HCl 13.9% cream or its vehicle alone induces phototoxic or photosensitisation skin reactions. In the contact sensitisation study, the intensity of reaction in most subjects was low and decreased substantially within 24 hours of challenge. These characteristics are indicative of irritation as opposed to allergic contact sensitisation. Under exaggerated conditions of repeated, occluded exposure, eflornithine HCl 13.9% cream produced signs of dermal irritation in most subjects. The mean cumulative irritation score for eflornithine HCl 13.9% cream was significantly greater than for vehicle alone, but significantly less than for the known irritant sodium lauryl sulphate (0.5%). These findings suggest that eflornithine HCl 13.9% cream could cause irritation reactions in clinical use in susceptible individuals or under exaggerated conditions. Adverse events during exaggerated treatment with eflornithine HCl 13.9% cream and vehicle alone were generally mild and none was serious. The only treatment-related adverse events in the four studies (315 subjects in total) were pruritus (three subjects) and dry skin (one subject) at test sites. The results of these studies together suggest that eflornithine HCl 13.9% cream will have a good dermal safety profile in clinical use, with a low risk of skin irritation, allergic reactions and phototoxicity. These results complement the findings of efficacy studies that show eflornithine HCl 13.9% cream to be a highly effective treatment for inhibiting facial hair growth (manuscript in preparation). The favourable dermal safety profile of eflornithine HCl 13.9% cream combined with its efficacy in reducing facial hair growth suggest that eflornithine HCl 13.9% cream offers a significant breakthrough in the management of unwanted facial hair. Table 1. Demographic characteristics of subjects enrolled in dermal safety studies Study Contact sensitisation Cumulative irritation Phototoxicity Photocontact allergy Subjects enrolled (No.) 230 30 25 30 Subjects completing (No.) 208 28 25 28 Age (years) mean 44.9 48.0 39.5 41.4 range 18-87 29-73 22-76 20-73 Gender (% female) 75.2 83.3 88.0 83.3 Race (%) Black 58.7 36.7 0.0 3.3 White 40.9 63.3 100.0 96.7 Asian/Pacific Islander 0.4 0.0 0.0 0.0 Table 2. Maximum irritation score five minutes and 24 hours after challenge in a modified Draize skin sensitisation test of eflornithine HCl 13.9% cream and its vehicle (contact sensitisation study) Maximum score on the irritation scale Eflornithine HCl 13.9% cream Vehicle Five minutes after challenge 24 hours after challenge Five minutes after challenge 24 hours after challenge No. % No. % No. % No. % 0 or 1 No sign of reaction or slight erythema 204 98.1 207 99.5 207 99.5 208 100.0 2 Noticeable erythema with slight infiltration 3 1.4 1 0.5 1 0.5 0 0.0 3 Erythema with marked oedema 0 0.0 0 0.0 0 0.0 0 0.0 4 Erythema with oedema and blistering 1 0.5 0 0.0 0 0.0 0 0.0 Total 208 100.0 208 100.0 208 100.0 208 100.0 Table 3. Maximum irritation scores recorded during the cumulative irritation study: three weeks of daily treatment with eflornithine HCl 13.9% cream, vehicle alone and 0.5% sodium lauryl sulphate in petrolatum Maximum score on irritation scale Eflornithine HCl 13.9% cream Vehicle Sodium lauryl sulphate No. % No. % No. % 0 No sign of reaction 0 0.0 0 0.0 0 0.0 1 Slight erythema 5 16.7 15 50.0 1 3.3 2 Noticeable erythema with slight infiltration 7 23.3 12 40.0 2 6.7 3 Erythema with marked oedema 1 3.3 2 6.7 0 0.0 4 Erythema with oedema and blistering 17 56.7 1 3.3 27 90.0 Total 30 100.0 30 100.0 30 100.0 Table 4. Total cumulative and mean scores by treatment (n = 30) during the cumulative irritation study: three weeks of daily treatment with eflornithine HCl 13.9% cream, vehicle alone and 0.5% sodium lauryl sulphate in petrolatum Irritation score Eflornithine HCl 13.9% cream Vehicle Sodium lauryl sulphate Cumulative* Mean? 1.33 0.76 3.09 Tukey's test? B C A *Sum of all readings for subjects for a given product (maximum score 2016) ?p < 0.001 (Friedman's test) ?Means with different letters are significantly different Table 5. Maximum irritation scores and scores 48 hours after irradiation during phototoxicity study with eflornithine HCl 13.9% cream and vehicle (with and without irradiation) or irradiation alone Maximum score on irritation scale Eflornithine HCl 13.9% cream n (%) Vehicle n (%) Untreated n (%) Irradiated Non-irradiated Irradiated Non-irradiated Irradiated Max 48 hour Max Max 48 hour Max Max 48 hour 0 No sign of reaction 10 (40) 24 (96) 25 (100) 10 (40) 24 (96) 25 (100) 10 (40) 24 (96) 1 Slight erythema 15 (60) 1 (4) 0 (0) 15 (60) 1 (4) 0 (0) 15 (60) 1 (4) 2 Noticeable erythema with slight infiltration 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 3 Erythema with marked oedema 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 4 Erythema with oedema and blistering 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Total 25 (100) 25 (100) 25 (100) 25 (100) 25 (100) 25 (100) 25 (100) 25 (100) Table 6. Irritation scores during photocontact allergy study after treatment with eflornithine HCl 13.9% cream or vehicle (with and without irradiation) or irradiation alone: scores up to 20 minutes or 24 hours after irradiation challenge Maximum score on irritation scale Eflornithine HCl 13.9% cream Vehicle Untreated Irradiated Non-irradiated Irradiated Non-irradiated Irradiated 20 min n (%) 24 hours n (%) 20 min n (%) 24 hours n (%) 20 min n (%) 24 hours n (%) 20 min n (%) 24 hours n (%) 20 min n (%) 24 hours n (%) 0 No sign of reaction 18 (64.3) 28 (100) 24 (85.7) 28 (100) 16 (57.1) 28 (100) 24 (85.7) 28 (100) 18 (64.3) 28 (100) 1 Slight erythema 10 (35.7) 0 (0) 4 (14.3) 0 (0) 12 (42.9) 0 (0) 4 (14.3) 0 (0) 10 (35.7) 0 (0) 2 Noticeable erythema with Sslight infiltration 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 3 Erythema with marked oedema 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 4 Erythema with oedema and blistering 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Total 28 (100) 28 (100) 28 (100) 28 (100) 28 (100) 28 (100) 28 (100) 28 (100) 28 (100) 28 (100) References Rittmaster, R. 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Chem. Soc., 100, 2551-2553. Oredsson, S., Anehus, S. and Heby, O. (1980). Inhibition of cell proliferation by DL-alpha-difluoromethylornithine, a catalytic irreversible inhibitor of ornithine decarboxylase. Acta Chem. Scand. B, 34, 457-458. Probst, E. and Krebs, A. (1975). Ornithine decarboxylase activity in relation to DNA synthesis in mouse interfollicular epidermis and hair follicles. Biochim. Biophys. Acta, 407, 147-157. Rook, A., Wilkinson, D. S. and Ebling, F. (1979). Textbook of Dermatology, Blackwell Scientific, Oxford, 3rd edn. Marzulli, F. N. and Maibach, H. I. (1996). Dermatoxicology. and Francis, Washington. Jordan, W. P., Jr. and King, S. E. (1977). Delayed hypersensitivity in females. The development of allergic contact dermatitis in females during the comparison of two predictive patch tests. Contact Derm., 3, 19-26. , L. D., Steinberg, M., Maibach, H. I. and Akers, W. A. (1972). A comparison of rabbit and human skin response to certain irritants. Toxicol. Appl. Pharmacol., 21, 369-382. Kligman, A. M. and Breit, R. (1968). The identification of phototoxic drugs by human assay. J. Invest. Dermatol., 51, 90-99. bheint@... Quote Link to comment Share on other sites More sharing options...
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