Disclosures: The authors disclosed receipt of the following financial support for the research, authorship, and publication of this manuscript. This work was supported by an unrestricted educational grant from La Roche-Posay Canada. All authors contributed to the study and the manuscript, reviewed it, and agreed with its content. LG: AbbVie, Amgen, Bausch Health, Boehringer Ingelheim, Celgene, Eli Lilly, Galderma, Janssen, La Roche Posay, LEO Pharma, Merck Frosst, Novartis, Pfizer, Sun Pharmaceuticals, and UCB – consultant, investigator, and speaker; BMS Consultant and investigator.

Abstract

Introduction: Over the years, the number of surgical excisions, cryosurgery, electrodesiccation, curettage, and facial laser treatment has increased. Presently pre- and post-procedural care and minor wound management remain highly variable, and standards are lacking. This review addresses peri-procedural treatment requirements to optimize outcomes, prevent infection, enhance comfort, and reduce downtime while reducing inflammation and time to healing.

Methods: A panel of eight Canadian dermatologists (panel) who perform dermato-surgery convened to discuss the findings of a structured literature search on peri-procedural measures for surgical excision, cryosurgery, electrodesiccation, curettage, and facial laser treatment. The information from the literature searches, together with the panels’ expert opinions and experience, was applied in this review.

Results: Peri-procedural measures depend on individual patient factors and the type of treatment. Post-procedure moisturizer application may be beneficial for promoting wound healing. Studies have shown no differences in infection rates between post-procedural sites treated with topical antibiotics and petrolatum-based products. Moreover, topical antibiotics are among the top ten allergic contact dermatitis-causing agents.

Conclusions: Cutaneous healing should occur with minimal discomfort and an esthetic scar. Applying a moisturizer without an antibiotic was shown to be beneficial in promoting cutaneous healing. Standards for peri-procedural care and minor wound management may support healthcare providers in improving patient outcomes.

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Introduction

Over the years, the number of skin surgery procedures (surgical shave and elliptical excision, Mohs surgery, cryosurgery, electrodesiccation, curettage, electrodesiccation and curettage (ED&C), laser, and other facial rejuvenation treatments) has increased. The American Society for Dermatologic Surgery reported over 15.6 million cosmetic treatments performed in 2020 in the United States (U.S.) alone.¹ About 13.3 million of these were minimally invasive cosmetic procedures, including neuromodulator injections, soft tissue filler injections, microdermabrasion and chemical peels).¹ The top minimally invasive cosmetic procedures comprised neurotoxins 3.65 million (33%), dermal fillers 1.85 million (32%), skin treatment (chemical peels, hydro-facials) 1.39 million (6%), hair removal 0.45 million (2%), skin treatment (combination Lasers) 0.43 million (4%) and skin tightening 0.39 million (7%).²

While many guidance and consensus documents exist that describe best practices for performing skin surgery procedures, few discuss specific pre- and post-procedure measures. Surveys of aesthetic medicine providers confirmed a lack of consistency in the types and duration of peri-procedural measures for dermatosurgery, laser, and minimally invasive cosmetic procedures.^3,4 Presently, skin surgery pre and post clinical care and minor wound management remain highly variable and there are no standards,^3,4 however, cutaneous healing should occur with minimal discomfort and an esthetic scar. This review addresses peri-procedural treatment requirements to optimize outcomes, prevent infection, enhance comfort, and reduce downtime while reducing inflammation and time to healing.

Methods

The project aims to provide insights into skin conditions and lesions created when performing dermatosurgery, minimally invasive cosmetic procedures, and facial laser treatment, followed by developing standards for these measures.

A panel of eight Canadian dermatologists (panel) who perform skin surgery was convened to discuss the findings of a structured literature search on peri-procedural measures for surgical excision, cryosurgery, electrodesiccation, curettage, and facial laser treatment.

We searched PubMed and Google Scholar (secondary source) databases for studies published from 2010 until September 2022. We divided the search terms into four groups to allow optimal results and avoid duplications.

Group 1: Pre-/post-procedure measures AND surgical excision OR curettage OR ED & C) OR cryotherapy OR facial laser treatment; AND Guidelines OR Algorithms OR consensus papers; AND Adverse events OR Complications OR Pain OR Bruising OR Swelling OR Discoloration OR Infection OR Reactivation of herpes simplex virus OR Antiviral medication OR Scarring OR Comfort OR Sun exposure; AND antimicrobial stewardship OR topical antimicrobials OR systemic antimicrobials

Group 2: Surgical excision, curettage, ED & C, cryotherapy AND healing by primary intent; AND post-procedure measures OR skincare OR topical wound treatment OR wound dressings

Group 3: Surgical excision healing by secondary intent; AND post-procedure measures OR skincare OR topical wound treatment OR wound dressings

Group 4: Peri-procedure measures for laser treatment; AND Guidelines OR Algorithms OR Consensus papers; AND Adverse events OR Complications OR Pain OR Bruising OR Swelling OR Discoloration OR Infection OR Reactivation of herpes simplex virus OR Antiviral medication OR Scarring OR Comfort OR Sun exposure OR Skincare OR wound healing regimen

Exclusion criteria were no original data, information not specific to peri-procedure measures for skin surgery, minimally invasive procedures, and facial laser treatment, and publication in a language other than English. The results of the searches were evaluated independently by two reviewers (AA, TE) and yielded 98 papers. After reviewing abstracts and removing duplicates and papers that did not contribute to this review (n = 43), fifty-five remained. Guidance and consensus documents are available on dermatosurgery, minimally invasive procedures, and facial laser treatment; however, few discussed peri-procedural measures and wound treatment which did not allow for grading.

Results

Procedures Included in the Review

The review addresses the following procedures: surgical excision, cryotherapy, electrodesiccation, curettage, ED&C, and facial laser treatment.

Surgical Excision

A Canadian national survey amongst dermatologists showed that epileptiform excisions, shave excisions, punch biopsies, curettage, and ED&C was most frequently performed, whereas Mohs micrographic surgery (MMS) was the least frequent procedure.⁵ These procedures are used to remove benign and malignant lesions.⁵

Adverse events are usually minor and include bleeding, hematoma, wound dehiscence, infection, discoloration (post-inflammatory hyper (PIH) or hypopigmentation), and atrophic, hypertrophic, or keloid scar formation.⁵

Curettage and Electrodesiccation

Curettage or electrodesiccation can be used to remove benign (e.g. condyloma acuminatum, seborrheic keratosis, pyogenic granuloma, excess granulation tissue) and malignant lesions. With malignant lesions, curettage is often combined with electrodesiccation (ED&C) or cryotherapy. For many indications, ED&C has been replaced by curettage alone, as it yields similar cure rates and a better cosmetic outcome.^12-16 Dermatologists routinely perform these procedures in their offices.

The disadvantage of curettage with or without electrodesiccation or cryotherapy is the absence of histopathologic margin evaluation.^13-15 Studies on low-risk non-melanoma skin cancers show 5-year ED&C cure rates from 91 to 97%.^15,16

Cryosurgery

Cryosurgery has several indications for both benign and malignant lesions. Benign lesions that can be treated with cryosurgery include seborrheic keratosis, verruca, skin tags, molluscum contagiosum, solar or senile lentigo, and actinic keratosis.^16-20 In the case of exophytic lesions, curettage should be considered prior to cryotherapy. This procedure can be delivered quickly and cost-effectively in an outpatient setting.^16-20

Recurrence rates of actinic keratoses treated with cryotherapy vary significantly (1–39%) in prospective studies likely due to a lack of homogeneity in patient and tumor selection, follow-up period, and inter-operator performance approach.^19,20 Malignant lesions can be treated with this modality, but the depth and extent of freezing may not be known without the use of a cryoprobe. Light cryotherapy often leaves no mark but may not remove the desired lesions. A deeper freeze may be associated with permanent white marks due to the destruction of melanocytes, postinflammatory hyperpigmentation, pseudoepitheliomatous hyperplasia, and depressed scars, which may resolve spontaneously, alopecia which may be permanent due to the destruction of hair bulge cells, and tissue distortion (e.g. nail dystrophy or notching of cartilage) due to damage to the nail matrix/cartilage.¹⁶ Cryosurgery should not be used for conditions that can be exacerbated by cold exposure (cryoglobulinemia, multiple myeloma, Raynaud disease, cold urticaria) and a previous history of cold-induced injury or poor circulation at the site or in that body part.¹⁷ Vasoconstriction induced by cryosurgery in poorly perfused areas may lead to tissue necrosis.¹⁷

Facial Laser treatment

Many different types of lasers are available, and laser treatment has many indications.³ Pulsed dye lasers (PDL) may be used for the treatment of port wine stains in adults and children. A further indication for PDL may be the treatment of telangiectatic rosacea.³ Other indications include radiodermatitis, ulcerated hemangioma, and erythrose of the neck.

For hair removal, various types of lasers, such as pulsed diode lasers, Nd: YAG lasers, or intense pulsed light (IPL) lasers, can be used.³ With the proper preparation and an experienced provider, patients with richly pigmented skin can also safely undergo laser and light-based treatments for hair removal, pigment abnormalities, skin resurfacing, and skin tightening.²¹ Facial rejuvenation aims to correct rhytides, telangiectasias, lentigines, and skin texture.³ Laser and energy devices may be used for facial resurfacing, depending on clinical indication, individual subject characteristics, and the operator’s expertise.^3,4 Lasers, such as CO2 or erbium laser, can be used to remove tattoos, Ota’s nevus, and, to a lesser degree, liver spots and Becker’s nevus.^3,21-24 These lasers permit dermabrasion in treating verrucous hematoma, extensive benign superficial dermo-epidermal lesions, and the esthetic treatment of non-muscular wrinkles, i.e., excepting wrinkles of the forehead and nasal sulcus.^21-24 Laser-assisted administration of photodynamic therapy (PDT) photosensitizers has demonstrated efficacy for superficial BCC.^25-27 The recurrence rates of BCC were markedly reduced in two randomized controlled trials using aminolaevulinic acid PDT with erbium compared to PDT and erbium.^25-27

Cutaneous adverse events with all types of laser treatment, such as reactive hyperemia, edema, scarring, and discomfort, may occur.^3,21-24

Pre-procedural Measures

All Discussed Procedures

Skin conditions and infections can exacerbate and cause complications following skin surgery.^3,4,28,29 For all patients considering having a procedure done, medical history including current and previous treatments, including procedures for the lesion under question, what the patient and treating physician hope to accomplish with the proposed procedure, current medications, and allergies, history of systemic disease, history of abnormal wound healing such as post-inflammatory dyspigmentations, abnormal scarring.^3,4,28,29 In patients that have had previous surgical treatments anywhere on their body, it is often good to assess the resultant scars prior to agreeing to perform a procedure on the individual.

Before the procedure, patients should attend the clinic with clean skin without makeup or cosmetics in the area to be treated.^30-34 Hair should be secured away from the treatment area. Patients should not shave since shaving can cause micro-wounds and increase the risk of infection.

Curettage, Electrodesiccation, ED&C, and Cryotherapy

Typically, additional pre-procedural measures are not required.

Laser Treatment

Laser devices are frequently used for facial rejuvenation. Device and treatment choice depends on individual patient characteristics, expectations, and physician expertise.^22-24 For optimal treatment outcomes, patients should be appropriately selected and screened, followed by a physical exam before treatment, depending on the type of procedure.^23,24 Outcomes of previous skin or surgical treatments are obtained, especially dermabrasion (if previously performed) responses.^28,29 People with hypertrophic scars, keloids, or changes in pigmentation will need peri-procedural cosmetic practices to reduce the risk of these complications or should be advised against the procedure.^28,29 Previously published surveys and algorithms confirmed more than 90% of clinicians recommended sun avoidance before, during, and after facial cosmetic treatments.^3,28,29

Peri-procedural measures are based on individual patient factors and the type of laser procedure.^21-24 For patients receiving ablative laser therapy, pre-treatment of underlying conditions, such as rosacea, dermatitis, and prevention of recurrences in patients with recurrent Herpes simplex, may reduce complications and enable adequate healing time to restore the skin’s barrier function.^3,28 Check patients for remote infections. Caution should be applied when considering extensive laser procedures in patients with compromised immune systems, such as HIV, cancer treatment, immunotherapy, or poorly controlled diabetes.^3-28

Measures During the Procedure

Surgical Excision

Prior to the procedure, the surgical site may be prepared with chlorhexidine (2%), isopropyl alcohol (70%), or hypochlorous acid (HOCL).^30-34 Povidone iodine is less commonly used since it is messy and permanently stains clothing. Chlorhexidine is an effective cleanser but may induce allergic contact dermatitis and can be toxic to the eyes and ears, whereas isopropyl alcohol is flammable and can irritate the skin.^31,32 Stabilized HOCL is highly active against bacteria, viruses, and fungal organisms without chlorhexidine’s oto or ocular toxicity; it has been proposed as a future gold standard for wound care.³³ HOCL has been shown to have dose-dependent favorable effects on fibroblast and keratinocyte migration compared to povidone-iodine and media alone.^33,34 It also increases skin oxygenation at treatment sites which may aid healing. There is evidence that HOCL may reduce the risk of hypertrophic scars and keloids as it reduces inflammation and the risk of infection. ^33,34

Local anesthesia and pain management can be customized depending need based on the procedure and patient factors and added at the treating physician’s discretion.

Cryosurgery, Electrodesiccation, Curettage, ED&C

Minimal skin preparation is needed for cryosurgery, ED or curettage if the procedure does not result in bleeding. Therefore, antiseptics are not typically indicated in the majority of procedures.¹⁶ However, topical antiseptics should be applied to lesions that are to be curetted or treated with ED&C.¹⁶

Pain management can be customized depending on the procedure and added at the treating physician’s discretion. Pre-procedure anesthesia should be considered for lesions to be curetted or treated with ED&C and large or extensive lesions. Topical anesthetics applied several hours before the procedure or intralesional anesthesia can help reduce surgical pain. For small lesions, injection of local anesthetic may be more painful than the procedure itself and is therefore not indicated.

Laser Treatment

Before the procedure, makeup removal and skin cleansing using a gentle cleanser is required.^30-34 The treatment site is prepared with chlorhexidine (2%), isopropyl alcohol (70%), or hypochlorous acid (HOCL).^30-34 Local anesthesia and pain management can be customized depending on the procedure and added at the discretion of the treating physician.^28,29

Post-procedural and Wound Healing Measures

Surgical Excision Healing by Primary Intent

A local anesthetic given before the procedure takes about 1-2 hours to wear off. For further pain management post-surgery, oral acetaminophen is preferred over aspirin, naproxen, or ibuprofen, as the latter encourages bleeding.

Topical postoperative wound care involves maintaining a protected wound and a clean, moisturized surface.^35,36 Wound care includes cleansing with either a gentle cleanser or water, applying a topical, and covering the wound with a dressing.^35,36 While previous investigators have evaluated methods for reducing risks of adverse events due to the treatment procedure, robust studies on post-procedural wound management for primarily closed wounds are lacking.^35-38

Physicians typically cover sutured wounds using either a dressing, adhesive tape strips, or both.^35-38 Wound dressings can be classified according to their function, material, and physical form of the dressing (Table 1).³⁵ Wound dressings for sutured wounds are typically left in place for 24-48 hours after surgery.^35-37 If there is a lot of tension on the wound or bleeding during the procedure, the dressing is typically left on for 2 or more days. The dressing can act as a physical barrier to protect the wound until skin continuity is restored and to absorb exudate from the wound, and prevent bacterial contamination from the external environment.^35-37 Some studies have found that the moist environment created by some dressings accelerates wound healing, although excessive exudate can cause maceration of the suture line and peri-wound skin.^35-37 A dressing should absorb wound exudate, minimize maceration and prevent bacterial contamination.³⁶

Table 1: Types of wound dressings and moisturizers

The utility of dressing surgical wounds beyond 48 hours of surgery is controversial, although^35-37 in addition to the above, dressings can prevent irritation from rubbing from clothing.

A systematic review on early versus delayed dressing removal after primary closure of clean superficial wounds found no detrimental effect on the patient when removing the dressing after 24 hours.³⁵ However, the point estimate supporting the conclusion is based on very low-quality evidence.³⁵

Cleansing the suture line after dressing removal post-procedure using an antimicrobial solution or applying an antimicrobial ointment is equally controversial.^35,36

The incidence of surgical site infections (SSI) varies between 1% and 80% depending upon the types of surgery, the hospital setting (community hospital, tertiary‐care hospital, etc.), the classification of surgical wounds, and the method of skin closure.³⁵ In addition, many skin surgeries are performed in the community in physician offices where infection rates range from 0.2% to 2.5%.⁴¹ Antimicrobial resistance is a growing concern, especially when antimicrobial products are used routinely and inappropriately.^39-44 Moisturizers are frequently used to keep the wound moist; however, evidence for beneficial effects on sutured wounds is inconclusive and mainly from small studies.^45-50

After suture removal, the topical application of a moisturizer containing madecassoside, panthenol, and copper-zinc-manganese has been shown to be beneficial.^45-48 The product is available as a cream, emollient, drops, gel, lotion, oil, ointment, solution, and spray in a concentration of 2-5%.^45-48 Petrolatum jelly and water-free petrolatum-containing ointments or products containing HOCL may also be used postoperatively to keep the wound moist, however, since they are occlusive, they may induce maceration.^49,50

In a study on postoperative wound care after MMS procedures (N = 76) patients were randomized to wound care with an ointment containing petrolatum, humectants, and natural barrier lipids (group 1: n = 27), white petrolatum (group 2: n = 32) or no ointment (group 3: n = 17).⁵⁰ Group 1 demonstrated an incidence of swelling and erythema of 52% (14/27); in group 2 erythema occurred in 12% (4/32) and swelling and erythema in 9% (3/27); and in group 3 erythema was noted in 12% (2/17) and swelling and erythema in 6% (1/17) patients.⁵⁰ The use of antibiotic-containing ointments is best avoided as they may cause allergic reactions and contribute to antimicrobial resistance.^39-44 Moreover, the rate of surgical site infections in minor surgical wounds is low and preventive use of topical antibiotics is not indicated.^35,44-52

If a hypertrophic scar develops, treatment with a silicone gel sheet or gel may improve the scar appearance and pain. Another option is self-adhesive propylene glycol and hydroxyethyl cellulose sheeting; however, evidence of the efficacy of these products in improving scar appearance and reduction of pain is inconclusive.⁵³

Surgical Excision, Curettage, ED&C, and Cryosurgery Healing by Secondary Intent

In a simplified model, wound healing processes occur in four phases 1) vascular response, 2) coagulation, 3) inflammation, and 4) new tissue formation.^54-57 During the initial inflammatory phase, the adaptive immune system is activated to prevent infection at the wound site.^54-57 Macrophages remove neutrophils, bacteria, and debris from the wound site. They then change phenotype to M2 macrophages, starting the proliferative and epithelialization phase, producing anti-inflammatory mediators and extracellular matrices.^54-57 If this phase is hindered, wound healing may be disturbed. The proliferative or epithelialization phase overlaps with the inflammatory phase and usually takes two to three weeks post-procedure.⁵⁴ During this phase, the dermal matrix matures, and inflammatory processes continue in the reticular dermis. The reticular dermis is sensitive to wound stress and infection and is affected by patient-related conditions such as age, sun exposure, or genetic profile.^54-57 Persistent inflammation plays a role in the development of hypertrophic or keloid scars, although it may not be the entire cause.^54-57 During the remodeling phase the wound contracts, and collagen remodeling occurs, which can last for up to a year post-procedure.

Pain management is similar to that previously discussed for primary healing wounds. Patients should be instructed to avoid sun exposure to the treated area, along with sun protection measures such as sunscreen with SPF 50 plus UVA block to prevent discoloration.^3,4,28,29

When a dressing is used post-procedure, the patient should be instructed to keep it dry and leave it in place for 24-48 hours. After dressing removal, a gentle, non-irritating cleanser can be used twice daily to cleanse the treated area.^3,4,28,29 The wound site must be handled with care, particularly during the initial healing phase of 7-10 days when newly formed epithelium can be early inadvertly removed.^3,4,28,29

Moisturizers or products containing HOCL may be applied to keep the wound moist and to promote wound healing (Table 2).^49,50 Similar to what was discussed for sutured wounds, moisturizers containing antibiotics should not be used on wounds not showing signs of infection to avoid allergic reactions and antimicrobial resistance.^39-44,49-52

Table 2: Complications from laser treatment

A moisturizer containing madecassoside, panthenol, and copper-zinc-manganese may be beneficial.^45-48 It is available as a cream, emollient, drops, gel, lotion, oil, ointment, solution, and spray in a concentration of 2-5%.^45-48,59 In an unpublished international observation study, 11,464 adults, children, and infants with a mean age of 31 years (1 week to 97 years) with superficial wounds applied the ointment for 14 days. Clinical (desquamation, cracks, erosion, erythema) and subjective symptoms (tightness, pain, burning sensation, pruritus) showed a significant improvement at 14 days, while tolerance and esthetic aspects of the ointment were rated good.

Wound Healing After Laser Procedures

For patients undergoing ablative procedures, prophylactic oral antivirals such as acyclovir (400 mg orally three times daily) or valacyclovir (500 mg orally two times daily), starting typically one day before resurfacing and continuing for 6–10 days post-procedure may be indicated.^3,28 Patients undergoing ablative laser treatment with baseline melasma or post-inflammatory hyperpigmentation may require pre-procedure lightening agents such as hydroquinone 2-4% cream twice per day in the morning and evening.^3,28

Gold and colleagues developed an algorithm for pre-/post-procedure measures for facial laser and energy device treatment and listed complications from laser treatment and actions that can be taken (Table 2).²⁸

Post-laser management is similar to that discussed for secondary healing wounds.

Limitation

Although few studies on peri-procedural measures for dermato-surgery care and minor wound management are available, the advisors recommend applying a moisturizer without antibiotics for antimicrobial stewardship and contact allergy avoidance.

Conclusion

Peri-procedural measures depend on individual patient factors and the type of dermato-surgery. Standards are required to support healthcare providers to optimize outcomes, prevent infection, enhance comfort, and reduce downtime while reducing inflammation and time to healing. Applying a moisturizer without an antibiotic was shown to be beneficial in promoting cutaneous healing. Studies are required to evaluate purpose-designed moisturizers for dermato-surgery post-procedural application improving patient outcomes.

¹Skin Centre for Dermatology, Peterborough, ON and Queen’s University, Kingston, ON, Canada
²Associate Professor, University of Toronto, ON, Canada
³Lynde Institute for Dermatology, Markham, ON, Canada
⁴Clinical Instructor, Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
⁵Assistant Professor in Clinical Teaching faculty of medicine, Sherbrooke University, Sherbrooke, QC, Canada
⁶Assistant Professor, Division of Dermatology, University of Ottawa, Ottawa, ON, Canada
⁷Dermatology, CHU de Québec-Université Laval, Quebéc, QC, Canada
⁸Centre hospitalier universitaire Dr-Georges-L.-Dumont, Moncton, NB, Canada
⁹Assistant Professor, Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada
¹⁰Queen’s University, Kingston, ON, Canada
¹¹Clinical Associate Professor, Memorial University of Newfoundland, St. John’s, NL, Canada
¹²Clinical Assistant Professor, Discipline of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada
¹³Associate Clinical Professor Dermatology, University of Calgary, AB, Canada
¹⁴Associate Professor, Dalhousie University, Halifax, NS, Canada
¹⁵Université de Montréal, Montréal and Dermatologie Sima Recherches, Verdun, QC, Canada
¹⁶Dermatology, CHU de Québec-Université Laval, Québec, QC, Canada
¹⁷Ottawa, ON, Canada
¹⁸Sunnybrook Health Sciences Centre and University of Toronto, Toronto, ON, Canada
¹⁹Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada

Introduction

Chronic hand dermatitis (CHD) can affect up to 10% of the population and have a significant impact on quality of life (QoL).^1-3 It presents as a chronic, recurrent, inflammatory condition with erythema, scaling, fissuring, pruritus and lichenification of the hands. The etiology is multi-factorial and includes both genetic and environmental factors.¹Treatment is notoriously difficult as symptoms frequently recur despite standard therapy. Undertreated CHD can lead to a substantial burden on patients as well as an economic burden on society due to reduced work productivity and many work-related compensation claims.^2-5

Recently, practical guidelines for the management of CHD were published in the Skin Therapy Letter, Family Practice Edition (October 2016).⁶ This series of cases using alitretinoin (Toctino®, GlaxoSmithKline and distributed by Actelion, Laval, QC) is a follow on to that publication to put the guidelines into context.

Abbreviations: AEs – adverse events, CHD – chronic hand dermatitis, ENT – ear, nose, and throat, HD – hand dermatitis, QoL – quality of life

Diagnosing HD – Important points to cover

• Determine if the patient has eczema, or a childhood history of eczema (erythematous, scaling patches with some fissuring in typical locations).
• Ask about a personal or family history of atopy, including asthma, seasonal ENT allergies, nasal polyps.
• Ask about a history of psoriasis and comorbidities such as psoriatic arthritis.
• Does the patient have occupational exposures that could lead to allergic or irritant contact dermatitis?
• Has the patient had any recent exposures to irritants? Frequent handwashing?
• Do a skin scraping for fungal KOH and culture to rule out tinea manuum, as needed.

Case

Case 1:

A 39-year old dairy farmer presented with a 15-year history of redness, scaling and painful fissuring of the hands. He has used multiple potent topical steroids over the years with only temporary benefit. Despite the continued use of topical steroids he reported that his symptoms always return. After a skin scraping for fungal culture was taken and reported negative, he was referred to a dermatologist for assessment.

A diagnosis of CHD was confirmed. Given the failure of potent topical steroids for >8 weeks and inability to attend regular phototherapy sessions, his dermatologist started him on alitretinoin 30 mg PO QD for a 6-month course. By week 12, his hands were almost clear and by week 24, his hands were clear. He stopped the medication after a 6-month course of alitretinoin and entered into remission. At follow up appointments at year 5 and year 11, his hands remained clear. (Figure 1 and 2)

• Alitretinoin (9-cis retinoic acid) is an endogenous retinoid (physiological vitamin A derivative) and is the only systemic agent approved for CHD. It has proven to be safe and effective for the treatment of CHD in controlled clinical trials7-10 and in real-world experience.^11-15
• In the pivotal BACH trial, 1032 patients with CHD were treated with alitretinoin (10 mg, 30 mg) or placebo for up to 24 weeks. The group that received alitretinoin 30 mg QD had up to a 75% median reduction in signs and symptoms and 48% were clear or almost clear at the week 24 time point.⁸
• In patients who were clear/almost clear, 67% did not relapse within 24 weeks off therapy. In those patients who did relapse, 80% of those re-treated with 30 mg QD recaptured their response.⁹
• Approximately half of those patients receiving 10 mg QD and 40% of those receiving 30 mg QD who did not initially respond to alitretinoin, did respond to retreatment with the 30 mg QD dose for an additional 24 weeks.¹⁰
• The majority of patients do not require long-term management with alitretinoin as some patients enter a remission period with 24 weeks of therapy. For those who relapse and require re-treatment, the majority recapture their response⁹ and in those patients who require ongoing therapy, there are no safety concerns with continuous dosing.^10,12,13

Figure 2. No further prescribed systemic or topical treatments since 2005. (2A) Year 5, (2B) Year 11.Photos courtesy of Dr. Yves Poulin

Case 2:

A 52-year old female teacher presented with a 15-year history of recurrent CHD. She had tried numerous moisturizers and mild to superpotent topical steroids over the years without relief. She tried 6 months of narrowband UVB phototherapy with only partial resolution. She was frustrated and looking for a better solution. Her past medical history is significant for obesity and hypothyroidism. Her dermatologist started her on alitretinoin 30 mg PO QD with excellent response. However, her baseline liver enzymes were 1.5 times the upper limit of normal and 2 months after initiating therapy, increased to 3 times the upper limit so the alitretinoin was discontinued.

Ultrasound demonstrated fatty liver and further work up revealed diabetes. After initiation of metformin and 10 kg of weight loss, the patient’s transaminases returned to within the normal range but her CHD flared. A repeat course of phototherapy and superpotent topical steroids failed again. Slow re-introduction of alitretinoin at 10 mg, followed by 20 mg and then 30 mg led to recapture of response and her transaminases have remained within normal range throughout a continued 3-year course of therapy with alitretinoin.

• In clinical trials, alitretinoin was well tolerated by the majority of patients, although a dose dependent effect was noted with the AE of headache (up to 21.6% with 30 mg dose, 11.6% with 10 mg dose) and with mucocutaneous side effects.^8-10
• Laboratory abnormalities consistent with a retinoid class effect were noted in the trials, with dose dependent elevations in serum cholesterol and triglycerides most commonly noted; reduced thyroid stimulating hormone was reported, but there were no cases of clinical hypothyroidism.^8-10
• A hepatic effect of alitretinoin was not identified in the clinical trials^8-10 or in real-world studies,^11,14 however transient and reversible increases in transaminases have been noted in the product monograph.¹⁶ In the case presented, her transaminitis was likely related to her underlying fatty liver; she had no further issues with ongoing alitretinoin use, once she had proper management of her comorbid conditions (obesity, diabetes). If persistent elevations in transaminases are noted, reduction of the dose or discontinuation should be considered.¹⁶
• Post-marketing surveillance of the use of alitretinoin has identified AEs of special interest in the retinoid class that were not identified in clinical trials. Depression has been reported as well as very rare cases of inflammatory bowel disease and benign intracranial hypertension.¹⁴
• Work-up and monitoring for patients taking alitretinoin is similar to other commonly used retinoids (isotretinoin, acitretin) and should include: baseline hepatic transaminases and lipid profiles, repeated at one month, and then every 2-3 months during therapy. Beta-HCG should be done in women of child-bearing potential prior to initiation of therapy and repeated monthly during therapy and one month after discontinuation.¹⁶
• Retinoids are potent teratogens so practitioners should follow the Pregnancy Prevention Program,¹⁶ and women of child-bearing potential should be counselled on strict pregnancy prevention, use of two highly effective forms of birth control simultaneously and be monitored monthly with a serum pregnancy test.¹⁶
• Of 2 pregnancies reported in the clinical trials and 12 in post-marketing reports, 13 pregnancies were terminated early (elective or spontaneous abortion) and one healthy baby was born. No congenital abnormalities have been reported to date.¹⁴

Case 3:

A 68-year old retired woman had been suffering from hand dermatitis for the past 3 years since she had been at home caring for her elderly husband. She had been applying emollients throughout the day and trying to avoid frequent hand washing. Neither the potent topical corticosteroid nor the topical calcineurin inhibitor prescribed for her have helped. She was finding chores at home difficult with fissured finger tips and could not enjoy her hobbies of knitting or gardening because of the painful fissures. She was started on alitretinoin at 30 mg PO QD and noted good response, however she suffered from frequent headaches. Her dose was reduced to 10 mg PO QD with partial return of her CHD symptoms. Addition of a potent topical steroid and a course of narrowband UVB phototherapy to the alitretinoin 10 mg QD provided an effective combination regimen to control her CHD.

• Although clinical trials excluded concomitant therapy with topical medications or phototherapy, these concomitant treatments are often continued or added in real-world practice.^11,13
• Narrowband UVB phototherapy has been shown to be effective in CHD.¹⁷
• We know from vast experience in treating psoriasis, the combination of retinoids and UVB phototherapy is a very safe and effective way to optimize treatment outcomes and can reduce the cumulative dose of UVB exposure.^18,19
• According to expert opinion based on the experiences of the authors, combination of alitretinoin with topical corticosteroids or phototherapy is safe, can improve responses and may be a good option for patients who can only tolerate the 10 mg QD dose or who have not reached clear/almost clear status with the 30 mg QD dose.¹³
• Regardless of the combination of treatments selected, always remember to assess adherence and counsel each patient on appropriate prevention and avoidance strategies, regular moisturization and proper use of medications.⁶ (see Figure 3)

Case 4:

A 34-year-old mechanic presented with a 3.5-year history of CHD. His job is dependent on the use of his hands and he has a young family to support. He responded poorly to multiple courses of mid to superpotent topical steroids and a topical calcineurin inhibitor. Contact dermatitis was suspected and he was referred to a dermatologist for patch testing.

Patch testing with the North American Contact Dermatitis Group standard series revealed a positive reaction to methylisothiazolinone, which happened to be an ingredient in the citrus hand scrub he used at work and in the wet wipes he used when changing his child’s diaper. Modification of his home and work place environment to avoid this allergen has improved his CHD somewhat but it is not clear and is still causing problems at work. He was fearful of jeopardizing his employment and requested further treatment. A course of alitretinoin at 30 mg QD was initiated with good response and he continued to avoid methylisothiazolinone at work and home.

• CHD may be related to a contact dermatitis, which can be either irritant contact dermatitis or in some cases allergic contact dermatitis.²⁰ Many times patients also have an underlying atopic diathesis putting them at increased risk of developing hand dermatitis.²¹
• Contact dermatitis should be suspected when patients are not responding to treatment or worsening despite therapy; these patients should be referred for patch testing.^20,21
• Many different allergens can be responsible for the onset or exacerbation of CHD. In this particular patient’s case, methylisothizolinene, a common preservative in personal care products,^21-23 was a factor. This outlines the importance of patch testing, and considering contact dermatitis in the differential diagnosis.
• Whether the patient has CHD of unknown etiology or due to irritant contact dermatitis, allergic contact dermatitis or underlying atopic dermatitis, alitretinoin is still an option for management as second line therapy after failure of potent or superpotent topical steroids. Patch testing can help determine if an allergen should be avoided as part of the management plan, although lengthy wait times for this test in some jurisdictions should not delay therapy. In some cases, once identified, allergen avoidance may be all that is necessary for symptom resolution.
• In the real-world observational study, PASSION, it was shown that treating CHD with alitretinoin resulted in significant and rapid improvement in symptoms, increased QoL and reduced work impairment. The number of patients rated as ‘disabled’ was reduced from 12.4% at baseline to 2.2% at week 24, and those reporting no work impairment increased from 2.7% at baseline to 63.7% at week 24, showing that alitretinoin can significantly reduce work incapacity.¹⁵

Conclusions

CHD is a common condition causing a significant impact on quality of life and an economic burden due to reduced productivity and cause for disability. Many patients do not respond to standard treatments, making it a challenging condition to manage. This case series is a follow on to a recent publication of practical guidelines for the general practitioner on the management of CHD, to put the use of alitretinoin in context. The addition of alitretinoin to our therapeutic armamentarium has changed the way we are able to manage patients who suffer from this condition, providing a safe and effective treatment option to improve QoL and reduce work impairment. When managing patients with CHD, we must always remember to confirm the diagnosis, assess adherence, counsel our patients on prevention and avoidance strategies, encourage moisturization and proper use of medications and refer patients for patch testing if a contact allergy is suspected.

Patient Resources:
https://eczemahelp.ca/
http://www.eczemacanada.ca/

Acknowledgement

The authors wish to acknowledge Evert Tuyp, MD, FRCPC for his editorial assistance in the preparation of this manuscript.

References

1. Thyssen JP, et al. Contact Dermatitis. 2010 Feb;62(2):75-87.
2. Lynde C, et al. J Cutan Med Surg. 2010 Nov-Dec;14(6):267-84.
3. Kouris A, et al. Contact Dermatitis. 2015 Jun;72(6):367-70.
4. Augustin M, et al. Br J Dermatol. 2011 Oct;165(4):845-51.
5. Cvetkovski R, et al. Br J Dermatol. 2005;152(1):93-8.
6. Gooderham M, et al. Skin Therapy Letter, Family Practice Edition. 2016 Oct;11(1):1-5.
7. Ruzicka T, et al. Arch Dermatol. 2004 Dec;140(12):1453-9.
8. Ruzicka T, et al. Br J Dermatol. 2008 Apr;158(4):808-17.
9. Bissonnette R, et al. Br J Dermatol. 2009 Feb;162(2) :420-6.
10. Lynde C, et al. Clin Exp Dermatol. 2012 Oct;37(7):712-7.
11. Diepgen TL, et al. Acta Derm Venereol. 2012 May;92(3)251-5.
12. Gulliver WP, et al. J Cutan Med Surg. 2012 May;92(3):251-5.
13. Ham K, et al. J Cutan Med Surg. 2014 Oct;18(5):332-6.
14. Morris M, et al. J Dermatolog Treat. 2016;27(1):54-8
15. Thaçi D, et al. J Dermatolog Treat. 2016 Nov;27(6):577-83.
16. Toctino® (alitretinoin) soft capsules (product monograph on the Internet). Mississauga (ON): GlaxoSmithKline Inc, Distributed by Actelion Pharmaceuticals Canada, 2016 [revised 04 APR 2016].
17. Sezer E, Etikan I. Photodermatol Photoimmunol Photomed. 2007 Feb;23(1):10-4.
18. Green C, et al. Br J Dermatol. 1992 Jul;127(1):5-9.
19. Ruzicka T, et al. Arch Dermatol. 1990 Apr;126(4):482-6.
20. Diepgen TL, et al. JDDG. 2015 Jan;13(1):77-85.
21. Mowad C, et al. J Am Acad Dermatol. 2016 Jun;74(6):1029-40.
22. Ham K, et al. Dermatitis. 2015 Jul-Aug;26(4):166-9.
23. Cahill JL, et al. Med J Australia. 2014 Mar;200(4):208

Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada

Conflicts of Interest:
CZ has no conflicts to disclose.

ABSTRACT
A triad approach to the treatment of acne and rosacea has been recommended. This integrated management approach includes patient education, selection of therapeutic agents, and initiation of an appropriate skin care regime. Proper skin care in patients undergoing treatment of both acne and rosacea includes use of products formulated for sensitive skin that cleanse, moisturize and photoprotect the skin. Both acne and rosacea are associated with epidermal barrier dysfunction, which can be mitigated by suitable skin care practices. Appropriate skin care recommendations for patients with acne and rosacea will be discussed.

Key Words:
acne, emollients, rosacea, photoprotection, skin barrier dysfunction, sunscreen, topical, transepidermal water loss

Acne

Acne vulgaris is the most common skin disease seen in dermatology office practice. Optimal management includes, in addition to selection of an appropriate therapeutic regimen, patient education and integration of proper skin care. Providing instructions on skin care and cosmetics to female acne patients improves quality of life compared to patients to whom no instructions are given.¹

Acne is associated with impaired epidermal barrier function.² Decreased stratum corneum hydration and reduced free sphingosine and total ceramide, indicative of an impaired stratum corneum intercellular lipid membrane, has been demonstrated in patients with acne. Although sebum excretion is increased in acne patients, alteration in the lipid composition of acne skin may further impair barrier function. Moreover, medications used to treat acne can alter stratum corneum integrity and function. An increase in transepidermal water loss has been shown with use of benzoyl peroxide, likely due to damage to the stratum corneum.³ Treatment with topical retinoids results in enhanced desquamation, reducing stratum corneum thickness and function. Use of appropriate skin care products in patients being treated for acne has been shown to increase adherence to pharmacological treatment and improve treatment outcomes.⁴

Cleansing

Although the majority of acne patients believe that suboptimal skin care and dirt on the skin contribute to acne,⁵ there are little scientific data to guide our recommendations regarding cleansing of acne prone skin.

The optimal frequency of cleansing is unclear, but most dermatologists recommend twice daily washing with a mild cleanser. One small study of males with mild to moderate acne compared the effect of face washing with a gentle cleanser once, twice or four times daily on acne severity.⁶ Although no statistically significant differences were noted between the groups, significant improvement in both open comedones and total inflammatory lesions were seen in the group washing twice daily. Worsening of acne was observed in the study group who washed once a day, whereas washing four times daily did not adversely affect acne severity.

Although more frequent facial cleansing may not aggravate acne, aggressive scrubbing of the involved areas should be avoided to prevent irritation and trauma to underlying comedones, leading to increased inflammation.

Moisturizing

As acne prone skin is associated with epidermal barrier dysfunction which can be aggravated by acne medications, regular use of an emollient is an importance part of acne therapy. Use of a noncomedogenic and nonacnegenic moisturizer is typically recommended. However, due to difficulties in testing for both comedogenicity and acnegenicity, including variability in individual patient susceptibility to acne formation, ensuring that a product will not trigger acne in a particular patient can be difficult.⁷

Sun Protection

Sun protection should also be recommended to acne patients.⁸ A systemic review found no convincing evidence that natural sunlight improves acne, although such studies are inherently difficult to conduct.⁹ Several oral acne treatments, including doxycycline and isotretinoin, are potentially photosensitizing.¹⁰ The US Food and Drug Administration official labelling for medications containing benzoyl peroxide and topical retinoids advises sun avoidance,^11,12 although no effect on ultraviolet Binduced erythema was shown with use of either benzoyl peroxide or adapalene in one study¹³. In addition to providing sun protection, the emollient component of the sunscreen may improve epidermal barrier function. Finally, sun protective measures may prevent or minimize postinflammatory hyperpigmentation, particularly in patients with higher skin types.¹⁴

Rosacea

TAs is the case with acne, proper skin care is an important component of the management of rosacea. A triad approach to rosacea care has been suggested, which includes treatment, patient education regarding triggers, and advice as to appropriate skin care and cosmetics.¹⁵ In a questionnaire sent to over 7000 individuals registered in the Canadian Rosacea Awareness Program, respondents expressed a strong interest in receiving more information on skin care, makeup and psychological aspects of rosacea.¹⁶

The involved skin of rosacea has been shown to exhibit increased transepidermal water loss due to impaired epidermal barrier function.¹⁷ Rosacea prone skin is also hyper-reactive; cutaneous insult results in prolonged vasodilation, exhibited clinically as facial erythema. Furthermore, the presence of an impaired stratum corneum barrier increases the irritancy of skin care products by enhancing penetration into the skin. Hence, skin care practices that optimize barrier function should be recommended.

Cleansing

Although skin cleansing is an important component of general skin care, surfactants contained in skin cleansers can weaken epidermal barrier function by disrupting proteins and lipids in the stratum corneum.¹⁸ Given the fact that patients with rosacea have impaired barrier function and a higher susceptibility to irritants, including sodium lauryl sulphate, mild cleansing is important.

The type of surfactant in the cleanser as well as its hydrogen ion concentration (pH) are major factors contributing to the irritant potential of a cleanser.¹⁸ Mild cleansers include synthetic detergents (syndets) and lipid-free cleansers. Syndet liquid cleansers or bars contain synthetic detergents and less than 10% soap. They have a favorable pH (5.5-7) and provide effective cleansing with less irritation potential than true soaps. Lipid-free cleansers have a neutral or slightly acidic pH. They are effective cleansers that leave a moisturizing film on the skin but do not lather.

Studies have shown benefits of mild cleansing in patients with rosacea. In a 4-week randomized, double-blind study of 70 patients with moderate rosacea who were using metronidazole 1% gel, subjects were instructed to use either a soap bar or a mild syndet bar. Use of the syndet cleanser reduced dryness, burning, stinging and itching compared to use of the soap bar.¹⁹

In addition to recommending an appropriate cleanser, physicians should advise rosacea patients to wash with lukewarm water, as hot water causes vasodilation and increased facial erythema. Mechanical trauma to the skin should also be minimized, including avoidance of granular exfoliants.

Astringents and toners, which are typically applied after cleansing, should likewise be avoided, as they tend to increase erythema and remove desirable oil from the skin.

Moisturizing

Use of appropriate moisturizers has several potential benefits in the management of rosacea. As rosacea skin has been shown to have increased transepidermal water loss, use of an emollient may improve barrier function and reduce dryness. Improved barrier function may also lead to reduced skin sensitivity and improved tolerance of topical medications.²⁰

Regarding choice of emollient, those containing potential irritants such as urea, glycolic acid, lactic acid, menthol and camphor should be avoided. Although the barrier dysfunction associated with rosacea may potentially increase allergenicity of skin care products, minimal data is available on the prevalence of contact allergy in rosacea patients.²¹ However, as fragrances can cause both irritant and allergic reactions, fragrance-free products should be recommended. Cream type moisturizers are generally preferred over thin lotions and gels.

Sun Protection

Daily sun protection is an important component of rosacea management. Sun exposure is a common trigger of acute flares of rosacea, and chronic photodamage may also contribute to the pathogenesis of rosacea.²² Acute ultraviolet light may aggravate rosacea by stimulating proinflammatory peptide production, reducing cutaneous antioxidant reserves, and increasing production of reactive oxygen species.²³ However, finding a welltolerated sunscreen can be difficult for rosacea patients. Selecting a cream based product containing an inorganic ultraviolet light filter and a silicone derivative, such as dimethicone orcyclomethicone, may reduce the likelihood of irritation.

Conclusion

Optimal management of both acne and rosacea includes initiation of an appropriate skin care regimen. This entails providing patients with advice regarding appropriate cleansing, moisturizing, and photoprotecting of the affected areas. Providing recommendations regarding skin care has been shown to improve quality of life in female acne patients and to be an unmet need in patients with rosacea. Integration of appropriate skin care in this patient population will improve barrier dysfunction and tolerability of prescribed therapy, leading to improved adherence and better treatment outcomes.

References

1. Matsuoka Y, Yoneda K, Sadahira C, et al. Effects of skin care and makeup under instructions from dermatologists on the quality of life of female patients with acne vulgaris. J Dermatol. 2006 Nov;33(11):745-52.
2. Thiboutot D, Del Rosso JQ. Acne vulgaris and the epidermal barrier. J Clin Aesthet Dermatol. 2013 Feb;6(2):18-24.
3. Weber SU, Thiele JJ, Han N, et al. Topical alpha-tocotrienol supplementation inhibits lipid peroxidation but fails to mitigate increased transepidermal water loss after benzoyl peroxide treatment of human skin. Free Radic Biol Med. 2003 Jan;34(2):170-6.
4. De Lucas R, Moreno-Arias G, Perez-Lopez M, et al. Adherence to drug treatments and adjuvant barrier repair therapies are key factors for clinical improvement in mild to moderate acne: the ACTUO observational prospective multicenter cohort trial in 643 patients. BMC Dermatol. 2015 Sept;15:17.
5. Tan JK, Vasey K, Fung KY. Beliefs and perceptions of patients with acne. J Am Acad Dermatol. 2001 Mar;44(3):439-45.
6. Choi JM, Lew VK, Kimball AB. A single-blinded, randomized, controlled clinical trial evaluating the effect of face washing on acne vulgaris. Pediatr Dermatol. 2006 Sept-Oct;23(5):421-7.
7. Draelos ZD. Cosmetics in acne and rosacea. Semin Cutan Med Surg. 2001 Sept;20(3):209-14.
8. Bowe WP, Kircik LH. The importance of protoprotection and moisturization in treating acne vulgaris. J Drugs Dermatol. 2014 Aug;13(suppl 7):s89-s94.
9. Magin P, Pond D, Smith W, et al. A systemic review of the evidence for ‘myths and misconceptions’ in acne management: diet, face-washing and sunlight. Fam Pract. 2005 Feb;22(1):62-70.
10. Drucker AM, Rosen CF. Drug-induced protosensitivity: culprit drugs, management and prevention. Drug Saf. 2011 Oct; 34(10):821-37.
11. Acanya® (clindamycin phosphate and benzoyl peroxide) Gel, 1.2%/2.5%, for topical use [Prescribing information]; revised February 2014. Valeant Pharmaceuticals, Bridgewater, NJ. Available at: http://www.acanyagel.com/ AcanyaPumpPI_FINAL.pdf. Accessed March 20, 2017.
12. Tazorac® (tazarotene) cream, 0.05% and 0.1%, for topical use [Prescribing information]; revised December 2013. Allergan, Inc., Irvine, CA. Available at: https://www.allergan.com/assets/pdf/tazorac_cream_pi. Accessed March 20, 2017.
13. Cetiner S, Ilknur T, Ozkan S. Phototoxic effects of topical azelaic acid, benzoyl peroxide and adapalene were not detected when applied immediately before UVB to normal skin. Eur J Dermatol. 2004 Jul-Aug;14(4):235-7.
14. Molinar VE, Taylor SC, Panya AG. What’s new in objective assessment and treatment of facial hyperpigmentation? Dermatol Clin. 2014 Apr;32(2):123-35.
15. Elewski BE, Draelos Z, Dreno B, et al. Rosacea-global diversity and optimized outcome: proposed international consensus from the rosacea international expert group. J Eur Acad Dermatol Venereol. 2011 Feb;25(2):188-200.
16. Shear NH, Levine C. Needs survey of Canadian rosacea patients. J Cutan Med Surg. 1999 Apr;3(4):178-81.
17. Dirschka T, Tronnier H, Folster-Holst R. Epithelial barrier function and atopic diathesis in rosacea and perioral dermatitis. Br J Dermatol. 2004 Jun;150(6):1136-41.
18. Farris PK. Skin care based on science: improving outcomes in rosacea. Cosmetic Dermatol. 2012 Feb;25(2):72-8.
19. Subramanyan K, Johnson AW. Role of mild cleansing in the management of sensitive skin. Poster presented at the American Academy of Dermatology 61st Annual Meeting. San Francisco, CA, Mar 21-16, 2003.
20. Del Rosso JQ. The use of moisturizers as an integral component of topical therapy for rosacea: clinical results based on the assessment of skin characteristics study. Cutis. 2009 Aug;84(2):72-6.
21. Jappe U, Schafer T, Schnuch A, et al. Contact allergy in patients with rosacea: a clinic-based, prospective epidemiological study. J Eur Acad Dermatol Venereol. 2008 Nov;22(10):1208-14.
22. Del Rosso JQ. Adjunctive skin care in the management of rosacea: cleansers, moisturizers, and photoprotectants. Cutis. 2005 Mar;75(Suppl 3):17-21.
23. Del Rosso JQ. Advances in understanding and managing rosacea: part 1: connecting the dots between pathophysiological mechanisms and common clinical features of rosacea with emphasis on vascular changes and facial erythema. J Clin Aesthet Dermatol. 2012 Mar;5(3):16-25.

Department of Medicine, University of Calgary, Calgary, AB, Canada

ABSTRACT

Optimal acne therapy must take into account not only acne type and severity, but also the impact of this skin disorder on the patient’s quality of life. Several validated instruments have been used to measure quality of life in acne patients. By using these instruments, acne patients have been shown to experience levels of social, psychological and emotional distress similar to those reported in patients with asthma, epilepsy and diabetes. Several studies have demonstrated that the disability caused by acne can be mitigated by effective therapy.

Key Words:
Acne vulgaris, quality of life

The psychological burden associated with acne was described years ago by Sulzberger and Zaidens¹: “There is probably no single disease which causes more psychic trauma, more maladjustment between parents and children, more general insecurity and feeling of inferiority and greater sums of psychic suffering than does acne vulgaris.” Despite general acceptance of the psychosocial impact of acne, measurement of its effect on quality of life (QOL) has only begun in recent years. This article will review the methods used to measure QOL in acne patients and what we have learned from this research.

Measurement of QOL

QOL is generally measured using validated questionnaires. Several instruments have been designed: for use in many different diseases, for skin disorders only, or for one particular disease such as acne. General health measures, which can be used to assess many diseases, include the Short-Form 36 (SF-36) and the General Health Questionnaire. These can be used to compare the impact of skin disease with that of diseases affecting other systems. Dermatology-specific measures include the Dermatology Life Quality Index (DLQI)² and Skindex.³ These are more sensitive indicators of the impact of skin disease on QOL and they can be used to compare one skin disease with another. Acne-specific QOL instruments include the Acne Disability Index (ADI)4 and the Cardiff Acne Disability Index (CADI).⁵ The CADI was derived from the ADI as a short, five-item questionnaire that could be used in clinical practice. Other acne-specific measures include the Acne-Specific Quality of Life (Acne-QOL) questionnaire^,6 which is designed for assessment of facial acne. A recently described four-item condensed version of the Acne-QOL⁷ was developed for use in routine clinical practice. The Acne Quality of Life (AQOL) scale⁸ focuses on the social and vocational aspects of acne. Greater impairment of QOL, as measured by the AQOL, was associated with greater levels of anxiety and depression in one study.⁹

Why Measure QOL?

Measuring the impact of acne on quality of life allows us to understand the disease from the patient’s point of view. In clinical research, new medications are increasingly being evaluated according to their impact on QOL, which is in addition to the traditional approach of assessing only treatment safety and efficacy. In clinical practice, understanding how a patient’s life is impacted by acne can help in selecting the most appropriate treatment for that patient and may enhance compliance.¹⁰

How Acne Impacts QOL Compared with Other Diseases

Although acne is sometimes considered to be unimportant in comparison with other medical conditions, the associated morbidity is significant. Mallon, et al.¹¹ measured QOL in 111 acne patients using the DLQI, Rosenberg’s measure of self-esteem, a version of the General Health Questionnaire, and the SF-36. The acne patients described levels of social, psychological and emotional problems that were as great as those reported by patients with asthma, epilepsy, diabetes, back pain or arthritis. Lasek, et al.¹² reported that adults with acne experienced functional and emotional effects comparable with those of patients who have psoriasis. Beattie, et al.¹³ used the Children’s Life Quality Index and the Children’s Dermatology Life Quality Index to evaluate patients aged 5–16 years with various skin diseases and compared them with children suffering from other chronic medical conditions. Health-related QOL impairment in children with skin disease was at least equal to that experienced by children with other chronic illnesses, but atopic dermatitis and psoriasis caused greater disability than did acne.

Acne Severity and QOL

Studies have failed to show a strong association between acne severity and QOL^.9,11,14 Hence, it is difficult to ascertain the extent of disability caused by a given severity of acne, as QOL is dependent on a host of correlating factors that are as yet poorly understood. Rapp, et al.¹⁵ reported that trait anger, the tendency to experience an angry mood easily, was significantly related to global and skin-related QOL, as well as to satisfaction with treatment. Furthermore, Krehci-Manwaring, et al.¹⁶ proposed that dispositional social sensitivity in acne patients was independently associated with poorer social functioning and QOL.

Age, Gender and QOL

Lasek, et al.¹² reported greater overall effects on QOL in older adult acne patients regardless of disease severity, with similar effects on both sexes. Jones-Caballero, et al.¹⁷ also found that older patients had a worse acne-related QOL, although its influence was small. In this study, women experienced greater QOL impairment, although acne was significantly more severe in men. In a recent study18 of Scottish teenagers aged 15–18 years, 11% of those with self-reported acne perceived their lives to be significantly affected by their acne. The rate of variance in this perception was negligable between the sexes.

Impact of Acne Treatment on QOL

Several studies have shown improvement in QOL with effective acne treatment.17,19,20 Using the SF-36, the DLQI, Rosenberg’s measure of self-esteem, and a version of the General Health Questionnaire, Newton, et al.20 monitored the QOL of patients who were referred to a dermatology clinic for acne treatment. As the clinical acne grade significantly improved with treatment, so did QOL, as measured by the four instruments used. Clinical and patient-assessed outcomes were most improved in isotretinoin treated patients. Two recent studies21,22 have shown that instruction in appropriate cosmetic use enhances QOL in female acne patients.

Conclusion

Acne can profoundly impact quality of life. As its effect on QOL does not always correlate with acne severity, the disability caused by acne must be taken into account when individualizing treatment. Effective acne therapy is associated with significant improvement in the quality of life of acne patients.

References

1. Sulzberger NB, Zaidens SH. Psychogenic factors in dermatologic disorders. Med Clin North Am 32:669-85 (1948).
2. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI): a simple practical measure for routine clinical use. Clin Exp Dermatol 19(3):210-6 (1994 May).
3. Chren MM, Lasek RJ, Quinn LM, et al. Skindex, a quality-of-life measure for patients with skin disease: reliability, validity, and responsiveness. J Invest Dermatol 107(5):707-13 (1996 Nov).
4. Motley RJ, Finlay AY. How much disability is caused by acne? Clin Exp Dermatol 14(3):194-8 (1989 May).
5. Motley RJ, Finlay AY. Practical use of a disability index in the routine management of acne. Clin Exp Dermatol 17(1):1-3 (1992 Jan).
6. Girman CJ, Hartmaier S, Thiboutot D, et al. Evaluating health-related quality of life in patients with facial acne: development of a self-administered questionnaire for clinical trials. Qual Life Res 5(5):481-90 (1996 Oct).
7. Tan J, Fung KY, Khan S. Condensation and validation of a 4-item index of the Acne-QoL. Qual Life Res 15(7):1203-10 (2006 Sep).
8. Gupta MA, Johnson AM, Gupta AK. The development of an Acne Quality of Life scale: reliability, validity, and relation to subjective acne severity in mild to moderate acne vulgaris. Acta Derm Venereol 78(6):451-6 (1998 Nov).
9. Yazici K, Baz K, Yazici AE, et al. Disease-specific quality of life is associated with anxiety and depression in patients with acne. J Eur Acad Dermatol Venereol 18(4):435-9 (2004 Jul).
10. Dreno B. Assessing quality of life in patients with acne vulgaris: implications for treatment. Am J Clin Dermatol 7(2):99-106 (2006).
11. Mallon E, Newton JN, Klassen A, et al. The quality of life in acne: a comparison with general medical conditions using generic questionnaires. Br J Dermatol 140(4): 672-6 (1999 Apr).
12. Lasek RJ, Chren MM. Acne vulgaris and the quality of life of adult dermatology patients. Arch Dermatol 134(4); 454-8 (1998 Apr).
13. Beattie PE, Lewis-Jones MS. A comparative study of impairment of quality of life in children with skin disease and children with other chronic childhood diseases. Br J Dermatol 155(1):145-51 (2006 Jul).
14. Ilgen E, Derya A. There is no correlation between acne severity and AQOLS/DLQI scores. J Dermatol 32(9):705-10 (2005 Sep).
15. Rapp DA, Brenes GA, Feldman SR, et al. Anger and acne: implications for quality of life, patient satisfaction and clinical care. Br J Dermatol 151(1):183-9 (2004 Jul).
16. Krejci-Manwaring J, Kerchner K, Feldman SR, et al. Social sensitivity and acne: the role of personality in negative social consequences and quality of life. Int J Psychiatry Med 36(1):121-30 (2006).
17. Jones-Caballero M, Chren MM, Soler B, et al. Quality of life in mild to moderate acne: relationship to clinical severity and factors influencing change with treatment. J Eur Acad Dermatol Venereol 21(2):219-26 (2007 Feb).
18. Walker N, Lewis-Jones MS. Quality of life and acne in Scottish adolescent schoolchildren: use of the Children’s Dermatology Life Quality Index (CDLQI) and the Cardiff Acne Disability Index (CADI). J Eur Acad Dermatol Venereol 20(1):45-50 (2006 Jan).
19. Grosshans E, Marks R, Mascaro JM, et al. Evaluation of clinical efficacy and safety of adapalene 0.1% gel versus tretinoin 0.025% gel in the treatment of acne vulgaris, with particular reference to the onset of action and impact on quality of life. Br J Dermatol 139(Suppl 52):26-33 (1998 Oct).
20. Newton JN, Mallon E, Klassen A, et al. The effectiveness of acne treatment: an assessment by patients of the outcome of therapy. Br J Dermatol 137(4):563-7 (1997 Oct).
21. Hayashi N, Imori M, Yanagisawa M, et al. Make-up improves the quality of life of acne patients without aggravating acne eruptions during treatment. Eur J Dermatol 15(4):284-7 (2005 Jul-Aug).
22. Matsuoka Y, Yoneda K, Sadahira C, et al. Effects of skin care and makeup under instructions from dermatologists on the quality of life of female patients with acne vulgaris. J Dermatol 33(11):745-52 (2006 Nov).

Department of Medicine, University of Calgary, Calgary, Alberta, Canada

Background

It is well known that the developing fetus can potentially be affected by any medication given to the mother. However, despite this, the use of medications during pregnancy is common and pregnant women often present for treatment of dermatological disease. A recent multinational survey indicated that 86% of women took an average of 2.9 medications during their pregnancy [Collaborative Group on Drug Use in Pregnancy. Int J Gynaecol Obstet 39(3):185-96 (1992 Nov)]

US FDA Pregnancy Categories

During the 1950s diethylstilbestrol and thalidomide use in early pregnancy both led to disastrous consequences for the
exposed offspring, which were not causally linked for years. These events led to the development of the US FDA Pregnancy
Categories (Table 1) that are assigned before a drug is released.

Acne

Topical

• Preferred during pregnancy
• Topical erythromycin (category B), clindamycin (category B), and benzoyl peroxide (category C) are safe
• Avoid topical retinoids
  • Case reports of congenital malformations with tretinoin (category C)
  • Use of adapalene (category C) and tazarotene (category X) are also not recommended.

Systemic

• Tetracyclines (category D) are associated with deciduous tooth staining, decreased bony growth, and maternal liver toxicity when taken after the first trimester.
• Erythromycin (category B) use in early pregnancy may be associated with a higher risk of cardiovascular malformations.
• Oral isotretinoin (category X) is a well-known teratogen. However, it is safe for women to conceive 1 month after this medication is stopped.

Rosacea

Topical metronidazole and azelaic acid are both category B and considered safe to use during pregnancy.

Psoriasis

Topical

• Topical corticosteroids (category C) are widely used in pregnancy, although intrauterine growth retardation has been reported.
• Only 6% of calcipotriene ointment (category C) is absorbed through the skin and is likely safe for localized disease.

Phototherapy

• Broadband UVB is considered the safest therapy for extensive psoriasis.
• PUVA is a potential teratogen, but adverse outcomes have not been reported.

Systemic

• Methotrexate (category X)
  • Can be used in women of childbearing potential who are using effective contraception.
  • Pregnancy should be avoided for at least one ovulatory cycle following cessation of the drug.
• Acitretin (category X)
  • Should not be prescribed for women of childbearing potential.
• Cyclosporin (category C) does not appear to pose a major risk to the fetus based on relatively small numbers.

Biologics

• Limited data available.
• Alefacept (category B) and efalizumab (category C)
• No evidence of teratogenicity in animal reproduction studies or in offspring of women who inadvertently became pregnant while taking either of these drugs
• Etanercept (category B)
• OTIS data [Chambers C, et al. J Am Acad Dermatol 56(2):38 (2007)]
• 35 pregnancies with first TM exposure
• 17 pregnancies have resulted in live births
• 3 congenital abnormalities – no consistent pattern
• Infliximab (category B)
• Multiple reports of exposure during pregnancy in women receiving treatment for rheumatoid arthritis and Crohn’s disease
• Used intentionally during pregnancy for induction or maintenance of remission in Crohn’s disease
• No evidence of embryotoxicity, teratogenicity or increased fetal loss
• Placental transfer documented.

Systemic Corticosteroids (category C)

• Have been associated with intrauterine growth retardation and a small increase in incidence of cleft lip with or without cleft palate with first trimester exposure.
• When needed, the benefits of short courses of oral corticosteroids appear to outweigh the fetal risks, especially when given beyond the first trimester.

Topical Calcineurin Inhibitors

• Tacrolimus and pimecrolimus (category C)
• Oral tacrolimus has not been associated with fetal loss or teratogenicity.
• To date there are no reports of adverse effects on pregnancy with topical use of tacrolimus or pimecrolimus.

Antihistamines

• Chlorpheniramine and diphenhydramine (category B) are the antihistamines of choice for oral and parenteral use, respectively.
• One case-control study associated use of diphenhydramine with cleft palate in first trimester [Saxen I. Lancet 1(7854):407-8 (1974 Mar)]
• Linked to retrolental fibroplasia in premature infants when taken in last 2 weeks.

Antivirals

• Topical imiquimod (category B) is minimally absorbed and limited data has not shown adverse fetal effects.
• Podophyllin and podophyllotoxin (category C) have been associated with fetal abnormalities and deaths.
• Acyclovir, famciclovir and valacyclovir (category B) are probably safe.

Antifungals

• Topical antifungals are safe because of negligible percutaneous absorption.
• Minimal data for oral terbinafine (category B).
• Oral fluconazole (category C) 400 mg/d appears to be teratogenic.
• Associated with a pattern of abnormalities involving the head and face, bones and heart.
• Smaller doses are likely safe.
• Itraconazole (category C)
• No significant risk for major abnormalities.
• Because of concern regarding the use of fluconazole, a structurally related triazole antifungal, avoidance of itraconazole is suggested in the first trimester.

Antibiotics (Systemic)

• Penicillins, cephalosporins, and azithromycin (category B) are generally considered safe in pregnancy.
• A large surveillance study observed a possible association between certain cephalosporins (cefaclor, cefalexin, ceftriaxone, and cephadrine) and congenital malformation with first TM exposure.[Briggs GG, et al. Drugs in Pregnancy and Lactation. 7th ed. Philadelphia (PA): Lippincott Williams and Wilkins (2005).]

Conclusion

Medications that are considered safe in pregnancy are available for the treatment of common dermatological disorders.
Knowledge of these medications is important when considering treatment options for both pregnant patients, and women of
childbearing potential.

Dermatologic Diagnostic Challenge

Question:

A 61 year old Caucasian male presents with chronic erythema of his cheeks and easy flushing. On questioning,
he notes that he never gets any “bumps” on his face, but he occasionally gets styes on his eyelids. He has no problems with
his blood pressure nor any history of diarrhea.

What is your diagnosis?

a. Systemic lupus erythematosus
b. Carcinoid syndrome
c. Erythematotelangiectatic rosacea
d. Periorificial dermatitis
e. Papulopustular rosacea

Case study submitted by Benjamin Barankin, MD, FRCPC

Department of Medicine, University of Calgary, Calgary, Alberta, Canada

ABSTRACT

Although the developing fetus was once considered protected from the outside world, we now know that it can potentially be affected by any medication given to the mother. Despite this knowledge, use of medications during pregnancy is common and pregnant women often present for treatment of dermatological disease. Therapeutic options available for these patients will be discussed.

Key Words:
pregnancy, congenital malformations

Two drugs given in the middle of the 20th century to pregnant women changed the attitude of physicians about the use of medications during this period. Diethylstilbestrol and thalidomide use in early pregnancy led to disastrous consequences for the exposed offspring, consequences that were not causally linked for years. These events led to the development of the US FDA Pregnancy Categories (see Table 1) that are now assigned before a drug is released.

Despite awareness that any medication taken during pregnancy can potentially affect the fetus, a recent multinational survey indicated that 86% of women took an average of 2.9 medications during pregnancy.¹ This article will review options for the treatment of a variety of common dermatological disorders during pregnancy (see Table 2).

Table 1: FDA Pregnancy Categories for Drugs.

Acne and Rosacea

Topical therapy is preferred for the treatment of acne during pregnancy.² Topical erythromycin (category B), clindamycin (category B) and benzoyl peroxide (category C) are considered safe in pregnancy. Use of topical tretinoin (category C) is not advised due to case reports of congenital malformations in infants whose mothers used tretinoin during the first trimester of pregnancy.^3,4 Moreover, some of these malform ations are consistent with those observed in retinoic acid embryopathy. However, the fetal risk, if any, from inadvertent exposure in early pregnancy appears to be very low.⁵ Use of adapalene (category C) and tazarotene (category X) is also not recommended.

Topical metronidazole (category B) is minimally absorbed and considered safe in pregnancy. Topical azelaic acid (category B) is also minimally absorbed and likely safe in pregnancy.

Tetracyclines (category D) are associated with deciduous tooth staining when taken after the first trimester, decreased bony growth, and maternal liver toxicity. However, inadvertent exposure in the first few weeks of pregnancy is extremely unlikely to be harmful.⁶ Erythromycin (category B) has long been considered safe in pregnancy. However, two recent Swedish studies have reported an increased risk of cardiovascular malformations with the use of oral erythromycin in early pregnancy.^7,8

Oral isotretinoin (category X) is a well-known teratogen. However, it is safe for women to conceive 1 month after this medication is stopped.

Table 2: Safe treatments for dermatological disorders during pregnancy.

Psoriasis

Topical corticosteroids (category C) have been widely used during pregnancy, although intrauterine growth retardation was reported in an infant whose mother applied 40mg/day of topical triamcinolone beginning at 12 weeks of gestation.⁹ Calcipotriene (category C) is approximately 6% absorbed when the ointment form is applied to psoriatic plaques and is likely safe in pregnancy for the treatment of localized psoriasis.¹⁰

Broadband ultraviolet B phototherapy is considered the safest therapy for extensive psoriasis during pregnancy, although overheating during treatment should be avoided. PUVA is a potential teratogen because it is known to be mutagenic and to induce sister chromatid exchanges. However, adverse outcomes have not been reported in studies of women exposed to PUVA during pregnancy.^11,12

Methotrexate and acitretin are both in pregnancy category X. Methotrexate can be used in women with childbearing potential who are using effective contraception. Pregnancy should be avoided for at least one ovulatory cycle after this medication is discontinued. Acitretin should not be prescribed for women of childbearing potential.

There are limited data on the safety of biologics used for the treatment of psoriasis during pregnancy. Animal reproduction studies of alefacept ¹³ (category B), a mouse analogue of efalizumab,¹⁴ and etanercept (category B)¹⁵ have shown no evidence of teratogenicity. No congenital malformations have been reported in the offspring of the few women who inadvertently became pregnant while taking alefacept or efalizumab (category C) in clinical trials. More data are available on the outcome of pregnancies exposed to etanercept given its utilization for the treatment of rheumatoid arthritis. Preliminary data from the Organization of Teratology Information Services (OTIS) study of pregnancy outcomes of women with rheumatoid arthritis exposed to anti-TNF therapy included information on 29 women exposed to etanercept. Spontaneous abortion, termination, and malformation rates were similar to those in the diseased and nondiseased control groups.¹⁶

Dermatitis

In some studies first trimester exposure to systemic corticosteroids (category C) has been associated with intrauterine growth retardation and a small increase in the incidence of cleft lip with or without cleft palate.^17,18 However, when needed, the maternal benefits of short courses of oral corticosteroids appear to outweigh the fetal risks, especially when given beyond the first trimester.

The topical calcineurin inhibitors, tacrolimus and pimecrolimus, are in pregnancy category C. Use of oral tacrolimus in pregnant organ transplant recipients has not been associated with fetal loss or teratogenicity thus far.⁵ Pimecrolimus has shown no evidence of teratogenicity in animal studies.¹⁹ To date, there have been no reports of adverse effects on pregnancy with topical use of either tacrolimus or pimecrolimus.

Chlorpheniramine and diphenhydramine (both category B) have been considered the antihistamines of choice for oral and parenteral use, respectively, in pregnancy,²⁰ although one case-control study showed an association between the use of diphenhydramine in the first trimester and cleft palate.²¹ Antihistamines in general have been linked to retrolental fibroplasia in premature infants when taken in the last 2 weeks of pregnancy.

Viral Infections

For the treatment of genital warts, trichloroacetic acid and physical modalities such as cryotherapy are felt to be safe in pregnancy. Imiquimod (category B) is minimally absorbed, and animal studies, as well as very limited data of use in pregnant women, have not shown adverse fetal effects.^22,23 Podophylline and podophyllotoxin (category C) are not recommended for use in pregnancy because of fetal abnormalities and deaths associated with maternal use.^24,25 Acyclovir, famciclovir and valacyclovir are all pregnancy category B, and pregnancy registries exist for each of these agents. No adverse effects on the fetus or newborn have been attributed to their use in pregnancy, but because we have more data on the use acyclovir in human pregnancy, some authors consider it to be the drug of choice when indicated in pregnancy.

Fungal Infections

The use of topical antifungals is considered safe in pregnancy because of negligible percutaneous absorption. Animal reproduction studies involving oral terbinafine (category B) have shown no abnormalities, but human pregnancy data are lacking.⁵ Oral fluconazole (category C) taken during the first trimester at a continuous daily dose of 400mg/day
or more appears to be teratogenic and associated with a pattern of abnormalities involving the head and face, bones, and heart.²⁶

Smaller doses of fluconazole, as used for treatment of vaginal candidiasis, have been associated with minimal or no risk of fetal abnormalities. The available data pertaining to human use of itraconazole (category C) indicates no significant risk for major abnormalities. However, because of concern regarding the use of fluconazole, a structurally related triazole antifungal, avoidance of itraconazole is suggested in the first trimester.

Bacterial Infections

Penicillins, cephalosporins and azithromycin are all pregnancy category B and are generally considered safe in pregnancy. However, a large surveillance study of Michigan Medicaid recipients conducted between 1985 and 1992 observed a possible association between certain cephalosporins (cefaclor, cephalexin, ceftriaxone and cephadrine) and congenital malformations when taken in the first trimester.⁵

Conclusion

Medications that are considered safe in pregnancy are available for the treatment of common dermatological disorders. Knowledge of these medications is important when considering treatment options for both pregnant patients and women of childbearing potential.

References

1. Collaborative Group on Drug Use in Pregnancy.Medication during pregnancy: an intercontinental cooperative study. Int J Gynaecol Obstet 39(3):185-96 (1992 Nov).
2. Koren G, Pastuszak A, Ito S. Drugs in pregnancy. NEngl J Med 338(16):1128-37 (1998 Apr).
3. Navarre-Belhassen C, Blanchet P, Hillaire-Buys D,Sarda P, Blayac JP. Multiple congenital malformations associated with topical tretinoin. Ann Pharmacother32(4):505-6 (1998 Apr).
4. Colley SM, Walpole I, Fabian VA, Kakulas BA. Topical tretinoin and fetal malformations. Med J Aust 168(9):467 (1998 May).
5. Briggs GG, Freeman RK, Yakke SJ. Drugs in Pregnancy and Lactation. 7th ed. Philadelphia (PA): Lippincott Williams and Wilkins (2005).
6. Rothman KF, Pochi PE. Use of oral and topical agents for acne in pregnancy. J Am Acad Dermatol 19(3):431-42 (1988 Sept).
7. Kallen BA, Otterblad Olausson P. Maternal drug use in early pregnancy and infant cardiovascular defect. Reprod Toxicol 17(3):255-61 (2003 May-June).
8. Kallen BA, Otterblad Olausson P, Danielsson BR. Is erythromycin therapy teratogenic in humans? Reprod Toxicol 20(2):209-14 (2005 Jul-Aug).
9. Katz VL, Thorp JM Jr, Bowes WA Jr. Severe symmetric intrauterine growth retardation
   associated with the topical use of triamcinolone. Am J Obstet Gynecol 162(2):396-7 (1990 Feb).
10. Tauscher AE, Fleischer AB Jr, Phelps KC, Feldman SR. Psoriasis and pregnancy. J Cutan Med Surg 6(6):561-70 (2002 Nov/Dec).
11. Stern RS, Lange R. Outcomes of pregnancies among women and partners of men with a history of exposure to methoxsalen photochemotherapy (PUVA) for the treatment of psoriasis. Arch Dermatol 127(3):347-50 (1991 Mar).
12. Gunnarskog JG, Kallen AJ, Lindelof BG, Sigurgeirsson B. Psoralen photochemotherapy
    (PUVA) and pregnancy. Arch Dermatol 129(3):320-3 (1993 Mar).
13. Amevive® (alefacept) Product Monograph, Biogen Idec Canada Inc, 2004.
14. Raptiva® (efalizumab) Product Monograph, Serono Canada Inc., 2005.
15. Enbrel® (etanercept) Product Monograph, Immunex Corporation, 2005.
16. Chambers CD, Johnson DL, Lyons Jones K. Pregnancy outcome in women exposed to anti-
    TNF-alpha medications: the OTIS rheumatoid arthritis in pregnancy study [Abstract 1224]. Arthritis Rheum 50(9): S479-80 (2004 Sept).
17. Carmichael SL, Shaw GM. Maternal corticosteroid use and risk of selected congenital anomalies. Am J Med Genet 86(3):242-4 (1999 Sept).
18. Rodriguez-Pinilla E, Martinez-Frias ML. Corticosteroids during pregnancy and oral clefts:
    a case-contol study. Teratology 58(1):2-5 (1998 Jul).
19. Elidel® (pimecrolimus) Product Monograph, Novartis Pharmaceuticals Canada Inc., 2003.
20. Schatz M, Petitti D. Antihistamines and pregnancy. Ann Allergy Asthma Immunol 78(2):157-9 (1997 Feb).
21. Saxen I. Letter: Cleft palate and maternal diphenhydramine intake. Lancet 1(7854):407-8 (1974 Mar).
22. Maw RD. Treatment of external genital warts with 5% imiquimod cream during pregnancy: a case report. BJOG 111(12):1475 (2004 Dec).
23. Einarson A, Costei A, Kalra S, Rouleau M, Koren G. The use of topical 5% imiquimod during
    pregnancy: a case series. Reprod Toxicol 21(1):1-2 (2006 Jan).
24. Karol MD, Conner CS, Watanabe AS, Murphrey KJ. Podophyllum: suspected teratogenicity from topical application. Clin Toxicol 16(3):283-6 (1980 May).
25. Chamberlain MJ, Reynolds AL, Yeoman WB. Medical memoranda. Toxic effect of podophyllum application in pregnancy. Br Med J 3(823):391-2 (1972 Aug).
26. Pursley TJ, Blomquist IK, Abraham J, Andersen HF, Bartley JA. Fluconazole-induced congenital anomalies in three infants. Clin Infect Dis 22(2):336-40 (1996 Feb).

Department of Medicine, University of Calgary, Calgary, Alberta, Canada

ABSTRACT

Topical metronidazole (Noritate® 1% Cream, Dermik; MetroCream™ 0.75% Cream, MetroLotion® 0.75% Lotion, Metrogel® 0.75% and 1% Topical Gel, Galderma) has been used for the treatment of rosacea for over 30 years. Several placebo-controlled trials have demonstrated its effectiveness in the treatment of moderate-to-severe rosacea. It is also effective in preventing relapses of disease and is well tolerated by most patients. A growing number of formulations are available.

Key Words:
rosacea, metronidazole, antibiotic, anti-inflammatory

Rosacea is one of the most common conditions seen by dermatologists. Its etiology and pathogenesis are unknown despite its high prevalence. Topical metronidazole, which was first reported to be effective in the treatment of rosacea in 1983,¹ remains a cornerstone of therapy. Although the use of metronidazole in the treatment of rosacea has been reviewed previously,^2,3 continued research has prompted this updated review.

Mechanism of Action

The mechanism of action of metronidazole in the treatment of rosacea is unclear. The efficacy of this broad spectrum antibiotic has been attributed to its antimicrobial and anti-inflammatory effects. In vitro studies have shown that metronidazole interferes with neutrophil release of reactive oxygen species that cause tissue injury at sites of inflammation.⁴ This antioxidant activity may be the basis of its anti-inflammatory effect in rosacea.

Pharmacokinetics

Metronidazole is poorly absorbed after topical application, with either undetectable or trace serum concentrations reported after topical use.^1,5 Based on pharmacokinetic data on the original 0.75% gel formulation, it was originally thought that the optimal application frequency should be twice daily. More recent research has shown that metronidazole is degraded into active metabolites that may prolong the clinical efficacy of the parent drug.⁶

Placebo-Controlled Trials

Metronidazole has been shown to be effective for the treatment of moderate-to-severe rosacea in a number of placebo-controlled trials (Table 1).^5,7-13 In a recent trial comparing metronidazole 1% gel, 1% cream, and gel vehicle applied once daily for 10 weeks, the efficacy of the 1% gel was at least that of the 1% cream and superior to the gel vehicle.⁸

Comparative Trials With Other Rosacea Treatments

A number of studies have compared topical metronidazole with other treatment options for rosacea. These are summarized in Table 2. Regardless of the formulation, studies have shown a significant reduction of papulopustular lesions and erythema scores compared with placebo. Although most studies have not shown improvement of telangiectasias, Tan, et al. reported a significant reduction in the telangiectasia score in patients with moderate-to-severe rosacea using metronidazole 1% cream with sunscreen SPF 15 (Rosasol®, Steifel Canada) for 12 weeks.¹² In their review of randomized controlled trials of patients with moderate-to-severe rosacea in the Cochrane Database of Systemic Reviews, van Zuuren, et al. concluded that topical metronidazole is more effective than placebo, but that the quality of studies evaluating rosacea treatments was generally poor, and that good randomized controlled trials that include quality of life assessments are needed.¹⁴

Comparative Trials Between Different Formulations of Metronidazole

Metronidazole is currently available in a variety of formulations, and comparative studies have shown equal efficacy. In a study comparing commercially available formulations of both metronidazole 0.75% and 1% cream, applied once daily for 12 weeks for the treatment of moderate-to-severe rosacea, both were equally effective.¹⁵

Remission and Relapse

In a study of patients who achieved remission of rosacea with the use of systemic tetracycline, two thirds relapsed within 6 months of treatment cessation.²³ Nielsen reported that metronidazole 1% cream applied daily or every other day is at least as effective in preventing relapses as tetracycline 250mg taken twice daily.²⁴ In a more recent study, metronidazole 0.75% gel applied twice daily maintained remission compared with vehicle after successful treatment with a combination of metronidazole gel and oral tetracycline.²⁵

Adverse Effects

Metronidazole is generally well tolerated, with adverse events reported in less than 5% of patients. Local reactions include dryness, redness, pruritus, aggravation of acne or rosacea, burning, and stinging. True allergic contact dermatitis is rare.²⁶

Conclusion

Topical metronidazole remains a cornerstone in the treatment of rosacea. Several placebo-controlled trials have confirmed its ability to reduce both inflammatory lesions and erythema. Daily dosing has been shown to be effective in numerous clinical trials. As well, metronidazole is effective is preventing relapses of rosacea.

References

1. Nielsen PG. Treatment of rosacea with 1% metronidazole cream. A double-blind study. Br J Dermatol 108(3):327-32 (1983 Mar).
2. McClellan KJ, Noble S. Topical Metronidazole. A review of its use in rosacea. Am J Clin Dermatol 1(3):191-9 (2000 May-Jun).
3. Gupta AK, Chaudhry M. Topical metronidazole for rosacea. Skin Therapy Lett 7(1):1-3,6 (2002 Jan).
4. Miyachi Y, Imamura S, Niwa Y. Anti-oxidant action of metronidazole: a possible mechanism of action in rosacea. Br J Dermatol 114(2):231-4 (1986 Feb).
5. Aronson IK, Rumsfield JA, West DP, Alexander J, Fischer JH, Paloucek FP. Evaluation of topical metronidazole gel in acne rosacea. Drug Intell Clin Pharm 21(4):346-51 (1987 Apr).
6. Lamp KC, Freeman CD, Klutman NE, Lacy MK. Pharmacokinetics and pharmacodynamics of the nitroimidazole antimicrobials. Clin Pharmacokinet 36(5):353-73 (1999 May).
7. Bleicher PA, Charles JH, Sober AJ. Topical metronidazole therapy for rosacea. Arch Dermatol 123(5):609-14 (1987 May).
8. Beutner K, Calvarese B, Graeber M. A multi-center, investigator-blind clinical trial to assess the safety and efficacy of metronidazole gel 1% as compared to metronidazole gel vehicle and metronidazole cream 1% in the treatment of rosacea. Presented at: American Academy of Dermatology 63rd Annual Meeting; 2005 Feb 18-22; New Orleans, P101.
9. Drake L, Leyden J, Lucky A, et al. Evaluation of topical metronidazole cream in rosacea. Presented at: American Academy of Dermatology 55th Annual Meeting; 1997 Mar 21-26; San Francisco, P65.
10. Breneman DL, Stewart D, Hevia O, Hino PD, Drake LA. A double-blind, multicenter clinical trial comparing efficacy of once-daily metronidazole 1 percent cream to vehicle in patients with rosacea. Cutis 61(1):44-7 (1998 Jan).
11. Jorizzo JL, Lebwohl M, Tobey RE. The efficacy of metronidazole 1% cream once daily compared with metronidazole 1% cream twice daily and their vehicles in rosacea: a double-blind clinical trial. J Am Acad Dermatol 39(3):502-4 (1998 Sep).
12. Tan JKL, Girard C, Krol A, et al. Randomized placebo-controlled trial of metronidazole 1% cream with sunscreen SPF 15 in treatment of rosacea. J Cutan Med Surg 6(6):529-34 (2002 Nov-Dec).
13. Breneman D, Bucko A, Friedman D, et al. Evaluation of topical metronidazole lotion in rosacea. Presented at: American Academy of Dermatology 56th Annual Meeting; 1998 Feb 27-Mar 4; Orlando, P289.
14. van Zuuren EJ, Graber MA, Hollis S, Chaudhry M, Gupta AK, Gover M. Interventions for rosacea. Cochrane Database Syst Rev (3):CD003262 (2005 May 20).
15. Dahl MV, Jarratt M, Kaplan D, Tuley MR, Baker MD. Once-daily topical metronidazole cream formulations in the treatment of the papules and pustules of rosacea. J Am Acad Dermatol 45(5):723-30 (2001 Nov).
16. Elewski BE, Fleischer AB Jr, Pariser DM. A comparison of 15% azaleic acid gel and 0.75% metronidazole gel in the topical treatment of papulopustular rosacea: results of a randomized trial. Arch Dermatol 139(11):1444-50 (2003 Nov).
17. Czernielewski J, Liu Y. Comparison of 15% azelaic acid gel and 0.75% metronidazole gel for the topical treatment of papulopustular rosacea. Arch Dermatol 140(10):1282-3 (2004 Oct).
18. Maddin S. A comparison of topical azelaic acid 20% cream and topical metronidazole 0.75% cream in the treatment of patients with papulopustular rosacea. J Am Acad Dermatol 40(6 Pt 1):961-5 (1999 Jun).
19. Lebwohl MG, Medansky RS, Russo CL, Plott RT. The comparative efficacy of sodium sulfacetamide 10%/sulfur 5% lotion and metronidazole 0.75% in the treatment of rosacea. J Geriatr Dermatol 3(5):183-5 (1995).
20. Torok HM, Webster G, Dunlap FE, Egan N, Jarratt M, Stewart D. Combination sodium sulfacetamide 10% and sulfur 5% cream with sunscreens versus metronidazole 0.75% cream for rosacea. Cutis 75(6):357-63 (2005 Jun).
21. Schachter D, Schachter RK, Long B, et al. Comparison of metronidazole 1% cream versus oral tetracycline in patient with rosacea. Drug Invest 3(4):220-4 (1991).
22. Monk BE, Logan RA, Cook J et al. Topical metronidazole in the treatment of rosacea. J Dermatolog Treat 2:91-3 (1991).
23. Knight AG, Vickers CFH. A follow-up of tetracycline-treated rosacea. Br J Dermatol 93(5):577-80 (1975 Nov).
24. Nielsen PG. The relapse rate for rosacea after treatment with either oral tetracycline or metronidazole cream. Br J Dermatol 109(1):122 (1983 Jul).
25. Dahl MV, Katz HI, Krueger GG, et al. Topical metronidazole maintains remissions of rosacea. Arch Dermatol 134(6):679-83 (1998 Jun).
26. Jappe U, Schnuch A, Uter W. Rosacea and contact allergy to cosmetics and topical medicaments-retrospective analysis of multicentre surveillance data 1995-2002. Contact Dermatitis 52(2):96-101 (2005 Feb).

ABSTRACT

Use of medications by breast-feeding mothers is not uncommon. When prescribing a medication to a nursing mother, the physician must weigh the potential risk of exposing the infant to the medication or the risks of not breast-feeding against the benefits of the medication to the mother. Information regarding the safety of common dermatological medications during lactation will be reviewed. Based on this information, treatment recommendations will be made.

Key Words:
breast-feeding, antimicrobials, antihistimines, immunomodulators, antipsoriatics, steriods, scabicides, anti-acne agents

Breast-feeding provides optimal nutrition in the first 6 months of life. Well documented benefits of breast-feeding include a decreased incidence of infantile diarrhea¹ and infection.² Other studies show a possible protective affect against sudden infant death syndrome,³ insulin dependent diabetes mellitus,⁴ Crohn’s disease,⁵ ulcerative colitis,⁵ lymphoma,⁶ and allergic disorders.⁷ The American Academy of Pediatrics (AAP) recommends exclusive breastfeeding for the first six months of life, continuing to a year or beyond with the addition of solid food at 6 months of age.⁸ In Canada, approximately 80% of new mothers initiate breast-feeding,⁹ while 30-40% are still nursing 6 months postpartum.¹⁰ Corresponding US figures are 64% and 29%, respectively.¹¹

The use of prescription and over-the-counter (OTC) medications is common for nursing mothers. In one study of 14,000 pregnant or breastfeeding women, 79% of them took at least one medication, while on average, 3.3 drugs were taken while breastfeeding.¹² Fortunately, severe adverse effects resulting from the presence of common medications in breast milk are uncommon. Of 838 infants exposed to medications through breast milk, 11% experienced minor reactions, and no serious reactions requiring medical attention or cessation of breastfeeding occurred.¹³ The adverse reactions that did occur were consistent with the known pharmacological affects of the causative agent.

Transfer of Medications into Breast Milk

A number of factors determine the passage of a drug into breast milk. These include characteristics of the mother, the infant and the drug itself. In general, drugs given to a nursing mother reach the infant in much lower concentrations than those given to a pregnant woman reach the fetus.¹⁴

Antimicrobials

Penicillins and cephalosporins are present only in trace amounts in breast milk, and are compatible with breast-feeding.¹⁵ Their use is associated with a remote risk of alterations in gastrointestinal flora causing diarrhea and allergic sensitization of the infant.¹⁶ Erythromycin is excreted into breast milk, but no adverse effects in infants exposed to this drug in breast milk have been reported,¹⁶ and it is considered compatible with breastfeeding by the AAP. Caution may be in order in when prescribing erythromycin to lactating mothers of newborns however, because of recent reports of pyloric stenosis in neonates treated with erythromycin.^17,18 It has been reported that the calcium present in breast milk may inhibit absorption of the small amount of tetracycline, however, use of tetracycline while breastfeeding is not advised, because the threshold for its affect on teeth and bone is unknown.¹⁴ Topical clindamycin is partially absorbed through the skin and small amounts may pass into breast milk. No problems have been reported in nursing infants with maternal use of topical clindamycin,¹⁹ although bloody diarrhea was reported in an infant of a mother on intravenous clindamycin.²⁰ No adverse effects on the infant have been reported with use of topical metronidazole during lactation, however the manufacturer advises against its use while breast-feeding.²¹

Acyclovir is considered safe during breast-feeding.^15,16 Experience with the use of valacyclovir and famciclovir during human lactation is lacking.¹⁶

Terbinafine and itraconazole are both excreted in breast milk, and the safety of their use during lactation is unknown. Parenteral fluconazole has been safely used in neonates with candidiasis, and based on this, Briggs states that its use is probably safe during breast-feeding.¹⁶ The manufacturers of these three antifungals do not recommend their use while breast-feeding and the AAP has no rating.^22,23,24

Antihistamines

Small amounts of antihistamines are excreted in breast milk. Their use is not recommended during breast-feeding because infants may be more susceptible to their adverse effects, particularly drowsiness and irritability.^19,25 Antihistamines may also reduce milk production in some women.

Immunomodulators

Both cyclosporine and methotrexate are excreted into breast milk, and considered contraindicated during breast-feeding by the AAP because of the possibility of immunosuppression, neutropenia, carcinogenesis and unknown affects on growth.¹⁵ Hydroxychloroquine is excreted in small amounts in breast milk and because of its slow elimination rate and potential to accumulate to toxic levels in infants, caution is advised with daily dosing.²⁶ The AAP, however, considers hydroxychloroquine to be compatible with breast-feeding.¹⁵ Tacrolimus is excreted in human milk. Topical tacrolimus is not recommended by the manufacturer during breastfeeding, because of the potential for systemic absorption with topical use.²⁷ The AAP does not rate tacrolimus.

Antipsoriatics

It is not known whether calcipotriol is excreted into breast milk. The manufacturer recommends its use only if the anticipated benefits outweigh the potential risks.²⁸ Methoxsalen excretion in human milk is also unknown and although there are no reports of adverse effects with its use during lactation, the manufacturer recommends use only when the probable benefits outweigh the potential risks.²⁹ Briggs recommends that breast-feeding be interrupted for at least 24 hours after administration of the drug because of its photosensitizing affect.¹⁶

Steroids

Trace amounts of prednisone and its metabolite prednisolone are excreted in breast milk.¹⁶ The AAP considers prednisone to be compatible with breastfeeding.¹⁵ Hypertension was reported in the infant of a woman who used a corticosteroid on the nipples.³⁰ Use of topical corticosteroids on the breasts prior to nursing should be avoided.

Because estrogen decreases the quantity and protein content of breast milk, the use of combination oral contraceptive pills should be avoided whenever possible in lactating mothers, especially in the first two months postpartum.³¹

Scabicides

It is not known if permethrin is excreted in human milk. Citing evidence of teratogenicity in animals, the manufacturer recommends temporary discontinuation of nursing or avoidance during lactation.³² Anderson considers its use to be safe during lactation.³³

Analgesics

Significant salicylate levels have been found in breast-fed neonates of mothers taking salicylates, raising concerns about metabolic acidosis, bleeding, altered pulmonary circulation and Reye’s syndrome.²⁶ There is one report of salicylate intoxication in an infant exposed through her mother’s milk.³⁴ The AAP recommends that it be used with caution in nursing mothers.¹⁵ Widespread use of topical salicylic acid should be avoided because of the potential for significant systemic absorption. Of the nonsteroidal anti-inflammatories, ibuprofen and flurbiprofen have the best documentation of safety during lactation because they do not enter breast milk in significant quantities.¹⁴ The AAP considers ibuprofen, indomethacin, and naprosyn to be compatible with breast-feeding.¹⁵ There is one case report of seizures in an infant exposed to indomethacin through breast milk.³⁵

Analgesics

There have been no reports of adverse effects from use of topical benzoyl peroxide and topical tretinoin during lactation.¹⁹ It is not known whether adapalene or tazarotene pass into breast milk. The manufacturers recommend caution with their use during lactation.^36,37 Spironolactone may pass into breast milk, but has not been reported to cause problems in nursing babies.19 The AAP considered spironolactone to be compatible with breastfeeding, ¹⁵ although its use during lactation is not recommended by the manufacturer.³⁸

Table 1: Compatibility of some dermatologic drugs during breastfeeding.

Conclusion

When considering a medication for a lactating mother, the benefits of breast-feeding need to be weighed against the potential risk of exposure of the infant to the drug in question. For the majority of dermatological conditions, alternatives that are compatible with breast-feeding are available, or treatment can be safely postponed until lactation is completed.

References

1. Popkin BM, Adair L, Akin JS, et al. Breast-feeding and diarrheal morbidity. Pediatrics 1990; 86: 874-882.
2. Beaudry M., Dufour R, Marcoux S. Relation between infant feeding and infections during the first six months of life. J Pediatr 1995; 126: 191-197.
3. Ford RPK, Taylor BJ, Mitchell EA, et al. Breastfeeding and the risk of sudden infant death syndrome. Int J Epidermiol 1993; 22: 885-890.
4. Mayer EJ, Hamman RF, Gay EC, et al. Reduced risk of IDDM among breast-fed children. Diabetes 1988; 37:1625-1632.
5. Rigas A, Rigas B, Glassman M, et al. Breast-feeding and maternal smoking in the etiology of Crohn’s disease and ulcerative colitis in childhood. Ann Epidemiol 1993; 3:387-392.
6. Davis MK, Savitz DA, Graubard BI. Infant feeding and childhood cancer. Lancet 1988; 2:365-368.
7. Gdalevich M, Mimouni D, David M, Mimouni M. Breast-feeding and the onset of atopic dermatitis in childhood: A systematic review and meta-analysis of prospective studies. J Am Acad Dermatol 2001; 45: 520-527.
8. American Academy of Pediatrics, Work Group on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics 1997; 100: 1035-1039.
9. Barber CM, Abernathy T, Steinmetz B, Charlebois J. Using a breastfeeding prevalence survey to identify a population for targeted programs. Can J Public Health 1997; 88:242-245.
10. Bourgoin G, Lahaie N, Rheaume B, et al. Factors influencing the duration of breastfeeding in the Sudbury region. Can J Public Health 1997; 88: 238-241.
11. Ryan AS. The resurgence of breastfeeding in the United States. Pediatrics 1997; 99:E12.
12. Collaborative Group on Drug Use in Pregnancy. Medication during pregnancy: An intercontinental cooperative study. Int J Gynecol Obstet 1992; 39:185–196.
13. Ito S, Blajchman A, Stephenson M, et al. Prospective follow-up of adverse reactions in breastfed infants exposed to maternal medication. Am J Obstet Gynecol 1993; 168:1393-1399.
14. Howard CR, Lawrence RA. Drugs and breastfeeding. Clin Perinatology 1999; 26: 447-478.
15. American Academy of Pediatrics Committee on Drugs. The transfer of drugs and other chemicals into human milk. Pediatrics 1994; 93:137-150.
16. Briggs GG, Freeman RK, Yaffee SL. Drugs in pregnancy and lactation, Fifth Edition, Baltimore: Williams and Wilkins, 1998.
17. Anonymous. Erythromycin – induced pyloric stenosis in infants. Prescrire International 2001; 10:16.
18. Honein MA, Paulozzi LJ, Himelright IM, et al. Infantile hypertrophic pyloric stenosis after pertussis prophylaxis with erythromycin: A case review and cohort study. Lancet 1999; 354: 2101-2105.
19. USP- DI. Drug Information for the Health Care Professional, Vol. 1, Nineteenth Edition, Taunton, MA: Rand McNally, 1999.
20. Mann CF. Clindamycin and breast-feeding. Pediatrics 1980; 66:1030-1031.
21. Metronidazole product monograph, Galderma Canada Inc., Thornhill, ON, Canada, 1996.
22. Terbinafine product monograph, Novartis Pharmaceuticals Canada Inc., Dorval, QC, Canada, 2002.
23. Itraconazole product monograph, Janssen-Ortho Inc., Toronto, ON, Canada, 2002.
24. Fluconazole product monograph, Pfizer Canada Inc., Kirkland, QC, Canada, 2001.
25. Reed BR, Dermatologic drug use during pregnancy and lactation. Dermatol Clinics 1997; 15:197-202.
26. Janssen NM, Genta MS. The effects of immunosuppressive and antiinflammatory medications on fertility, pregnancy and lactation. Arch Intern Med 2000; 160:610-619.
27. Tacrolimus product monograph, Fujisawa Canada Inc., Markham, ON, Canada, 2001.
28. Calcipotriol product monograph, Leo Pharma Inc., Thornhill, ON, Canada, 2001
29. Methoxsalen product monograph, ICN Canada Ltd. Montreal, QC, Canada, 1992.
30. DeStefano P, Bongo C, Borgna – Pignatti C, et al. Factitious hypertension with mineralocorticoid excess in infants. Helv Paediatr Acta 1983; 38:185-189.
31. Spencer JP,Gonzalez LS, Barnhart DJ. Medications in the breast-feeding mother. Am Fam Phys 2001; 64:119-126.
32. Permethin product monograph, Glaxo Smith Kline,Mississauga, ON, Canada, 2002.
33. Anderson PO. Drug use during breast-feeding. Clin Pharm 1991; 10:594-624.
34. Clark JH, Wilson WG. A 16-day-old breast-fed infant with metabolic acidosis caused by salicylate. Clin Pediatr 1981; 20:53-54.
35. Eeg-Olofsson O,Malmros I, Elwin CE, Steen B. Convulsions in a breast-fed infant after maternal indomethacin. Lancet 1978; 2:215.
36. Adapalene product monograph, Galderma Canada Inc., Thornhill, ON, Canada, 2002.
37. Tazarotene product monograph, Allergan, Markham, ON, Canada, 2001.
38. Spironolactone product monograph, Pharmacia Canada Inc., Mississauga, ON, Canada, 2001.

Industry News

Schering-Plough Recalls Specific Lots of Claritin-D® 12-hour Tablets

In February 2002, Shering-Plough announced a voluntary recall of specific lots of Claritin-D® 12-hour (5mg loratidine/120mg pseudoephedrine sulfate) tablets directed to wholesale accounts and retail pharmacies. These products were manufactured between August 1999, and June 2001. They are indicated for the relief of symptoms of seasonal allergic rhinitis.

Schering-Plough as part of its standard quality-control procedures conducted stability testing of specific lots of this product including dissolution tests to determine the rate that tablets dissolve and the amount of active ingredients released. Test results indicated that some tablets in these lots did not demonstrate full release of pseudoephedrine at the 5^th hour per specification, although be 25 minutes later all tested samples met specifications for releasing the decongestant component. The company believes that this short delay poses no medical risk to patients.

This recall is being conducted with the knowledge of the US FDA.