FormalPara Key Points

Isotretinoin monitoring recommendations for otherwise healthy patients include the baseline lipid profile, and liver profile (including alanine aminotransferase and aspartate aminotransferase) at baseline and around month 2, or when peak daily dose is achieved. However, γ-glutamyltransferase may be more indicative of liver injury. Creatine kinase may be monitored in physically active patients.

High, low, and low intermittent dosing regimens have been reported to be well tolerated and with varying degrees of efficacy. The standard dosing regimen (achieving a cumulative dose of 120–150 mg/kg) is associated with some recurrences but there are limitations of previous studies. The current recommendation based on consensus is to treat until the acne is clear, and continue for 1 more month. Patients with more severe disease may require higher cumulative doses.

Patient counseling, use of patient-independent contraception, and limiting the ‘use’ of abstinence to previously sexually inactive women only may decrease fetal exposure to isotretinoin.

1 Introduction

Acne vulgaris is one of the most common diseases encountered by dermatologists, affecting approximately 80% of the population at some point during their lives [1]. Oral isotretinoin has been available since 1982 and has resulted in significant improvement in the lives of numerous acne patients. Despite its unparalleled efficacy, isotretinoin continues to have controversies surrounding it, most of which are based on scant data, opinion, or anecdote; however, the potential array of adverse effects and potential risk of birth defects must be taken into consideration. Recent large-scale reviews have helped shed light on pregnancy risk and prevention, mental health disorders, and inflammatory bowel disease (IBD). The controversies surrounding isotretinoin have limited and restricted its use due to unplanned pregnancies and misinformation leading to unwarranted fears among parents, guardians, and patients who could benefit from the medication. Isotretinoin has been life-changing for numerous patients and is currently the only treatment available to have a long-term potentially curative effect on acne. Acne can produce significant scarring, both physical and psychological, but early and effective acne treatment can prevent these problems.

Recent advances and studies are helping to clarify ideal dosing regimens and ideal cumulative threshold dosing. Additionally, recent reviews and recommendations help support more standardized laboratory evaluations.

The aim of this article was to review what is new in dosing and adherence when using isotretinoin to treat acne vulgaris. The article will discuss safety, potential adverse effects and how to manage them, and laboratory monitoring to help practitioners optimize their use of oral isotretinoin in treating patients with acne.

2 Methods

The information provided herein is a summary of recently published studies and guidelines gathered by a review of the current literature regarding isotretinoin and acne. When the author’s clinical experience is considered, it is noted.

3 Indications

Oral isotretinoin is indicated for patients with severe and/or treatment-resistant acne vulgaris. It is the most effective acne treatment currently available and the first-line treatment for patients with severe cystic, nodular, or other actively scaring acne [2]; however, all acne lesions, not only cysts and nodules, have the potential to result in permanent scars. Thus, when first-line treatments are ineffective for patients with moderate acne, isotretinoin may be considered. The recommendations from the American Academy of Dermatology guidelines, as well as other organizations around the world, is to limit the use of oral antibiotics to minimize and avoid the development of antibiotic-resistant bacteria [3]. Systemic antibiotics can be used for the acute management of acne, but then discontinued after 3–4 months whenever possible, with the goal of maintaining improvement with topical therapy such as a topical retinoid and/or topical antimicrobial agent. When unable to sustain skin clearance of acne, isotretinoin may be considered. Early and aggressive acne treatment can prevent permanent scarring of the skin. Oral isotretinoin is the most effective treatment of acne vulgaris, and the best option to potentially have long-term sustained clearance.

4 Potential Adverse Effects and Their Management

With the exception of its teratogenic effects, the adverse effects of isotretinoin are generally mucocutaneous, dose-dependent, and reversible with discontinuation of the medication [4, 5].

4.1 Mucocutaneous Adverse Effects

The most common adverse effects resemble symptoms of hypervitaminosis A, including dryness of lips, skin, and eyes. It is helpful to emphasize to patients the importance of gentle skin care, including the avoidance of other topical acne treatments that may be irritating while taking isotretinoin. A non-soap, gentle cleanser, and generous gentle emollient application can help prevent xerosis and skin irritation while taking isotretinoin.

Dryness of lips occurs in nearly all patients (90–100%) [6]; frequent and generous applications of petroleum jelly or a similar emollient can help minimize dryness. When severe, hydrocortisone 1% balm is available over-the-counter.

Dryness of nasal and oral mucosa occurs in 30–50% of patients. Moisturizing with petroleum jelly or saline products to the nares is generally effective.

Dry eyes and blepharoconjunctivitis occurs in approximately 14% of patients and can typically be controlled with ocular lubricants [7]. These adverse effects are common but are dose-dependent, manageable, and transient, improving and/or resolving with dose decreases and/or cessation of therapy [4, 5, 8].

4.2 Systemic Adverse Effects

Headaches are commonly reported in patients taking isotretinoin but at rates similar to the general population and not extreme in intensity or duration. However, while rare, headaches also occur in more serious conditions, including pseudotumor cerebri, and may need to be evaluated if persistent, severe, and/or associated with vision changes or vomiting [5].

Joint and muscle aches are reported in approximately 15% of patients and can typically be monitored and treated with a non-steroidal anti-inflammatory drug or aspirin if needed [5, 8].

4.3 Depression

The concern and controversy over the potential association with depression and suicide is based on uncommonly reported cases [9, 10]. Additionally, acne itself causes depression, anxiety, and other psychological issues [11,12,13]. Multiple studies have found no causative effect between isotretinoin and depression; however, these studies are epidemiologic and cannot exclude an idiosyncratic adverse reaction in an individual [14,15,16,17,18,19]. Several studies have shown improvement in anxiety and depression following isotretinoin treatment for acne [20,21,22].

Nonetheless, reports of depression and suicide while taking isotretinoin do exist [9, 23]. The patient’s overall health and well-being is most important and there is a high baseline rate of anxiety, depression, suicide, and suicidal ideation in young adults (the population most commonly affected by acne requiring isotretinoin treatment).

A meta-analysis of 31 controlled studies found no evidence of increased depression or suicide rates during isotretinoin treatment [24]. Depression scores improved with acne treatment; however, with possible idiosyncratic individual reactions to isotretinoin and the overall high risk of depression and suicide in adolescents and young adults, it is important to screen patients for depression and mood issues before and during the course of isotretinoin. If patients have a history of or active depression, they can often be co-managed with their mental health provider. If mood issues arise while taking isotretinoin, the medication can be stopped while mental health issues are addressed [25]. Open communication between the isotretinoin prescriber, the patient and family, and the mental health care provider is key.

4.4 Pregnancy

Isotretinoin is a teratogen that was initially documented following its 1982 release, with several reports of congenital malformations [26]. Three different risk management programs have been implemented since that time, with each program being more restrictive but no more effective in preventing the approximately 150 pregnancy exposures that occur yearly [27, 28]. The iPledge program, currently in place in the US, was established in 2006 and requires women of childbearing potential to abstain or to commit to using two forms of contraception for the duration of the course of therapy and for at least 30 days after completion of the isotretinoin course. Patients must have two negative pregnancy tests 1 month apart before starting isotretinoin, and monthly thereafter. Approximately one-third of women admitted to non-compliance with contraception practices [28]. Increased use of patient-independent contraception and limiting the ‘use’ of abstinence to previously sexually inactive women only may decrease fetal exposure to isotretinoin [28]. Contraceptive education is required, especially patients’ understanding of the relative effectiveness of various forms of birth control (i.e. that no single form of birth control is 100% effective), which proves the need for two forms of contraception [29].

4.5 Inflammatory Bowel Disease

The association between IBD (including both Crohn’s Disease and ulcerative colitis) continues to be proven to be controversial and with little evidence. While some studies showed a possible association [30, 31], more recent larger studies have shown no association between isotretinoin and IBD [32,33,34,35].

5 Laboratory Monitoring and Interpretation

In the past, laboratory monitoring for patients taking isotretinoin varied widely among prescribers, at times being obtained monthly; however, a recent series has helped to standardize monitoring. For healthy patients, it is recommended to perform liver function tests (typically alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) and lipid profile (ideally fasting) at baseline and at month two (or when peak dosing is achieved) [36]. Further testing may be considered if fasting values are significantly abnormal or their medical or family history indicates a higher risk [37].

The most common laboratory abnormality seen in patients taking isotretinoin is elevation of triglycerides, which normalizes to patient’s own baseline following cessation or completion of the isotretinoin treatment course [38, 39]. Elevations in triglyceride levels during short courses of isotretinoin typical for the treatment of acne are a marker of atherosclerosis risk, not a cause of it [40,41,42,43]. The importance of noting triglyceride elevation during the treatment course is to note the potential increased atherosclerosis risk later in life; prolonged and continuous use of isotretinoin in patients with underlying lipid disorders is not recommended [44]. The short-term concern and reason triglycerides are monitored while taking isotretinoin is concern for the development of hypertriglyceride-induced pancreatitis, which is extremely rare, with only four reports in nearly 40 years [40].

When triglycerides are elevated, it can be helpful to repeat the test and be certain the patient was fasting. For moderate elevations (300–500 mg/dL) of triglycerides, recommendations include weight reduction, increased physical activity, and a low-fat, low-carbohydrate, low-alcohol diet. Recent reports found that omega-3 fatty acid supplements may be a useful adjunct to manage triglyceride levels in patients taking isotretinoin, especially those with elevated triglyceride levels at baseline [45,46,47,48].

When triglyceride levels are over 500 mg/dL, the isotretinoin dose can be decreased, in addition to the lifestyle and diet changes previously mentioned. If the triglyceride levels remain elevated, treatment with a lipid-lowering agent may be required (such as a fibric acid derivative, niacin, or statin). Triglyceride elevations > 800 to 1000 mg/dL can cause pancreatitis and isotretinoin may need to be stopped until lipids are better managed. Pancreatitis rarely develops while taking isotretinoin; it occurs idiosyncratically more commonly than due to hypertriglyceridemia. While it is a rare complication, patients should be aware of the symptoms of pancreatitis [40]. Lipid elevations are reversible upon cessation of isotretinoin; however, it has been shown that these patients often have lipid issues later in life (independent of isotretinoin) [42].

Liver function tests traditionally often refer to ALT and AST when monitoring isotretinoin patients; however, these markers are also present in muscle tissue and red blood cells and correlate more with creatine kinase (CK) levels. This suggests elevated AST and ALT may correlate more with muscle than liver tissue [49]. γ-Glutamyltransferase (GGT) may be more specific for liver injury during isotretinoin therapy.

One may consider checking serum CK levels, especially in physically active patients. Some experts recommend checking baseline CK levels in all patients, and regular monitoring in those with baseline abnormalities and/or athletes engaging in strenuous physical activity [49, 50]. There is no current consensus on this but at least one documented death from rhabdomyolysis has been reported (CK levels over five times the normal value) [51]. Patients who have CK levels approaching or exceeding five times the reference value may discontinue or reduce strenuous physical activity or isotretinoin dosage until the CK level approaches their individual baseline pre-isotretinoin level [50] (see Table 1 for a summary of laboratory monitoring recommendations).

Table 1 Management of laboratory abnormalities
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6 Dosing

Isotretinoin is often initiated at a dose of approximately 0.5 mg/kg/day when treating severe acne, to minimize severe flaring at the start of treatment. The dose is then increased toward 1 mg/kg/day, as tolerated by the patient, as adverse effects (especially cheilitis and xerosis) often increase with higher doses [8] (see Fig. 1 for an isotretinoin prescribing checklist). Patients with very severe acne at baseline may require starting at an even lower dose of isotretinoin with or without concomitant oral corticosteroids to prevent a severe flare and increased risk of scarring, also known as pseudo acne fulminans [3]. One recommended protocol is to start prednisone 0.5–1.0 mg/kg/day for 4–6 weeks, then gradually decrease the dose. Oral isotretinoin can be continued at 0.5 mg/kg/day and increased gradually, while the prednisone is tapered [52, 53].

Fig. 1
figure 1

Isotretinoin checklist. Guidelines for female patients of child-bearing potential are shown in italics. 1Consider in physically active patients, at baseline. May monitor regularly in those with baseline abnormalities and/or athletes engaging in strenuous physical activity. 2GGT: shown to be more indicative of liver injury versus aspartate aminotransferase and alanine aminotransferase [49]. LFTs liver function tests, GGT γ-glutamyltransferase, CK creatine kinase, bid twice daily

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After the introduction of isotretinoin, a target dose range of 120–150 mg/kg over a 4- to 6-month time period was recommended to improve remission rates and decrease recurrences [54, 55]; however, a systematic literature review [56] found the cumulative dose target range was based on studies that were not designed to evaluate the role of cumulative dose on relapse rates [57]. Another retrospective chart review of over 1400 patients treated with isotretinoin found 22% required a second course of therapy (follow-up time ranging from 12 months to 5 years), and neither the daily nor the cumulative dose had an effect on the relapse rate as long as treatment was continued for at least 2 months after the complete resolution of acne lesions [57]. The 2018 consensus statement from the Global Alliance to Improve Outcomes in Acne agreed and concluded that a good target for isotretinoin dosing recommends treating until the acne is completely clear and continue for 1 more month [25]. Based on the author’s anecdotal evidence, especially in seeing different prescribing habits and approaches, the two targets (120–150 mg/kg vs. treating until clear and then continuing for an additional month) often end up resulting in the same endpoint. Patients with more recalcitrant disease may require higher cumulative doses to clear their skin [58].

Several reports of alternative dosing regimens have been described. High cumulative doses of isotretinoin (> 220 mg/kg compared with < 220 mg/kg) may decrease relapse rates and the need for repeat courses of treatment [59]. Higher cumulative dosing appears to be well tolerated—only rash was more common in the higher-treatment-dose group.

Low-dose intermittent and fixed low-dose regimens of isotretinoin have been used with varying degrees of success for acne, mostly mild to moderate acne. The low-dose intermittent regimen has been proven to be well tolerated [60] and effective for treating acne and consists of 0.5 mg/kg/day for 1 week every 4 weeks for a treatment course of 6 months [61, 62]. Fixed low-dose regimens have varying protocols; 20 mg daily and 20 mg every other day can be effective in moderate acne [63, 64]. A low-dose regimen report suggested decreased frequency and severity of mucocutaneous adverse effects, and increased patient compliance [61,62,63,64,65]. Long-term relapse rates are unknown. This option may be suited for moderate acne but is not recommended for patients of childbearing potential [66] (see Table 2 for a summary and comparison of various proposed dosing regimens).

Table 2 Isotretinoin dosing regimen
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7 Surgical and Other Procedures

There has been concern in the past regarding isotretinoin potentially disrupting the healing process after injury or procedure; however, an observational study found that isotretinoin was not associated with the development of hypertrophic scars or keloids [67]. There is no issue with wisdom tooth extraction during a course of isotretinoin [68]. Systematic reviews have also recently found no evidence to delay cutaneous surgery or many cosmetic procedures during or immediately after completing a course of isotretinoin [69, 70]; however, it is recommended to avoid mechanical dermabrasion and fully ablative laser while taking isotretinoin [69].

8 Post-Treatment Prophylaxis

Since approximately 20% of patients have relapse of acne necessitating a second course of isotretinoin [71,72,73,74], prescribers may consider post-treatment prophylaxis with a topical retinoid, which helps maintain post-treatment clearance [75]. Given how sensitive patients’ skin is during and immediately following completion of an isotretinoin course, patients may need to wait 1–2 months before gradually starting a topical retinoid regimen for maintenance.

9 Conclusions

Isotretinoin is the most effective treatment currently available for acne. Patients who are good candidates for the treatment typically do very well and are extremely satisfied. While there are potential adverse effects, with close monitoring and good patient counseling these can be monitored for and can typically be easily managed.