Am J Clin Dermatol DOI 10.1007/s40257-015-0127-7

THERAPY IN PRACTICE

Adverse Effects of Acne Medications: Recognition and Management Mollie D. Oudenhoven1 • Megan A. Kinney1 • Diana B. McShane1 Craig N. Burkhart1 • Dean S. Morrell1



Ó Springer International Publishing Switzerland 2015

Abstract Acne vulgaris is a very common chronic inflammatory disease of the skin. The clinical features of acne range from non-inflammatory comedones to inflammatory nodules. While often perceived as an adolescent disease, the prevalence remains high into adulthood, and the manifestations can have detrimental psychosocial effects. It is therefore not surprising that many patients are motivated to seek treatment. The existing treatment strategies for acne are complex due to the multifactorial pathogenesis of the disease. Although it is difficult to cure, four categories of medications have proved efficacious in reducing acne lesions: topical agents, systemic antibiotics, systemic retinoids, and hormonal agents. Unfortunately, these medications can cause adverse effects that may limit their use. Typically, these adverse effects are mild and transient and can be remedied by altering the dose or frequency of the offending agent. However, more serious adverse effects can occur that pose a significant health risk to the patient. Understanding how to recognize and manage the adverse effects of common acne therapies is imperative to providing the safest and most appropriate treatment for each patient. This article focuses on the recognition and management of adverse effects associated with current acne medications.

& Dean S. Morrell [email protected] 1

Department of Dermatology, University of North Carolina School of Medicine, 410 Market Street, #400, Chapel Hill, NC 27516, USA

Key Points The most common adverse effects of acne medications are mild and transient. These adverse effects may reduce compliance but typically do not require cessation of treatment. Management includes decreasing the dosage or the frequency of the medication, especially for topical treatments. Rare adverse effects can occur with systemic therapies that may pose a significant risk to the health of the patient. It is imperative for providers to be aware of these possible effects as prompt cessation of therapy is necessary. Appropriate treatment should be individualized to the patient and should appropriately weigh the risks and benefits.

1 Introduction Acne vulgaris represents the most common dermatologic condition and is a chronic inflammatory disease of the pilosebaceous unit. The clinical features of acne include noninflammatory lesions (open and closed comedones) and inflammatory lesions (pustules, papules, or nodules) that occur in a distribution corresponding to the greatest density of pilosebaceous units: face, neck, upper chest, and back [1–3]. Four pathophysiologic mechanisms are known to play pivotal roles in the formation of acne lesions: (1) androgen-mediated increase in sebum production, (2) abnormal proliferation and desquamation of keratinocytes

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within hair follicles, (3) follicular plugging leading to micro-comedone formation, and (4) Propionibacterium acnes proliferation leading to release of inflammatory mediators [4, 5].

2 Current Therapies, Associated Adverse Effects, and Management Numerous medications have been developed that target one or more of the pathogenic processes. The following agents are often used in combination to improve efficacy given the multifactorial pathogenesis of acne. Current clinical guidelines focus on severity and degree of inflammation to determine the appropriate treatment regimen; however, significant variations in management exist across primary and specialty care (Table 1) [6]. 2.1 Topical Therapies Topical therapies are the mainstay of treatment for mild to moderate acne. Benzoyl peroxide, salicylic acid, azelaic acid, and retinoids are commonly used for mild comedonal acne, whereas topical antibiotics and medications with bacteriostatic properties are more effective against inflammatory acne. Most of the topical preparations are available in a variety of strengths and formulations, and selection of the appropriate vehicle may help limit side effects. Gels, washes, and solutions tend to be more drying than creams, lotions, and ointments [7]. In general, topical agents have fewer adverse effects than oral agents due to low systemic absorption; however, they can cause skin irritation that may reduce patient compliance and limit utility [8]. 2.1.1 Topical Retinoids Retinoids are vitamin A derivatives that act as comedolytics by normalizing desquamation of the epithelial lining, thereby inhibiting obstruction of the pilosebaceous unit. The three main topical retinoids are tretinoin (first generation), tazarotene (third generation), and adapalene (third generation) [9]. Local adverse effects that commonly occur with topical application of retinoids include peeling, erythema, dryness, burning, and itching. These effects are dose dependent [3, 10]. Tazarotene is the most irritating of the topical retinoids, with local skin irritation reported in half of patients with daily use [11–14]. In comparative studies, adapalene has proven to have a favorable side-effect profile, with less skin irritation and better tolerability [10, 15]. In addition to skin irritation, retinoids may increase ultraviolet (UV) light sensitivity by thinning the stratum corneum; thus, daily use of sunscreen is recommended [3, 16].

Retinoid-induced skin irritation tends to improve with time, often peaking around the fourth week of treatment and then slowly subsiding [13]. Irritation can be minimized by reducing the frequency of treatment, applying a small pea-sized amount of the medication to cover the entire face, starting with a lower strength preparation, or switching to a different formulation such as a cream or lotion [3]. In addition, limiting exposure to UV light, avoiding weather extremes, and applying a daily noncomedogenic moisturizer can help attenuate symptoms. Concomitant use of benzoyl peroxide and salicylic acid may potentiate retinoid-induced peeling and erythema and should be avoided if irritation already exists [17]. Systemic adverse effects and laboratory abnormalities have not been reported with any of the topical retinoids. Both tretinoin and adapalene are pregnancy category C, whereas tazarotene is pregnancy category X. Tretinoin and adapalene should only be used in pregnancy if the benefits outweigh risks. Tazarotene is contraindicated in pregnancy, and physicians should inquire about appropriate contraceptive use before starting therapy. While recent studies have demonstrated no increased risk of spontaneous abortion or major or minor birth defects when pregnant women were exposed to topical retinoids in their first trimester, recommendations remain based on early studies indicating a risk of retinoid embryopathy with oral retinoid therapy [16–19]. 2.1.2 Topical Antibiotics Topical antibiotics are indicated for mild to moderate acne. These agents inhibit proliferation of P. acnes and are most active against inflammatory lesions. Antibiotics used for topical acne therapy include clindamycin and erythromycin. Local skin irritation that manifests as erythema, dryness, and burning at the application site is the most common adverse effect associated with topical antibiotic use [17, 20–24]. Similar to other topical agents, changing the formulation may help improve symptoms. Rare case reports have indicated that systemic absorption of topical clindamycin can lead to diarrhea and pseudomembranous colitis [20, 25, 26]. Studies have shown no clear association, but given the remote risk, topical clindamycin should not be used in patients with regional enteritis, ulcerative colitis, or antibiotic-associated colitis [27]. To further reduce the risk of colitis, consider applying the medication to limited areas and avoid use on the trunk. Therapy should be stopped immediately if patients present with symptoms of prolonged diarrhea, gastrointestinal distress, or a recent diagnosis of pseudomembranous colitis, and a referral should be made to their primary care physician. Upon resolution of symptoms, it is advisable to initiate a different topical antibiotic.

Adverse Effects of Acne Medications Table 1 Summary of adverse effects of acne therapy and their management Acne medication

Common adverse effects

Management

Topical retinoids: adapalene, tretinoin, tazarotene

Local skin irritation Pregnancy category: adapalene/tretinoin = C; tazarotene = X

Reduce frequency of use; decrease strength; change type of retinoida; change vehicleb; apply with non-comedogenic moisturizerc

Topical antibiotics: clindamycin, erythromycin

Local skin irritation; diarrhea/colitis, especially with clindamycin; antibacterial resistance, especially with erythromycin

Reduce frequency of use; change vehicleb; stop therapy; combine treatment with benzoyl peroxide to prevent resistanced

Topical agents

Pregnancy category B Benzoyl peroxide

Irritant/allergic contact dermatitis; bleaching of towels/clothing Pregnancy category C

Salicylic acid

Local skin irritation; salicylate toxicity, inner ear damage, and hypoglycemia: RARE Pregnancy category C

Reduce frequency of use; change vehicleb; washes may be better tolerated than leave-on formulations; use white towels, pillowcases, etc.; stop therapy if any allergic/irritant contact dermatitis Reduce frequency of use; change vehicleb; washes may be better tolerated than leave-on formulations; stop therapy immediately if any signs/symptoms of systemic toxicity

Glycolic acid

Increased photosensitivity

Wear sunscreen

Azelaic acid

Transient erythema/irritation

Reduce frequency of use; change vehicleb

Pregnancy category B Dapsone

Temporary yellow discoloration of the skin/clothing when combined with benzoyl peroxide Rare: nasopharyngitis/headache No hematologic changes

Stop treatment if yellow discoloration occurs; do not apply at the same time as benzoyl peroxide; perform a comprehensive physical exam if patients experience systemic symptoms

Pregnancy category C Sodium sulfacetamide

Chemical peels: TCA, glycolic acid, salicylic acid, Jessner’s solution

Pregnancy category C

Local irritation

Generally safe in patients with history of oral sulfa allergy, but avoid if previous allergic reaction to topical sulfa drugs

Erythema, desquamation, pain, pruritus; hyperpigmentation in darker skinned individuals

Use glycolic acid in darker skinned individuals; diligent sun protection during and after treatment

Vaginal candidiasis; GI upset/pill-induced esophagitis/IBD; phototoxicity

Do not use tetracyclines in pregnant women or children aged \8 years; tetracycline should be taken on an empty stomach to help with absorption

Oral antibiotics Tetracyclines: tetracycline, doxycycline, minocycline

In children/pregnancy: cartilage and bone growth abnormalities, tooth discoloration Doxycycline: most phototoxic, photo-onycholysis Minocycline: vertigo, blue/black/brown discoloration of the skin, autoimmune disease, hepatitis Pregnancy category D

TMP-SMX

Severe, but rare side effects including Stevens– Johnson, hypersensitivity reactions, and blood dyscrasias

Doxycycline: take with food/use extended-release formulation/lower dose to minimize GI upset. Avoid UV exposure Minocycline: lower dose/use extended-release formula to help prevent systemic effects; check periodic LFTs and ANA levels for patients receiving treatment for [1–2 years; stop treatment immediately if systemic effects occur; administration of systemic steroids may help resolve symptoms; can switch to another tetracycline Stop therapy if systemic effects occur

Pregnancy category C Azithromycin

Amoxicillin

GI upset; increased risk of arrhythmias that can lead to cardiovascular death Pregnancy category B

Antacids prior to treatment can prevent GI upset; consider alternate therapy with personal/strong family history of cardiovascular disease

Generally well tolerated; adverse effects similar to those of all antibiotics

Switch to alternate antibiotic if systemic side effects occur

Pregnancy category B

M. D. Oudenhoven et al. Table 1 continued Acne medication

Common adverse effects

Management

Metrorrhagia, nausea, vomiting, breast tenderness, headaches

Discontinue for DVT, MI, stroke, and hypertension; should not use in patients who smoke due to the increased risk of a hypercoagulable state

Hormonal agents OCP

Rare: DVT, MI, stroke, abnormal lipid indices, glucose intolerance, and hypertension in young women Spironolactone

Contraindicated in pregnancy Breast tenderness, menstrual irregularities, fatigue, dizziness, headache; hypotension, hyperkalemia Pregnancy category C

Flutamide

Hepatotoxicity

Cyproterone acetate

Contraindicated in pregnancy Oligomenorrhea, melasma, fluid retention, nausea/ vomiting Rare: hepatotoxicity, blood clotting disorders Contraindicated in pregnancy

Lower dose and/or add OCP to alleviate menstrual irregularities; check potassium levels in the first month of treatment and monitor thereafter to screen for hyperkalemia Serial monitoring of LFTs; withdraw therapy immediately if elevated Not approved for use in the USA; do not use in patients with liver disease or clotting disorders; consider monitoring LFTs, and withdraw therapy immediately if elevated

Systemic retinoids Isotretinoin

Dry skin, dry lips, cheilitis; decreased night vision, headache, benign intracranial hypertension; elevated LFTs and lipid indices; psychiatric disturbances/IBD controversial Pregnancy category X

Females: baseline and monthly pregnancy tests. Patients required to use two modalities of contraception or must exercise absolute abstinence in accordance with iPledge; stop treatment immediately if concerned about benign intracranial hypertension; screen for depressive symptoms; check baseline LFTs and lipid indices with repeat testing monthly/at physician’s discretion

ANA anti-nuclear antibody, DVT deep vein thrombosis, GI gastrointestinal, IBD inflammatory bowel disease, LFT liver function tests, MI myocardial infarction, OCP oral contraceptive pill, TCA trichloroacetic acid, TMP-SMX trimethoprim–sulfamethoxazole, UV ultraviolet a

Retinoids in order of increasing irritation: adapalene \ tretinoin \ tazarotene

b

Vehicles in order of increasing irritation: ointments \ creams \ lotions/solutions \ alcohol-based wipes \ gels

c

Applying with a moisturizer may decrease the potency of the retinoid, but improve its tolerability

d

Different combination topical products are also available to increase compliance for benzoyl peroxide, antibiotics, and retinoids

Increasing antibacterial resistance to not only P. acnes, but also Staphylococcal and Streptococcal spp. is a growing concern with long-term topical antibiotic use [28–31]. This can lead to both therapeutic failure and increased susceptibility to infections at other anatomic sites [30]. While resistance has emerged to all topical antimicrobial agents, erythromycin resistance is the most common and the drug has demonstrated waning efficacy relative to clindamycin [24, 28]. In an effort to reduce resistance, avoid using topical antibiotics as maintenance therapy or monotherapy. Instead, treatment should be combined with a topical retinoid and/or benzoyl peroxide and limited to the shortest possible duration. Furthermore, simultaneous use of oral and topical antibiotics should be avoided, especially if they are chemically different [31]. All topical antibiotics are pregnancy category B. These therapies are generally considered to be safe during pregnancy but treatment should only be continued if the benefits outweigh possible risks [17, 27].

2.1.3 Other Topical Agents Benzoyl peroxide is a non-antibiotic antimicrobial that inhibits P. acnes formation by creating reactive oxygen species within the hair follicle. It also has weak comedolytic and anti-inflammatory properties [1]. The most common adverse effects include local erythema, dryness, and peeling [32, 33]. This irritation usually improves with time and can be managed by reducing the strength of the preparation without sacrificing efficacy [34]. In addition, allergic contact dermatitis can occur in rare cases and warrants cessation of therapy [35, 36]. No systemic effects have been reported; however, it is pregnancy category C and therefore should be avoided during pregnancy [27, 32, 33]. The most popular hydroxy acids used to treat acne include salicylic and glycolic acids. Salicylic acid is a component of many over-the-counter preparations and has comedolytic effects [3]. Topical use most commonly causes local irritation, especially at concentrations over

Adverse Effects of Acne Medications

2 % [17]. While no systemic toxicities have been associated with the use of topical acne products containing salicylic acid, numerous case reports exist of salicylate toxicity, toxic inner ear damage, and hypoglycemia in patients using topical salicylic acid for hyperkeratotic skin conditions for prolonged periods of time over large surface areas [17, 37–39]. Signs and symptoms of salicylate toxicity include gastrointestinal disturbances, hearing loss, altered mental status, increased respiratory rate, and an anion-gap metabolic acidosis with concomitant respiratory alkalosis [39]. Toxic inner ear damage results in sensorineural hearing loss, and hypoglycemia can lead to episodic sweating, jitteriness, lightheadedness, syncope, and altered mental status. These systemic effects are related to the percutaneous absorption of salicylic acid, which is significantly more efficient (9–25 %) than other topical agents and increases even further in diseased skin [38, 40]. While unlikely to occur, patients exhibiting signs or symptoms of salicylate toxicity should be sent to the local emergency department for further management. Hearing loss and hypoglycemia should be managed with drug cessation, and a comprehensive history and physical examination should be undertaken to rule out other potential etiologies. Glycolic acid is an alpha-hydroxy acid and was the first to be added to cosmetic products. In addition, to treating acne, it is recommended for hyperpigmentation and antiaging. When using a daily glycolic acid product, it is important to wear sun protection, as this topical increases sun sensitivity. While sensitization to UVB is greater than to UVA, increased risk of skin cancers with its use is inconclusive. Glycolic acid is safe to use in pregnancy [41, 42]. Azelaic acid has antimicrobial, comedolytic, and antiinflammatory properties. Common adverse effects include transient erythema and irritation [43, 44]. There have been isolated reports of hypopigmentation but no evidencebased support for this association [3, 17]. Nonetheless, darker-skinned individuals should be monitored closely for this potential effect given increased susceptibility [3]. Conversely, patients with significant post-inflammatory hyperpigmentation may actually benefit from the hypopigmentation effects of azelaic acid. No systemic adverse effects have been reported [45]. Dapsone has both antimicrobial and anti-inflammatory properties and offers documented efficacy for the reduction of both inflammatory and non-inflammatory lesions [21, 46]. Oral dapsone is known to cause hemolytic anemia, especially in patients with G6PD deficiency. However, studies have shown no significant hematologic changes in patients using topical dapsone [47]. Caution must be used when combining topical dapsone with benzoyl peroxide, as this combination can cause temporary yellow discoloration of the skin [48]. Rare systemic adverse effects include

headache (20 %) and nasopharyngitis (15 %) [49]. A physical examination should be performed and other diagnoses ruled out before these symptoms are attributed to topical dapsone use. While dapsone has some structural similarities to sulfonamides, dapsone is not a sulfonamide and cross-reaction has not been demonstrated [50]. Sodium sulfacetamide is a bacteriostatic antibacterial in the sulfonamide group that inhibits bacterial DNA synthesis. Sodium sulfacetamide 10 % is typically combined with 5 % sulfur in various formulations for the treatment of acne. Adverse effects of sodium sulfacetamide are infrequent and are typically limited to local irritation and poor compliance due to the smell. Any patient with a history of allergic reaction to topical sulfa drugs should not use this agent, but it is generally well-tolerated even in patients with a history of an oral sulfa allergy [17]. Irritation from any topical can be managed by decreasing the application frequency or reducing the strength of preparation. Benzoyl peroxide, salicylic acid, dapsone, and sodium sulfacetamide are pregnancy category C, whereas azelaic acid is category B. Glycolic acid is not rated. Therefore, azelaic acid and/or glycolic acid may be preferable in pregnancy, but all can be considered for use during pregnancy if the benefits outweigh risks [27]. 2.1.4 Chemical Peels Chemical peels are applied to the skin to destroy a portion of the epidermis (superficial), the entire epidermis into the papillary dermis (medium), or the epidermis into the reticular dermis (deep). Generally, superficial chemical peels are used to target acne and can consist of a number of agents alone or in combination with varying concentrations. Whether the peel can be performed at home, by an aesthetician, or needs physician supervision is based on the agent used, its concentration, and the depth of the peel. While the gold standard for treating acne is a trichloroacetic acid (TCA) peel, the other common agents used to target acne are glycolic acid, salicylic acid, and Jessner’s solution peels. Side effects consist of various levels of erythema, desquamation, pain, and/or pruritus. In darker skin, there is an increased risk of post-inflammatory hyperpigmentation. Additional rare side effects include infection, allergic reaction, or side effects from technical errors in application [51]. Glycolic acid peels have demonstrated efficacy with less risk of hyperpigmentation in darker skin types. However, more sessions may be necessary [52, 53]. Salicylic acid peels do not appear to increase the risk of salicylate toxicity despite having a higher concentration of salicylic acid (20 vs. 6 % for other topical formulations) since they are typically applied to a limited surface area [54]. While many studies have demonstrated the efficacy of superficial chemical peels for

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2.2 Oral Antibiotics

Furthermore, tetracycline is the most likely antibiotic in its class to cause candidiasis and tooth discoloration [62, 64]. Because absorption is reduced in the presence of food and dairy products, tetracycline should be taken on an empty stomach [64].

Oral antibiotics are indicated for moderate to severe acne as they exert both anti-microbial and anti-inflammatory effects by inhibiting P. acnes proliferation, thereby reducing the release of bacteria-mediated inflammatory cytokines. In addition, they are an alternative treatment for acne that is refractory to topical therapies or covers a large surface area. First-line oral agents include tetracyclines [28, 56]. Other antibiotics, including trimethoprim–sulfamethoxazole, amoxicillin, and azithromycin can be effective in the treatment of acne but are used less frequently. As with topical formulations, oral antibiotics should be combined with other therapies to reduce resistance and increase efficacy.

2.2.1.2 Doxycycline The most common adverse effect of doxycycline is gastrointestinal distress [57, 58, 64]. Unlike tetracycline, this agent should be taken with food to help minimize gastric irritation. Some studies have suggested a possible association between the use of tetracyclines, particularly doxycycline, and the development of inflammatory bowel disease; however, not all studies have demonstrated a link and no study has demonstrated a causal association [65–67]. Doxycycline is the most phototoxic of the tetracyclines, causing erythema and edema in sun-exposed areas in addition to photo-onycholysis (Fig. 1) [58, 68]. Patients need to be advised to avoid direct sun exposure and to wear appropriate sunscreen.

2.2.1 Tetracyclines

2.2.1.3 Minocycline The adverse effects of minocycline can be more serious than those of the other oral antibiotics used in the treatment of acne [69]. Minocycline is more likely to cause central nervous system disturbances than are other tetracyclines. Vertigo (significantly higher prevalence in women), dizziness, ataxia, and lightheadedness occur as a result of vestibular toxicity and tend to resolve with cessation of treatment [70–72]. Starting treatment at a lower dose or using the extended-release formula can help prevent these effects [64]. While rare, intracranial hypertension also occurs more frequently in patients taking minocycline, especially when combined with oral retinoid use [71, 73–75]. Minocycline therapy has been associated with either a blue/black or ruddy brown discoloration of the skin that most commonly occurs in acne scars, over the shins, or in

acne, few head-to-head trials have compared chemical peels with other acne therapies. Generally, chemical peels are used in conjunction with other agents [55].

Tetracyclines are the most important antibiotics for acne, especially tetracycline, doxycycline, and minocycline. The adverse effects of tetracyclines are varied but quite rare. All tetracyclines are contraindicated in pregnant women and children younger than 8 years as they can affect cartilage and bone growth, and be absorbed into the teeth, resulting in yellow discoloration [28]. Common adverse effects of all tetracyclines include vaginal candidiasis in susceptible females, gastrointestinal upset, and phototoxicity [57, 58]. Benign intracranial hypertension and Sweet syndrome are rare, more serious side effects associated with the use of all tetracyclines [59–61]. Sweet syndrome is characterized by painful red nodules over the upper torso with accompanying fever, malaise, and leukocytosis that requires prompt cessation of the tetracycline and supportive management [60]. Pill-induced esophagitis can also occur if tetracyclines are taken immediately before bedtime. Generally, we recommend taking this medication no less than 30 min prior to laying down and taking it with a meal and/or large glass of water. 2.2.1.1 Tetracycline Tetracycline has exhibited longstanding safety and efficacy in the treatment of acne, although there have been periodic shortages in the US market. The most common reported side effect of oral tetracycline is gastrointestinal upset [57, 62]. Studies have shown that long-term therapy favors multi-drug-resistant organisms in the intestines and can also affect the gastrointestinal flora of close contacts [30]. Skin reactions, ranging from rash, pruritus, and phototoxicity to acneiform and fixed-drug eruptions, are also common [57, 63, 64].

Fig. 1 Photo-onycholysis: separation of the distal nail plate from the nail bed consistent with photo-onycholysis. Most commonly seen in patients taking doxycycline with concomitant ultraviolet exposure

Adverse Effects of Acne Medications

sun-exposed areas (Fig. 2). This usually develops after long-term use and/or cumulative doses over 100 g and tends to slowly resolve with cessation of treatment [76, 77]. If the pigmentation does not fade, a Q-switched ruby laser may help improve discoloration [78]. As with doxycycline, pigmentation of teeth is also possible, especially if given to children aged less than 8 years, although this pigmentation tends to be in a mid-tooth distribution versus the more proximal tooth discoloration in tetracycline or doxycycline. The development of autoimmune diseases has been reported with the use of minocycline and represents a rare but serious adverse effect. These diseases include drug-induced lupus, autoimmune hepatitis, serum sickness-like reaction, and hypersensitivity syndrome [79–83]. Hypersensitivity syndrome and serum sickness-like reaction are early-onset reactions that typically occur within 2 months of starting therapy and are characterized by fever, malaise, and arthralgias with or without organ involvement. Initial evaluation should include complete blood count, chemistry panel, liver function tests (LFTs), urinalysis, and a chest radiograph, with further studies chosen based on physical examination findings [63]. Drug-induced lupus typically starts after 2 years of treatment and is characterized by fever, musculoskeletal complaints, malaise, fatigue, pleuropulmonary involvement, and positive antinuclear antibody (ANA) titers [79, 80, 83]. If patients are treated chronically ([1–2 years) with minocycline, periodic liver function and ANA testing should be considered in addition to monitoring for clinical signs and symptoms [74]. While only a minority of patients with ANA seroconversion develop clinical disease, it is prudent to discontinue treatment after a positive ANA test to prevent further complications [82, 83]. Hepatitis can occur from either a hypersensitivity or an autoimmune reaction. Hypersensitivity-induced hepatitis

tends to occur a few weeks after drug initiation and presents with rash and eosinophilia. In contrast, autoimmune hepatitis tends to occur in younger patients receiving longterm therapy who present with lupus-like symptoms and elevated liver enzymes [79, 83, 84]. In either case, it is advisable to stop treatment and start systemic steroids [84]. 2.2.2 Other Antibiotics Trimethoprim–sulfamethoxazole (TMP-SMX), azithromycin, and amoxicillin represent second-line antibacterial agents for the treatment of acne. Generally they are prescribed when cost is a factor or alternative agents are ineffective or intolerable. TMP-SMX is generally used with caution given the severe, albeit rare, side effects, which include Stevens– Johnson syndrome, hypersensitivity reactions, and blood dyscrasias such as thrombocytopenia, neutropenia, anemia, and agranulocytosis [64, 85, 86]. Thrombocytopenia is the most common blood dyscrasia to occur, but, overall, these events are rare and do not require complete blood count monitoring [85]. TMP-SMX is pregnancy category C and should not be used during pregnancy. Azithromycin is generally well-tolerated, causing only mild and transient gastrointestinal disturbances that can be alleviated with the use of antacids prior to treatment [87, 88]. However, recent case studies have indicated a small absolute increased risk of arrhythmias leading to cardiovascular death, especially in those with a high baseline risk of cardiovascular disease [89]. Amoxicillin is also welltolerated with adverse effects that include those common to all oral antibiotics. When compared with azithromycin, amoxicillin does not exhibit an increased cardiovascular risk. Amoxicillin and azithromycin are pregnancy category B and therefore are safe for use during pregnancy. 2.3 Hormonal Agents Hormonal agents are a useful adjunct for women who have moderate to severe acne [28]. These agents are available in two forms—combined oral contraceptive pills (OCP) and androgen-receptor blockers such as spironolactone. These agents decrease sebum production by suppressing androgen-mediated effects on the sebaceous gland [90]. All hormonal agents are contraindicated in men and pregnant women due to the risk of feminization in males as a result of the anti-androgenic effects [28]. 2.3.1 Oral Contraceptives

Fig. 2 Minocycline-induced hyperpigmentation: blue–black pigmentation within an old facial acne scar that is consistent with type I minocycline-induced skin pigmentation—the most common type of hyperpigmentation

Several contraindications to OCPs exist, notably a history of stroke, venous thromboembolism (VTE), myocardial infarction, breast cancer, uncontrolled hypertension,

M. D. Oudenhoven et al.

smoking when older than 35 years, and migraine with aura. Therefore, a thorough medical history and a review of the contraindications should be reviewed before prescribing this medication. Side effects to OCPs are common and can hinder compliance. Common transient side effects include metrorrhagia, nausea, vomiting, breast tenderness, headache, and lower extremity edema [91]. These symptoms tend to resolve after two to three cycles as the body adjusts to the hormones and can also be attenuated by lowering the estrogen dose. More serious adverse effects include VTE, myocardial infarction, and stroke, which occur more frequently in patients with a history of diabetes, migraine with aura, hypertension, or smoking [92–94]. An important consideration when prescribing OCPs is the type of progestin in the formulation. Unlike endogenous progesterone, synthetic progestin has androgenic activity that can actually exacerbate acne. Choosing OCPs with low androgenic properties such as the third-generation progestins, norgestimate and desogestrel, can help prevent worsening acne symptoms [95]. However, third-generation progestins, in addition to drospirenone, have been associated with a sixfold increase in the risk of VTE. This risk can be decreased by reducing the estrogen dose and switching to a formulation containing levonorgestrel, which has the lowest increased risk of VTE compared with the other progestins [94, 96]. Providers should keep in mind that choosing an appropriate OCP requires balancing the efficacy (i.e., preventing acne exacerbations) with safety (i.e., preventing vascular events). 2.3.2 Androgen-Receptor Blockers Spironolactone is the most commonly used androgen-receptor blocker. Adverse effects of spironolactone are dose related and include breast tenderness, menstrual irregularities, fatigue, dizziness, and headache [28, 97, 98]. Irregular menstrual bleeding can be remedied by lowering the dose of spironolactone and starting an OCP [94]. Spironolactone also acts as an aldosterone-receptor antagonist and therefore exerts a diuretic effect that can lead to reductions in blood pressure and to electrolyte abnormalities. Hyperkalemia is the most common and most concerning electrolyte abnormality, especially if patients are taking higher doses, using non-steroidal anti-inflammatory drugs (NSAIDs) or angiotensin-converting enzyme inhibitors, or have cardiac or renal compromise [97, 99]. Potassium levels should be checked during the first month of treatment and monitored thereafter to determine whether any dose adjustments need to be made. Patients should also try to avoid extra potassium in their diet. Cyproterone acetate is a progestational anti-androgen that is not available in the USA [28]. Cyproterone can cause amenorrhea or oligomenorrhea due to dose-

dependent endometrial atrophy in addition to nausea, vomiting, fluid retention, lower extremity edema, headache, and melasma. In rare cases, it has been associated with fatal fulminant hepatitis and blood clotting disorders [28, 100]. Flutamide is a non-steroidal anti-androgen approved for prostate cancer that has been used for treatment of acne and hirsutism in females. Similar to cyproterone acetate, its use is limited due to case reports of dose- and age-dependent fatal hepatitis [101–103]. Serial LFTs should be monitored closely and therapy should be stopped immediately in the case of elevation [101]. Furthermore, women taking androgen-receptor antagonists should use appropriate contraception to prevent pregnancy. 2.4 Isotretinoin Isotretinoin is a metabolite of vitamin A that is thought to target all four pathogenic factors that contribute to acne. Use of isotretinoin is indicated for severe inflammatory acne, nodulocystic acne, or recalcitrant disease [104]. Due to its origin as a vitamin A derivative, many of the adverse effects of isotretinoin are similar to those of hypervitaminosis A syndrome, which consists of mucocutaneous, ophthalmic, gastrointestinal, neurologic, psychiatric, and rheumatologic manifestations. Mucocutaneous toxicity in the form of xeroderma, dry eyes, dry lips, and cheilitis is the most common side effect of isotretinoin. Cheilitis is almost ubiquitous among patients receiving isotretinoin therapy and can be attenuated with continual application of lip balms and emollients [105]. Dryness of the nares can result in epistaxis. Vitamin E was initially reported to prevent many of the retinoidinduced mucocutaneous effects, but double-blind randomized controlled trials have not found a significant improvement in adverse effects with vitamin E supplementation [106, 107]. Occasionally, patients may develop a dermatitis that is most commonly seen on the forearms and dorsum of the hands in the winter months. This manifestation is more typical in patients who have a baseline history of atopic dermatitis and can be managed with topical steroids [108]. Diffuse hair loss and thinning consistent with telogen effluvium has also been reported [109]. Exacerbation of acne is a well-recognized side effect that typically occurs in the first few weeks of initiating therapy. If acne is severe, initiating isotretinoin therapy with an oral corticosteroid or starting at a lower dose can decrease the severity of this flare in the first 4 weeks of therapy. Treatment of an unanticipated exacerbation can involve the addition of oral steroids or dapsone [110–112]. Decreased night vision, fatigue, lethargy, and headaches can occasionally occur with isotretinoin therapy. If headaches become persistent, are not relieved by over-thecounter analgesics, and are associated with visual

Adverse Effects of Acne Medications

disturbances, papilledema, or nausea and vomiting, the patient should be evaluated for benign intracranial hypertension (pseudotumor cerebri) [61, 105, 113, 114]. Symptoms tend to occur early in the course of treatment, and concomitant use of minocycline or tetracycline can increase the risk of developing this potential side effect [61, 115]. If suspected, isotretinoin should be discontinued immediately and referrals should be made for imaging and ophthalmologic examination. While a clear association has not been established, several conflicting reports have been published regarding a potential dose-dependent increased risk of inflammatory bowel disease in patients using isotretinoin, especially if tetracycline is used concomitantly [67, 116, 117]. Signs and symptoms of inflammatory bowel disease, including abdominal pain, diarrhea, and bloody stools, require cessation of isotretinoin and referral to a gastroenterologist for further evaluation. Myalgias occur in up to 15 % of patients and can be associated with elevated creatinine phosphokinase (CPK) levels, especially in athletes [118]. CPK levels tend to normalize within 2 weeks if the patient stops strenuous activity. If symptoms persist or CPK levels remain high despite modifying activity levels, isotretinoin should be discontinued [119]. Isotretinoin can also be associated with a mild to moderate elevation in liver enzymes and serum lipid indices, especially triglycerides [105, 113]. Baseline laboratory values for cholesterol, fasting serum triglyceride, and liver function enzymes should be performed with follow-up testing 4–8 weeks later. Testing can be stopped if laboratory values are normal; however, any abnormality necessitates monthly testing [95]. Dose reduction and/or the addition of anti-hyperlipidemic agents is warranted for serum triglyceride levels [500 mg/dL [120]. First-line agents include niacin and fibrates. Furthermore, a dose reduction should be considered if LFTs are two- to threefold higher than normal values. If laboratory values fail to improve despite these interventions, isotretinoin should be discontinued. Serum LFTs and lipid levels should return to baseline levels within a few months [121, 122]. Lifestyle changes may be satisfactory for lesser elevations in both triglycerides and LFTs. Repeat laboratory testing is always indicated for outlying results, as non-fasting state, viral illness, or recent exercise can also affect these values. Depression, suicidal ideation, and suicide have been reported in patients taking oral isotretinoin; however, evidence supporting a causal relationship has been lacking and may be subject to confounding given the known association between depression and acne [123–127]. Nevertheless, given the known psychiatric comorbidity in dermatologic patients and the possibility for an association, it is important for providers to be aware of risk factors for suicide and to monitor for depression, depressive symptoms, or suicidal ideation so atrisk patients can receive appropriate care [123].

Isotretinoin is a well-known teratogen, with an increased risk of spontaneous abortion and major malformations occurring in 30 % of infants exposed during the first trimester [128]. The characteristic pattern of malformation involves craniofacial, cardiac, thymic, and central nervous system defects [129]. Because isotretinoin is a known teratogen, the US FDA began strictly regulating its distribution in 2006 through the iPLEDGE program in an effort to prevent the use of isotretinoin during pregnancy. iPLEDGE requires abstinence or two forms of contraception, in addition to baseline and monthly pregnancy tests, for females of child-bearing potential. Patients must have two negative pregnancy tests and pass a comprehension test prior to starting therapy. Monthly pregnancy tests and comprehension questions continue for females throughout therapy until 1 month after discontinuing treatment. Both males and females without child-bearing potential must also be enrolled in iPLEDGE and participate in monthly office visits. Unfortunately, this program has only had a minimal impact on increasing contraceptive use and preventing conception in patients taking isotretinoin [95, 130].

3 Conclusion Current acne therapies target one or more of the known mechanisms involved in the pathogenesis of the disease. Adverse effects exist for both topical and systemic therapies. The best treatment options are those that reduce acne severity while minimizing adverse effects (see Table 1). Topical agents primarily cause local irritation that can be minimized by decreasing the frequency or dose of the medication. Systemic agents can rarely cause mild, transient adverse effects. However, rare severe adverse reactions can occur that pose a significant threat to the health of the patient. Understanding how to recognize and manage the adverse effects of common acne therapies is imperative to providing the safest and most appropriate treatment to each patient. Acknowledgments No sources of funding were used to prepare this review. None of the authors have conflicts of interest that are directly related to the content of this review.

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Adverse effects of acne medications: recognition and management.

Acne vulgaris is a very common chronic inflammatory disease of the skin. The clinical features of acne range from non-inflammatory comedones to inflam...
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