D ermatologists are no strangers to using many different combinations of drugs to help treat patients’ myriad dermatoses. However, with the advent of corticosteroid foam formulations, an old familiar friend (the corticosteroid) can be teamed up with a new(er) kid on the block (the foam vehicle) to use in conjunction with a whole host of agents. To see what combination therapies practitioners have tapped into in this genre, this article reviewes pharmacokinetic studies evaluating drug penetration and compatibility of topical corticosteroids formulated in a specific foam vehicle with other topical agents likely to be used in combination in the clinical setting. This article shares case studies using combination treatments, and, where available, highlights pharmacokinetic information related to agents other than topical corticosteroids formulated in the same foam vehicle. A Look at the Combination Therapies Highlighted in this Article Topical corticosteroid foam formulations available in the United States include betamethasone valerate (BMV) 0.12 % foam (Luxiq) and clobetasol propionate (CP) 0.05% foam (Olux). Both are approved for use in adult patients with steroid-responsive dermatoses affecting the scalp, with CP foam also approved for treatment of psoriasis affecting both scalp and non-scalp sites. BMV foam and CP foam have both been shown to be effective for several dermatoses affecting off-scalp locations. Since topical corticosteroids are commonly used in combination with other agents, such as topical calcineurin inhibitors, calcipotriene (Do-vonex) and tazar-otene (Tazorac), this article evaluates the interaction and impact of the foam vehicle when used in combination with other topical agents. Available studies suggest compatibility with several other vehicles and therapeutic agents from both cutaneous pharmacokinetic and clinical perspectives. Compatibility, Penetration and Clinical Impact The following reviews topical calcipotriene and topical calcineurin inhibitors and discuss their compatibility with the foam vehicle. BMV Foam/CP Foam and Topical Calcipotriene. Although monotherapy with calcipotriene has produced only modest benefit for the treatment of chronic plaque psoriasis, the combination of calcipotriene with other modalities such as a topical corticosteroids, topical tazarotene and phototherapy (UVB, PUVA) are frequently utilized due to recognition of overall improvement in therapeutic benefit.1 The potential instability of topically applied calcipotriene when used in combination with other modalities, such as UVA exposure, has been recognized. This tendency has warranted a closer analysis of calcipotriene’s stability when it’s used concurrently with individual chemical agents and specific vehicles.1 One such study used an in vitro model with human skin obtained from three cadaver donors. The stability of calcipotriene, which was applied as solution alone after 4 and 12 hours, was compared with results obtained when calcipotriene solution was applied 2 to 3 minutes after either BMV foam or CP foam.2 The concentration of calcipotriene after repeated washings of the skin was measured with high-pressure liquid chromatography (HPLC). This experiment demonstrated that after calcipotriene alone was applied to the skin, over time recovery of calcipotriene from skin surfaces greatly decreased. Researchers found that after 4 hours, 63% of the calcipotriene was recovered, compared with only 49% of the agent after 12 hours. Of course, factors that contribute to a lower percentage of calcipotriene on the skin’s surface include the following: • deeper permeation into the skin over time • exfoliation • metabolic degradative processes • photodegradation. When study participants applied either BMV foam or CP foam prior to calcipotriene, no reduction occurred in the recovery rates of intact calcipotriene from the skin surface within 4 hours, and minimal changes were seen within 12 hours. Corticosteroid Foam and Topical Calcineurin Inhibitors. An observational trial evaluated combination therapy with BMV foam and pimecrolimus 1% cream applied twice daily for the treatment of pediatric and adults patients (n = 12) presenting with a flare of atopic dermatitis. Results demonstrated rapid clearance or marked improvement within 7 days or less of clinical signs of the disease in 83% of patients and pruritus in 91% of patients.3 A significant observation was rapid reduction of pruritis, usually within the first 1 to 3 days in most patients. Overall, excellent tolerability and patient acceptability was noted with one child (age 5 years) discontinuing therapy due to stinging of the skin; transient mild or moderate stinging was noted after application of BMV foam in four children, ages 2, 6, 7 and 8 years, without interruption of therapy In the trial discussed above utilizing BMV foam and topical pimecrolimus, BMV foam was applied before pimecrolimus 1% cream. This order of application was selected as the foam vehicle rapidly dissipates into skin without residue, supporting a high level of compatibility when used prior to application of other topical agents, including moisturizers. In an in vitro study utilizing dermatomed human skin, the impact of sequential use of BMV foam and tacrolimus ointment (Protopic) (applied to the same skin site in either order) on cutaneous penetration of BMV over a 24-hour period was analyzed.4 Results were compared to those obtained after application of BMV foam alone. Regardless of whether BMV foam was applied 5 minutes before or after tacrolimus ointment, a steady increase in the cumulative amount of BMV penetration was observed over 24 hours. Cumulative amount (% dose) of BMV penetrating skin was greatest with application of BMV foam followed by tacrolimus ointment. Interestingly, cumulative BMV penetration after 24 hours was slightly higher when BMV foam was applied 5 minutes after tacrolimus ointment than after BMV foam alone. In addition to establishing the compatibility of BMV foam when used concomitantly with tacrolimus ointment, this study suggests that BMV skin penetration from the foam vehicle is not adversely impacted by concurrent use of an ointment base, regardless of the order of application. Maximum penetration of BMV occurs if foam is applied before the ointment base. The highly effective clinical response observed with the BMV foam-topical pimecrolimus (Elidel) combination suggests compatibility when BMV foam is applied prior to a cream vehicle.3 Case Studies: BMV and CP Foams Used in Combination with Other Agents The following case reviews and summaries demonstrate clinical applications of BMV foam and CP foam used effectively in combination with other topical agents. Chronic Plaque Psoriasis Case Summary. A 63-year-old male presented with a 10-year history of plaque psoriasis involving the knees and legs (see top left photo on page 63). Multiple plaques were noted on both knees and anterior surfaces of both legs. Previous treatment included topical tar preparations and topical corticosteroids. Recent use of triamcinolone 0.1% ointment over a period of 8 weeks produced a partial response in terms of plaque thickness and erythema (40% to 50% reduction). At this point, the patient was diagnosed with “partially treated chronic plaque psoriasis.” Treatment was changed to CP foam followed by calcipotriene 0.05% ointment twice daily for the first 2 weeks. At this point, topical calcipotriene was continued twice daily every day with reduction of CP foam to “weekend therapy” using two applications on 2 consecutive days per week (Saturday and Sunday). When used concomitantly, the patient was instructed to apply CP foam before calcipotriene ointment. Response. Significant continued improvement was noted after the first 2 weeks, with 80 % clearance of lesions observed over the first 4 weeks. Complete clearance of most lesions occurred after 8 weeks of combination therapy with residual lesions almost completely cleared. Maintenance of disease control was sustained with this approach (see photo at top right). Both the patient and physician rated the response as “marked improvement.” Cosmetic acceptability and ease of use were rated by the patient as “excellent.” No adverse events were noted. Summary. The initial combination of CP foam and calcipotriene ointment over an 8-week period, followed by reduction of CP foam use to twice daily on two consecutive days (“weekend therapy”) along with continued use of calcipotriene twice daily every day, is a highly effective method for the treatment of chronic plaque psoriasis. In addition, the risk of side effects associated with topical corticosteroid application is reduced due to the lessened frequency of application. The potential for tachyphylaxis is reduced due to intermittent corticosteroid application. Atopic Dermatitis Case Summary. A 7-year-old male presented with a 2-year history of atopic dermatitis. The current exacerbation began 4 weeks ago. Eczematous patches were noted bilaterally on the upper and lower extremities including antecubital and popliteal fossae (see top left photo on page 64). Disease severity was graded as moderate. Pruritus was rated as severe. Current therapy included only a gentle cleanser and emollient without success. Treatment was initiated twice daily with BMV foam followed in 5 to 10 minutes by pimecrolimus 1% cream. Specific cleanser and moisturizer products were provided with usage instructions given. Response. Complete clearance of the eruption was reported within 4 days. Pruritus cleared completely within 2 days (see top right photo on page 64). After BMV foam application on the first 2 days, transient stinging was noted that did not interfere with compliant use of either BMV foam or topical pimecrolimus. After the first 2 days of therapy, stinging was no longer noted and no other adverse reactions were observed. Summary. The topical combination of a corticosteroid and calcineurin inhibitor is highly effective in clearing signs and symptoms of atopic dermatitis. In many patients, the response to treatment is rapid, including the resolution of pruritus and visible signs of the disease. Although further study is needed in larger trials, an additive or synergistic effect is suspected based on the observations of highly effective clinical response in several patients and the different modes of action of corticosteroids and calcineurin inhibitors. Once disease exacerbation is achieved, the topical calcineurin inhibitor may be used to maintain disease control early at the immediate onset of signs and symptoms, along with appropriate skin care practices and avoidance of recognized flare factors. Topical corticosteroid therapy is reinitiated upon the development of uncontrolled flare of the disease. During treatment with the topical corticosteroid, application of the topical calcineurin inhibitor is also continued. This approach may serve to optimize long term control of atopic dermatitis by sustaining a more even and prolonged maintenance of a “disease-free” state and by keeping the patient off of the “therapeutic roller coaster.” The rapid onset and high efficacy of topical corticosteroid therapy is preserved by this approach while at the same time decreasing the risk for adverse effects due to reduced duration of use and lessened frequency of need.8 Alopecia Areata Case Summary. A 42-year-old female presented with multiple discoid and oblong patches of alopecia areata located on the scalp (see bottom left photo above). Onset was noted approximately 2 months prior to presentation. No previous history of alopecia areata was noted and the patient was on no treatment for the disorder. Past medical history and medication history were unremarkable. Treatment options and risks were reviewed. Therapy was initiated with twice daily application of BMV foam followed by pimecrolimus 1% cream. Response. After 4 weeks of therapy, a marked increase in terminal hair growth was noted diffusely within patches of scalp alopecia (see bottom right photo above). A 75% improvement in overall increased hair regrowth was observed. At this point, intralesional corticosteroid injections were completed to residual sites that were significantly minimized in the area of involvement as compared to baseline. Full regrowth was observed at follow-up 6 weeks later. Summary. The observation in uncontrolled trials that cyclosporin, an orally administered calcineurin inhibitor, stimulates hair regrowth in patients with alopecia areata opens a new avenue of therapeutic endeavor.10 Due to the potential systemic toxicity associated with oral cyclosporin, careful evaluation of the benefit-versus-risk ratio limits consideration of its use to severe and extensive cases of alopecia areata, with treatment carefully selected based on an assessment of the individual patient. The availability of topical calcineurin inhibitors offers potential therapy with a highly favorable benefit-versus-risk assessment. The case presented above demonstrates a highly positive response to twice-daily combination therapy with BMV foam and topical pimecrolimus. The author has observed two other cases with a similar favorable response using the same combination regimen.11 A 38-year-old female exhibited 60% regrowth within 6 weeks and a 9-year-old female demonstrated 50% regrowth after 4 weeks. The ability to induce relatively rapid regrowth of hair, including a marked partial response, is significant in the treatment of alopecia areata, especially as topical monotherapy with a variety of agents is commonly fraught with failure. When effective, conventional topical therapies for alopecia areata are often slow in onset. The ability of the BMV foam-pimecrolimus cream combination to quickly induce significant hair regrowth (50% to 75%) in the three cases reported above provided a high level of patient satisfaction and confidence and allowed for a marked decrease in the amount and extent of intralesional corticosteroid injection required. Winning Combinations Available evidence supports the compatibility of BMV foam (Luxiq) and CP foam (Olux) used in combination with several other topical agents, including calcipotriene, pimecrolimus and tacrolimus. Topical combination therapy approaches offer significant advantages when rationally utilized. Depending on the disease state under treatment, potential and observed advantages of combination therapy using topical corticosteroids with other agents include additive or synergistic therapeutic effect, rapid onset of clinical benefit, reduced application frequency, prevention of tachyphylaxis and decreased risk of adverse reactions.
Winning Combinations
D ermatologists are no strangers to using many different combinations of drugs to help treat patients’ myriad dermatoses. However, with the advent of corticosteroid foam formulations, an old familiar friend (the corticosteroid) can be teamed up with a new(er) kid on the block (the foam vehicle) to use in conjunction with a whole host of agents. To see what combination therapies practitioners have tapped into in this genre, this article reviewes pharmacokinetic studies evaluating drug penetration and compatibility of topical corticosteroids formulated in a specific foam vehicle with other topical agents likely to be used in combination in the clinical setting. This article shares case studies using combination treatments, and, where available, highlights pharmacokinetic information related to agents other than topical corticosteroids formulated in the same foam vehicle. A Look at the Combination Therapies Highlighted in this Article Topical corticosteroid foam formulations available in the United States include betamethasone valerate (BMV) 0.12 % foam (Luxiq) and clobetasol propionate (CP) 0.05% foam (Olux). Both are approved for use in adult patients with steroid-responsive dermatoses affecting the scalp, with CP foam also approved for treatment of psoriasis affecting both scalp and non-scalp sites. BMV foam and CP foam have both been shown to be effective for several dermatoses affecting off-scalp locations. Since topical corticosteroids are commonly used in combination with other agents, such as topical calcineurin inhibitors, calcipotriene (Do-vonex) and tazar-otene (Tazorac), this article evaluates the interaction and impact of the foam vehicle when used in combination with other topical agents. Available studies suggest compatibility with several other vehicles and therapeutic agents from both cutaneous pharmacokinetic and clinical perspectives. Compatibility, Penetration and Clinical Impact The following reviews topical calcipotriene and topical calcineurin inhibitors and discuss their compatibility with the foam vehicle. BMV Foam/CP Foam and Topical Calcipotriene. Although monotherapy with calcipotriene has produced only modest benefit for the treatment of chronic plaque psoriasis, the combination of calcipotriene with other modalities such as a topical corticosteroids, topical tazarotene and phototherapy (UVB, PUVA) are frequently utilized due to recognition of overall improvement in therapeutic benefit.1 The potential instability of topically applied calcipotriene when used in combination with other modalities, such as UVA exposure, has been recognized. This tendency has warranted a closer analysis of calcipotriene’s stability when it’s used concurrently with individual chemical agents and specific vehicles.1 One such study used an in vitro model with human skin obtained from three cadaver donors. The stability of calcipotriene, which was applied as solution alone after 4 and 12 hours, was compared with results obtained when calcipotriene solution was applied 2 to 3 minutes after either BMV foam or CP foam.2 The concentration of calcipotriene after repeated washings of the skin was measured with high-pressure liquid chromatography (HPLC). This experiment demonstrated that after calcipotriene alone was applied to the skin, over time recovery of calcipotriene from skin surfaces greatly decreased. Researchers found that after 4 hours, 63% of the calcipotriene was recovered, compared with only 49% of the agent after 12 hours. Of course, factors that contribute to a lower percentage of calcipotriene on the skin’s surface include the following: • deeper permeation into the skin over time • exfoliation • metabolic degradative processes • photodegradation. When study participants applied either BMV foam or CP foam prior to calcipotriene, no reduction occurred in the recovery rates of intact calcipotriene from the skin surface within 4 hours, and minimal changes were seen within 12 hours. Corticosteroid Foam and Topical Calcineurin Inhibitors. An observational trial evaluated combination therapy with BMV foam and pimecrolimus 1% cream applied twice daily for the treatment of pediatric and adults patients (n = 12) presenting with a flare of atopic dermatitis. Results demonstrated rapid clearance or marked improvement within 7 days or less of clinical signs of the disease in 83% of patients and pruritus in 91% of patients.3 A significant observation was rapid reduction of pruritis, usually within the first 1 to 3 days in most patients. Overall, excellent tolerability and patient acceptability was noted with one child (age 5 years) discontinuing therapy due to stinging of the skin; transient mild or moderate stinging was noted after application of BMV foam in four children, ages 2, 6, 7 and 8 years, without interruption of therapy In the trial discussed above utilizing BMV foam and topical pimecrolimus, BMV foam was applied before pimecrolimus 1% cream. This order of application was selected as the foam vehicle rapidly dissipates into skin without residue, supporting a high level of compatibility when used prior to application of other topical agents, including moisturizers. In an in vitro study utilizing dermatomed human skin, the impact of sequential use of BMV foam and tacrolimus ointment (Protopic) (applied to the same skin site in either order) on cutaneous penetration of BMV over a 24-hour period was analyzed.4 Results were compared to those obtained after application of BMV foam alone. Regardless of whether BMV foam was applied 5 minutes before or after tacrolimus ointment, a steady increase in the cumulative amount of BMV penetration was observed over 24 hours. Cumulative amount (% dose) of BMV penetrating skin was greatest with application of BMV foam followed by tacrolimus ointment. Interestingly, cumulative BMV penetration after 24 hours was slightly higher when BMV foam was applied 5 minutes after tacrolimus ointment than after BMV foam alone. In addition to establishing the compatibility of BMV foam when used concomitantly with tacrolimus ointment, this study suggests that BMV skin penetration from the foam vehicle is not adversely impacted by concurrent use of an ointment base, regardless of the order of application. Maximum penetration of BMV occurs if foam is applied before the ointment base. The highly effective clinical response observed with the BMV foam-topical pimecrolimus (Elidel) combination suggests compatibility when BMV foam is applied prior to a cream vehicle.3 Case Studies: BMV and CP Foams Used in Combination with Other Agents The following case reviews and summaries demonstrate clinical applications of BMV foam and CP foam used effectively in combination with other topical agents. Chronic Plaque Psoriasis Case Summary. A 63-year-old male presented with a 10-year history of plaque psoriasis involving the knees and legs (see top left photo on page 63). Multiple plaques were noted on both knees and anterior surfaces of both legs. Previous treatment included topical tar preparations and topical corticosteroids. Recent use of triamcinolone 0.1% ointment over a period of 8 weeks produced a partial response in terms of plaque thickness and erythema (40% to 50% reduction). At this point, the patient was diagnosed with “partially treated chronic plaque psoriasis.” Treatment was changed to CP foam followed by calcipotriene 0.05% ointment twice daily for the first 2 weeks. At this point, topical calcipotriene was continued twice daily every day with reduction of CP foam to “weekend therapy” using two applications on 2 consecutive days per week (Saturday and Sunday). When used concomitantly, the patient was instructed to apply CP foam before calcipotriene ointment. Response. Significant continued improvement was noted after the first 2 weeks, with 80 % clearance of lesions observed over the first 4 weeks. Complete clearance of most lesions occurred after 8 weeks of combination therapy with residual lesions almost completely cleared. Maintenance of disease control was sustained with this approach (see photo at top right). Both the patient and physician rated the response as “marked improvement.” Cosmetic acceptability and ease of use were rated by the patient as “excellent.” No adverse events were noted. Summary. The initial combination of CP foam and calcipotriene ointment over an 8-week period, followed by reduction of CP foam use to twice daily on two consecutive days (“weekend therapy”) along with continued use of calcipotriene twice daily every day, is a highly effective method for the treatment of chronic plaque psoriasis. In addition, the risk of side effects associated with topical corticosteroid application is reduced due to the lessened frequency of application. The potential for tachyphylaxis is reduced due to intermittent corticosteroid application. Atopic Dermatitis Case Summary. A 7-year-old male presented with a 2-year history of atopic dermatitis. The current exacerbation began 4 weeks ago. Eczematous patches were noted bilaterally on the upper and lower extremities including antecubital and popliteal fossae (see top left photo on page 64). Disease severity was graded as moderate. Pruritus was rated as severe. Current therapy included only a gentle cleanser and emollient without success. Treatment was initiated twice daily with BMV foam followed in 5 to 10 minutes by pimecrolimus 1% cream. Specific cleanser and moisturizer products were provided with usage instructions given. Response. Complete clearance of the eruption was reported within 4 days. Pruritus cleared completely within 2 days (see top right photo on page 64). After BMV foam application on the first 2 days, transient stinging was noted that did not interfere with compliant use of either BMV foam or topical pimecrolimus. After the first 2 days of therapy, stinging was no longer noted and no other adverse reactions were observed. Summary. The topical combination of a corticosteroid and calcineurin inhibitor is highly effective in clearing signs and symptoms of atopic dermatitis. In many patients, the response to treatment is rapid, including the resolution of pruritus and visible signs of the disease. Although further study is needed in larger trials, an additive or synergistic effect is suspected based on the observations of highly effective clinical response in several patients and the different modes of action of corticosteroids and calcineurin inhibitors. Once disease exacerbation is achieved, the topical calcineurin inhibitor may be used to maintain disease control early at the immediate onset of signs and symptoms, along with appropriate skin care practices and avoidance of recognized flare factors. Topical corticosteroid therapy is reinitiated upon the development of uncontrolled flare of the disease. During treatment with the topical corticosteroid, application of the topical calcineurin inhibitor is also continued. This approach may serve to optimize long term control of atopic dermatitis by sustaining a more even and prolonged maintenance of a “disease-free” state and by keeping the patient off of the “therapeutic roller coaster.” The rapid onset and high efficacy of topical corticosteroid therapy is preserved by this approach while at the same time decreasing the risk for adverse effects due to reduced duration of use and lessened frequency of need.8 Alopecia Areata Case Summary. A 42-year-old female presented with multiple discoid and oblong patches of alopecia areata located on the scalp (see bottom left photo above). Onset was noted approximately 2 months prior to presentation. No previous history of alopecia areata was noted and the patient was on no treatment for the disorder. Past medical history and medication history were unremarkable. Treatment options and risks were reviewed. Therapy was initiated with twice daily application of BMV foam followed by pimecrolimus 1% cream. Response. After 4 weeks of therapy, a marked increase in terminal hair growth was noted diffusely within patches of scalp alopecia (see bottom right photo above). A 75% improvement in overall increased hair regrowth was observed. At this point, intralesional corticosteroid injections were completed to residual sites that were significantly minimized in the area of involvement as compared to baseline. Full regrowth was observed at follow-up 6 weeks later. Summary. The observation in uncontrolled trials that cyclosporin, an orally administered calcineurin inhibitor, stimulates hair regrowth in patients with alopecia areata opens a new avenue of therapeutic endeavor.10 Due to the potential systemic toxicity associated with oral cyclosporin, careful evaluation of the benefit-versus-risk ratio limits consideration of its use to severe and extensive cases of alopecia areata, with treatment carefully selected based on an assessment of the individual patient. The availability of topical calcineurin inhibitors offers potential therapy with a highly favorable benefit-versus-risk assessment. The case presented above demonstrates a highly positive response to twice-daily combination therapy with BMV foam and topical pimecrolimus. The author has observed two other cases with a similar favorable response using the same combination regimen.11 A 38-year-old female exhibited 60% regrowth within 6 weeks and a 9-year-old female demonstrated 50% regrowth after 4 weeks. The ability to induce relatively rapid regrowth of hair, including a marked partial response, is significant in the treatment of alopecia areata, especially as topical monotherapy with a variety of agents is commonly fraught with failure. When effective, conventional topical therapies for alopecia areata are often slow in onset. The ability of the BMV foam-pimecrolimus cream combination to quickly induce significant hair regrowth (50% to 75%) in the three cases reported above provided a high level of patient satisfaction and confidence and allowed for a marked decrease in the amount and extent of intralesional corticosteroid injection required. Winning Combinations Available evidence supports the compatibility of BMV foam (Luxiq) and CP foam (Olux) used in combination with several other topical agents, including calcipotriene, pimecrolimus and tacrolimus. Topical combination therapy approaches offer significant advantages when rationally utilized. Depending on the disease state under treatment, potential and observed advantages of combination therapy using topical corticosteroids with other agents include additive or synergistic therapeutic effect, rapid onset of clinical benefit, reduced application frequency, prevention of tachyphylaxis and decreased risk of adverse reactions.
D ermatologists are no strangers to using many different combinations of drugs to help treat patients’ myriad dermatoses. However, with the advent of corticosteroid foam formulations, an old familiar friend (the corticosteroid) can be teamed up with a new(er) kid on the block (the foam vehicle) to use in conjunction with a whole host of agents. To see what combination therapies practitioners have tapped into in this genre, this article reviewes pharmacokinetic studies evaluating drug penetration and compatibility of topical corticosteroids formulated in a specific foam vehicle with other topical agents likely to be used in combination in the clinical setting. This article shares case studies using combination treatments, and, where available, highlights pharmacokinetic information related to agents other than topical corticosteroids formulated in the same foam vehicle. A Look at the Combination Therapies Highlighted in this Article Topical corticosteroid foam formulations available in the United States include betamethasone valerate (BMV) 0.12 % foam (Luxiq) and clobetasol propionate (CP) 0.05% foam (Olux). Both are approved for use in adult patients with steroid-responsive dermatoses affecting the scalp, with CP foam also approved for treatment of psoriasis affecting both scalp and non-scalp sites. BMV foam and CP foam have both been shown to be effective for several dermatoses affecting off-scalp locations. Since topical corticosteroids are commonly used in combination with other agents, such as topical calcineurin inhibitors, calcipotriene (Do-vonex) and tazar-otene (Tazorac), this article evaluates the interaction and impact of the foam vehicle when used in combination with other topical agents. Available studies suggest compatibility with several other vehicles and therapeutic agents from both cutaneous pharmacokinetic and clinical perspectives. Compatibility, Penetration and Clinical Impact The following reviews topical calcipotriene and topical calcineurin inhibitors and discuss their compatibility with the foam vehicle. BMV Foam/CP Foam and Topical Calcipotriene. Although monotherapy with calcipotriene has produced only modest benefit for the treatment of chronic plaque psoriasis, the combination of calcipotriene with other modalities such as a topical corticosteroids, topical tazarotene and phototherapy (UVB, PUVA) are frequently utilized due to recognition of overall improvement in therapeutic benefit.1 The potential instability of topically applied calcipotriene when used in combination with other modalities, such as UVA exposure, has been recognized. This tendency has warranted a closer analysis of calcipotriene’s stability when it’s used concurrently with individual chemical agents and specific vehicles.1 One such study used an in vitro model with human skin obtained from three cadaver donors. The stability of calcipotriene, which was applied as solution alone after 4 and 12 hours, was compared with results obtained when calcipotriene solution was applied 2 to 3 minutes after either BMV foam or CP foam.2 The concentration of calcipotriene after repeated washings of the skin was measured with high-pressure liquid chromatography (HPLC). This experiment demonstrated that after calcipotriene alone was applied to the skin, over time recovery of calcipotriene from skin surfaces greatly decreased. Researchers found that after 4 hours, 63% of the calcipotriene was recovered, compared with only 49% of the agent after 12 hours. Of course, factors that contribute to a lower percentage of calcipotriene on the skin’s surface include the following: • deeper permeation into the skin over time • exfoliation • metabolic degradative processes • photodegradation. When study participants applied either BMV foam or CP foam prior to calcipotriene, no reduction occurred in the recovery rates of intact calcipotriene from the skin surface within 4 hours, and minimal changes were seen within 12 hours. Corticosteroid Foam and Topical Calcineurin Inhibitors. An observational trial evaluated combination therapy with BMV foam and pimecrolimus 1% cream applied twice daily for the treatment of pediatric and adults patients (n = 12) presenting with a flare of atopic dermatitis. Results demonstrated rapid clearance or marked improvement within 7 days or less of clinical signs of the disease in 83% of patients and pruritus in 91% of patients.3 A significant observation was rapid reduction of pruritis, usually within the first 1 to 3 days in most patients. Overall, excellent tolerability and patient acceptability was noted with one child (age 5 years) discontinuing therapy due to stinging of the skin; transient mild or moderate stinging was noted after application of BMV foam in four children, ages 2, 6, 7 and 8 years, without interruption of therapy In the trial discussed above utilizing BMV foam and topical pimecrolimus, BMV foam was applied before pimecrolimus 1% cream. This order of application was selected as the foam vehicle rapidly dissipates into skin without residue, supporting a high level of compatibility when used prior to application of other topical agents, including moisturizers. In an in vitro study utilizing dermatomed human skin, the impact of sequential use of BMV foam and tacrolimus ointment (Protopic) (applied to the same skin site in either order) on cutaneous penetration of BMV over a 24-hour period was analyzed.4 Results were compared to those obtained after application of BMV foam alone. Regardless of whether BMV foam was applied 5 minutes before or after tacrolimus ointment, a steady increase in the cumulative amount of BMV penetration was observed over 24 hours. Cumulative amount (% dose) of BMV penetrating skin was greatest with application of BMV foam followed by tacrolimus ointment. Interestingly, cumulative BMV penetration after 24 hours was slightly higher when BMV foam was applied 5 minutes after tacrolimus ointment than after BMV foam alone. In addition to establishing the compatibility of BMV foam when used concomitantly with tacrolimus ointment, this study suggests that BMV skin penetration from the foam vehicle is not adversely impacted by concurrent use of an ointment base, regardless of the order of application. Maximum penetration of BMV occurs if foam is applied before the ointment base. The highly effective clinical response observed with the BMV foam-topical pimecrolimus (Elidel) combination suggests compatibility when BMV foam is applied prior to a cream vehicle.3 Case Studies: BMV and CP Foams Used in Combination with Other Agents The following case reviews and summaries demonstrate clinical applications of BMV foam and CP foam used effectively in combination with other topical agents. Chronic Plaque Psoriasis Case Summary. A 63-year-old male presented with a 10-year history of plaque psoriasis involving the knees and legs (see top left photo on page 63). Multiple plaques were noted on both knees and anterior surfaces of both legs. Previous treatment included topical tar preparations and topical corticosteroids. Recent use of triamcinolone 0.1% ointment over a period of 8 weeks produced a partial response in terms of plaque thickness and erythema (40% to 50% reduction). At this point, the patient was diagnosed with “partially treated chronic plaque psoriasis.” Treatment was changed to CP foam followed by calcipotriene 0.05% ointment twice daily for the first 2 weeks. At this point, topical calcipotriene was continued twice daily every day with reduction of CP foam to “weekend therapy” using two applications on 2 consecutive days per week (Saturday and Sunday). When used concomitantly, the patient was instructed to apply CP foam before calcipotriene ointment. Response. Significant continued improvement was noted after the first 2 weeks, with 80 % clearance of lesions observed over the first 4 weeks. Complete clearance of most lesions occurred after 8 weeks of combination therapy with residual lesions almost completely cleared. Maintenance of disease control was sustained with this approach (see photo at top right). Both the patient and physician rated the response as “marked improvement.” Cosmetic acceptability and ease of use were rated by the patient as “excellent.” No adverse events were noted. Summary. The initial combination of CP foam and calcipotriene ointment over an 8-week period, followed by reduction of CP foam use to twice daily on two consecutive days (“weekend therapy”) along with continued use of calcipotriene twice daily every day, is a highly effective method for the treatment of chronic plaque psoriasis. In addition, the risk of side effects associated with topical corticosteroid application is reduced due to the lessened frequency of application. The potential for tachyphylaxis is reduced due to intermittent corticosteroid application. Atopic Dermatitis Case Summary. A 7-year-old male presented with a 2-year history of atopic dermatitis. The current exacerbation began 4 weeks ago. Eczematous patches were noted bilaterally on the upper and lower extremities including antecubital and popliteal fossae (see top left photo on page 64). Disease severity was graded as moderate. Pruritus was rated as severe. Current therapy included only a gentle cleanser and emollient without success. Treatment was initiated twice daily with BMV foam followed in 5 to 10 minutes by pimecrolimus 1% cream. Specific cleanser and moisturizer products were provided with usage instructions given. Response. Complete clearance of the eruption was reported within 4 days. Pruritus cleared completely within 2 days (see top right photo on page 64). After BMV foam application on the first 2 days, transient stinging was noted that did not interfere with compliant use of either BMV foam or topical pimecrolimus. After the first 2 days of therapy, stinging was no longer noted and no other adverse reactions were observed. Summary. The topical combination of a corticosteroid and calcineurin inhibitor is highly effective in clearing signs and symptoms of atopic dermatitis. In many patients, the response to treatment is rapid, including the resolution of pruritus and visible signs of the disease. Although further study is needed in larger trials, an additive or synergistic effect is suspected based on the observations of highly effective clinical response in several patients and the different modes of action of corticosteroids and calcineurin inhibitors. Once disease exacerbation is achieved, the topical calcineurin inhibitor may be used to maintain disease control early at the immediate onset of signs and symptoms, along with appropriate skin care practices and avoidance of recognized flare factors. Topical corticosteroid therapy is reinitiated upon the development of uncontrolled flare of the disease. During treatment with the topical corticosteroid, application of the topical calcineurin inhibitor is also continued. This approach may serve to optimize long term control of atopic dermatitis by sustaining a more even and prolonged maintenance of a “disease-free” state and by keeping the patient off of the “therapeutic roller coaster.” The rapid onset and high efficacy of topical corticosteroid therapy is preserved by this approach while at the same time decreasing the risk for adverse effects due to reduced duration of use and lessened frequency of need.8 Alopecia Areata Case Summary. A 42-year-old female presented with multiple discoid and oblong patches of alopecia areata located on the scalp (see bottom left photo above). Onset was noted approximately 2 months prior to presentation. No previous history of alopecia areata was noted and the patient was on no treatment for the disorder. Past medical history and medication history were unremarkable. Treatment options and risks were reviewed. Therapy was initiated with twice daily application of BMV foam followed by pimecrolimus 1% cream. Response. After 4 weeks of therapy, a marked increase in terminal hair growth was noted diffusely within patches of scalp alopecia (see bottom right photo above). A 75% improvement in overall increased hair regrowth was observed. At this point, intralesional corticosteroid injections were completed to residual sites that were significantly minimized in the area of involvement as compared to baseline. Full regrowth was observed at follow-up 6 weeks later. Summary. The observation in uncontrolled trials that cyclosporin, an orally administered calcineurin inhibitor, stimulates hair regrowth in patients with alopecia areata opens a new avenue of therapeutic endeavor.10 Due to the potential systemic toxicity associated with oral cyclosporin, careful evaluation of the benefit-versus-risk ratio limits consideration of its use to severe and extensive cases of alopecia areata, with treatment carefully selected based on an assessment of the individual patient. The availability of topical calcineurin inhibitors offers potential therapy with a highly favorable benefit-versus-risk assessment. The case presented above demonstrates a highly positive response to twice-daily combination therapy with BMV foam and topical pimecrolimus. The author has observed two other cases with a similar favorable response using the same combination regimen.11 A 38-year-old female exhibited 60% regrowth within 6 weeks and a 9-year-old female demonstrated 50% regrowth after 4 weeks. The ability to induce relatively rapid regrowth of hair, including a marked partial response, is significant in the treatment of alopecia areata, especially as topical monotherapy with a variety of agents is commonly fraught with failure. When effective, conventional topical therapies for alopecia areata are often slow in onset. The ability of the BMV foam-pimecrolimus cream combination to quickly induce significant hair regrowth (50% to 75%) in the three cases reported above provided a high level of patient satisfaction and confidence and allowed for a marked decrease in the amount and extent of intralesional corticosteroid injection required. Winning Combinations Available evidence supports the compatibility of BMV foam (Luxiq) and CP foam (Olux) used in combination with several other topical agents, including calcipotriene, pimecrolimus and tacrolimus. Topical combination therapy approaches offer significant advantages when rationally utilized. Depending on the disease state under treatment, potential and observed advantages of combination therapy using topical corticosteroids with other agents include additive or synergistic therapeutic effect, rapid onset of clinical benefit, reduced application frequency, prevention of tachyphylaxis and decreased risk of adverse reactions.
