Effectiveness and safety of different dosing regimens of isotretinoin for acne vulgaris: a systematic review

Abstract

This systematic review aimed to examine the effectiveness and safety of different isotretinoin dosing regimens for treating acne vulgaris. Isotretinoin is known as a potent treatment for moderate to severe acne, but its use is associated with dose-dependent side effects. This review aims to evaluate the comparative effectiveness of various dosing strategies, including high-dose, low-dose, and intermittent regimens. A comprehensive search of electronic databases was conducted, and 15 randomized controlled trials were included in the final analysis. The findings indicate that low-dose and intermittent dosing regimens offer comparable efficacy to high-dose regimens while minimizing adverse effects such as mucocutaneous reactions, including cheilitis and xerosis. The results highlight the potential for personalized isotretinoin therapy, which can reduce the severity of side effects while maintaining clinical effectiveness. Further research is needed to assess long-term outcomes, including relapse rates and the safety profile of these dosing regimens over extended periods. Clinicians should consider individual patient characteristics when selecting isotretinoin dosing strategies to balance therapeutic efficacy and tolerability.

Introduction

Acne vulgaris is a prevalent inflammatory condition of the skin which affects nearly 80% of adolescents and young adults. The Global Burden of Disease Study 2010 identified acne vulgaris as the eighth most prevalent skin condition, with a worldwide prevalence estimated at 9.38% across all age groups [1]. Acne prevalence varies by country and age group, with studies showing that between 35% and nearly 100% of adolescents experience acne at some stage in their lives [2]. Acne lesions are classified into two types: non-inflammatory (which include open comedones, known as blackheads, and closed comedones, known as whiteheads) and inflammatory (such as papules, pustules, nodules, and cysts). These lesions can result in skin scarring and pigmentation, often requiring long-term and consistent treatment [3]. Acne lesions commonly appear on the face, neck, upper back, and chest. Various types of acne exist, including neonatal and infantile acne, occupational acne, acne conglobata, acne fulminans, acne mechanica, excoriated acne, chloracne, and drug-induced acne (triggered by substances like anabolic steroids, corticosteroids, isoniazid, lithium, and phenytoin). While these types share clinical and histological similarities with acne vulgaris, they can be differentiated by factors such as the clinical context, severity, and associated symptoms [4].

While most cases can be managed with topical and oral therapies, severe or treatment-resistant acne often necessitates the use of isotretinoin, a potent retinoid that addresses multiple pathogenic factors, including sebum production, follicular hyperkeratinization, Cutibacterium acnes proliferation, and inflammation [5]. However, despite its efficacy, isotretinoin has well-documented dose-dependent side effects, such as mucocutaneous dryness, dyslipidaemia, and hepatotoxicity, prompting the exploration of different dosing regimens [6].

Isotretinoin, a potent retinoid, is widely regarded as the most effective systemic treatment for moderate to severe acne vulgaris. The drug’s mechanism of action targets multiple pathogenic pathways of acne, including sebaceous gland activity, follicular keratinization, and inflammation. However, isotretinoin is associated with significant dose-dependent side effects, which necessitate the exploration of different dosing regimens to optimize its safety and efficacy. Various studies have compared the efficacy and safety of different isotretinoin dosing strategies, including high-dose, low-dose, and intermittent regimens. For instance, high cumulative doses (> 220 mg/kg) have been shown to reduce relapse rates but at the expense of more severe side effects, such as retinoid dermatitis and cheilitis [7]. Conversely, low-dose regimens (e.g., 20 mg/day) have demonstrated comparable efficacy to standard dosing but with significantly fewer adverse effects, particularly mucocutaneous issues [6]. Moreover, intermittent regimens have been explored as a means to balance efficacy and safety, with promising outcomes in reducing side effects while maintaining clinical effectiveness [8].

This systematic review aims to evaluate the effectiveness and safety of various isotretinoin dosing regimens for acne vulgaris, synthesizing findings from randomized controlled trials and observational studies. By comparing daily, alternate-day, and low-dose strategies/regimens, this review seeks to provide a comprehensive understanding of how different dosing schedules influence both therapeutic outcomes and the incidence of adverse effects in patients with acne vulgaris.

Methods

Databases and search strategy

A comprehensive literature search was conducted across four electronic databases: PubMed, Embase, Cochrane Library, and Web of Science. The search date was set at 25 September 2024. To capture relevant studies on isotretinoin dosing regimens for the treatment of acne vulgaris, the following keywords were used in combination with appropriate Boolean operators: “Isotretinoin”, “Low dose”, “High dose”, “Conventional dose” and “Intermittent dose.” The search strategy was adapted to each database’s specific search fields and operators. Only peer-reviewed articles published in English were included.

Inclusion and exclusion criteria

Population: Studies were included if they involved patients diagnosed with acne vulgaris, ranging from mild to severe forms. Eligible studies involved patients aged 12 years and older.

Intervention: Studies were included if they investigated the effects of oral isotretinoin at any dosing regimen. This encompassed low-dose, standard-dose, high-dose, and intermittent dosing protocols, as well as cumulative dosing strategies. The analysis also included studies comparing isotretinoin regimens with placebo, other oral acne treatments, or adjunctive therapies, provided that isotretinoin dosing was clearly defined.

Comparators: Comparative studies between different isotretinoin dosing regimens or comparisons with other acne treatments, such as antibiotics or hormonal therapy, were included, as long as dosing schedules were specified.

Outcomes: The review included studies that reported on at least one of the following primary outcomes:

1. Efficacy measures: These include acne lesion count reduction, acne clearance rates, and changes in acne severity scores, such as Global Acne Grading System (GAGS) or Investigator’s Global Assessment (IGA) scores.

2. Safety outcomes: Studies that evaluated the occurrence of adverse effects, including common side effects such as cheilitis, xerosis, liver enzyme elevations, and lipid abnormalities, were considered. Psychiatric effects and treatment adherence data were also included if reported.

Two reviewers independently screened the titles and abstracts of the articles retrieved from the database searches. Studies that met the inclusion criteria based on the population, intervention, and outcomes were selected for full-text review. Discrepancies were resolved through discussion or by consulting a third reviewer.

Data extraction

A standardized data extraction form was used to collect key information from each study. The extracted data included:

• Study design (e.g., randomized controlled trials, cohort studies).

• Study population characteristics (age, gender, severity of acne).

• Description of the intervention (dosing regimen of isotretinoin, duration of treatment).

• Comparative interventions, if applicable.

• Efficacy outcomes (e.g., acne lesion count reduction, acne clearance rates).

• Safety outcomes (e.g., incidence of side effects such as cheilitis, liver enzyme elevations, psychiatric events).

• Duration of follow-up.

• Study funding sources and potential conflicts of interest.

Quality assessment

The methodological quality of the included studies was assessed using the Cochrane Risk of Bias tool for randomized controlled trials and the Newcastle-Ottawa Scale for observational studies. This included evaluation of selection bias, performance bias, detection bias, and reporting bias. Studies with high methodological rigour were prioritized for data synthesis, while those with a significant risk of bias were noted.

Results

Study selection

A comprehensive search across four major databases yielded 1,065 records related to isotretinoin dosing regimens for acne vulgaris. Following the removal of 257 duplicates, a total of 808 unique records were identified for screening. These records were initially evaluated by title and abstract, which led to the exclusion of 617 studies. The remaining 191 studies were subjected to full-text review, during which 176 studies were excluded due to reasons such as lack of relevant comparisons, insufficient reporting of key outcomes, or an inappropriate study design. Ultimately, 15 randomized controlled trials (RCTs) (Table 1) met the inclusion criteria and were included in the final analysis. These studies, which were conducted in countries such as India, Pakistan, Libya, Turkey, Syria, South Korea, Nepal, and Iran, had sample sizes ranging from 55 to 254 participants and treatment durations from 3 to 6 months.

Table 1.

Characteristics of studies included in the systematic review

Study	Year	Country	Study design	Sample size	Duration	Dosing regimen	Comparator
Agarwal	2011	India	RCT†	120	4 months	1 mg/kg/day, 1 mg/kg/day (alternate day), 1 mg/kg/day for 1 week/weeks (pulse), 20 mg alternate day	Conventional fixed versus conventional intermittent and/or low doses
Akman	2007	Turkey	RCT	66	6 months	Group 1: Isotretinoin 0.5 mg/kg/day for the first 10 days of each month for 6 months Group 2: Isotretinoin 0.5 mg/kg/day daily for the first month, then the first 10 days of each month for 5 months Group 3: Conventional isotretinoin 0.5 mg/kg/day daily for 6 months	Conventional fixed dose versus conventional intermittent
Dawood	2020	Pakistan	RCT	254		Group A: 1 mg/kg of oral isotretinoin on alternate days Group B: 1 mg/kg of oral isotretinoin daily for 1 week out of every 4 weeks
Dhaked	2016	India	RCT	234	6 months	Group A: 20 mg of oral isotretinoin daily Group B: 20 mg of oral isotretinoin on alternate days	Low fixed dose daily versus low intermittent dose
El-Sherif	2013	Libya	RCT	55	4 months	Group 1: 20 mg of oral isotretinoin daily Group 2: 20 mg of oral isotretinoin twice daily for 7 days every month	Low fixed dose daily versus low intermittent dose
Faghihi	2017	Iran	RCT	60	6 months	Group 1: 0.25 mg/kg/day of oral isotretinoin Group 2: 0.5 mg/kg/day of oral isotretinoin	Low fixed dose versus conventional fixed dose
Kaseem	2022	Syria	RCT	107	6 months	Group A: 0.5–1 mg/kg daily for 24 weeks Group B: 0.25–0.4 mg/kg daily for 24 weeks Group C: 0.5–0.7 mg/kg daily for 1 week every 4 weeks (intermittent)	Low fixed versus conventional fixed versus conventional intermittent dose
Kothari	2021	India	RCT	90	6 months	Group A: 0.5 mg/kg/day (daily) for 24 weeks Group B: 0.5 mg/kg on alternate days for 24 weeks Group C: 20 mg daily for 24 weeks	Low fixed versus conventional fixed versus conventional intermittent dose
Lee	2011	South Korea	RCT	60	6 months	Group A: 0.5–0.7 mg/kg/day for 24 weeks. Group B: 0.25–0.4 mg/kg/day for 24 weeks Group C: 0.5–0.7 mg/kg/day for 1 week out of every 4 weeks for 6 weeks	Conventional fixed versus low dose fixed versus conventional intermittent
Niazi 2015	2015	Pakistan	RCT	60	6 month	Group A (daily dose): 20 mg/day for 6 months Group B (alternate-day dose): 20 mg on alternate days for 6 months	Low dose daily versus alternate days
Shetti	2017	India	RCT	100	4 months	Group A (continuous dosing): 20 mg oral isotretinoin once daily for 4 months Group B (intermittent dosing): 20 mg oral isotretinoin once daily for 1 week out of every 4 weeks	Low-dose fixed versus low-dose intermittent
Syed	2019	Pakistan	RCT	110	4 months	Group A (low dose): 20 mg oral isotretinoin once daily for 16 weeks. Group B (high dose): 1 mg/kg/day oral isotretinoin for 16 weeks	Low dose daily vs. conventional dose daily
Aryal	2018	Nepal	RCT	74	6 months	Group A (daily dose): 20 mg oral isotretinoin once daily for 6 months Group B (pulse dose): 20 mg oral isotretinoin thrice a week (alternate days) for 6 months	Low dose daily vs. low dose intermittent
Faysal	2022	Pakistan	RCT	100	4 months	Group A: 0.5–0.75 mg/kg oral isotretinoin once daily for 1 week every 4th week for 4 months Group B: 0.5–0.75 mg/kg oral isotretinoin once daily for 4 months	Conventional fixed versus conventional intermittent
Hafeez	2020	Pakistan	RCT	140	3 months	Group A (low dose): 20 mg/day for 12 weeks. Group B (conventional dose): 80 mg/day for 12 weeks	Low versus conventional dose

RCT – randomized controlled trial.

The 15 RCTs [6, 9–21] included in this systematic review were conducted across diverse geographical regions, including South Asia (India, Pakistan, Nepal), the Middle East (Iran, Syria, Libya), and East Asia (South Korea). This range of study locations adds to the generalizability of the findings across different populations.

The sample sizes of the studies varied significantly, ranging from 55 participants in El-Sherif et al. [16] to 254 participants in Dawood et al. [18]. Most of the studies had sample sizes between 60 and 140, providing sufficient statistical power for intra-study comparisons, although the smaller studies may have limited generalizability.

The included studies had treatment durations ranging from 3 to 6 months, which aligns with typical isotretinoin treatment regimens for acne vulgaris. Longer-term follow-up post-treatment was observed in a few studies, such as Shetti et al. [8] and Aryal et al. [20], which allowed for assessments of relapse rates and long-term adverse effects. However, studies with shorter follow-up periods may have missed the full spectrum of side effects, particularly those that emerge later.

A key characteristic of the studies was the diversity of isotretinoin dosing regimens evaluated. Some studies compared high-dose (1 mg/kg/day) regimens with low-dose (20 mg/day) treatments, such as Syed and Ahmed [6] and Kothari et al. [11]. Other studies, like Dhaked et al. [17] and El-Sherif [16], focused on continuous versus intermittent dosing regimens, exploring the balance between efficacy and safety. Niazi and Shehzad [10] and Lee et al. [12] offered insights into alternate-day dosing strategies, which aimed to minimize side effects without compromising therapeutic outcomes.

Efficacy was measured in most studies through standard dermatological scales such as the Global Acne Grading System (GAGS), Investigator’s Global Assessment (IGA), or total acne lesion counts. These outcomes were used consistently across studies, allowing for some comparability. However, safety outcomes varied slightly, with most studies reporting on common adverse effects like cheilitis and xerosis, while others, such as Lee et al. [12] and Kassem et al. [19], included more detailed laboratory markers like liver enzyme elevations and lipid changes.

The studies covered a broad range of populations, with ages starting from 12 years, capturing both adolescent and adult acne cases. The geographical diversity of the included studies suggests that isotretinoin’s efficacy and safety profile are applicable across different ethnic and environmental contexts. However, the absence of studies from North America and Europe might limit the generalizability of the results to Western populations (Figure 1).

Figure 1.

PRISMA flow diagram for study selection process

Risk of bias

The risk of bias across the 15 included studies was generally low to moderate. Most studies used appropriate randomization methods and allocation concealment, minimizing selection bias. However, a few studies lacked detailed reporting on these aspects, leading to an unclear risk of bias. Blinding of participants and personnel was variable, with some studies employing single- or double-blind designs, while others were open-label, which may have introduced performance bias, particularly in the reporting of subjective outcomes like side effects. Despite this, most studies used objective outcome measures such as the Global Acne Grading System (GAGS), reducing the risk of detection bias. Attrition bias was low as most studies reported high retention rates and conducted intention-to-treat analyses. Reporting bias was minimal for efficacy outcomes, but some studies selectively reported safety outcomes, particularly laboratory findings related to lipid and liver function changes. Overall, while some risks were present, the studies were qualified for inclusion and provided reliable data on isotretinoin dosing regimens (Figure 2).

Figure 2.

Risk of bias assessment of studies

Efficacy of different dosing regimens

Conventional fixed-dose vs. low-dose and intermittent regimens

Several of the included studies compared the efficacy of conventional fixed-dose isotretinoin regimens (typically 1 mg/kg/day) with low-dose (e.g., 20 mg/day) or intermittent dosing protocols. In the study by Agarwal et al. [9], conventional high-dose isotretinoin regimens demonstrated superior early efficacy, especially during the first 8 weeks of treatment. However, by the 16-week mark, there were no significant differences in acne clearance between the high-dose group and the low-dose or intermittent dosing groups. This finding was echoed by Kothari et al. [11], where low-dose regimens showed similar acne lesion reductions as high-dose regimens, but with a significantly lower incidence of adverse effects, particularly mucocutaneous reactions. The data suggest that while high-dose isotretinoin may result in faster early improvements, the overall long-term effectiveness of low-dose or intermittent regimens is comparable.

Additionally, Akman et al. [21] compared conventional dosing (0.5 mg/kg/day) with an intermittent regimen, finding that both dosing strategies resulted in similar acne lesion reduction. However, the intermittent group experienced fewer severe side effects. This suggests that intermittent dosing could be a viable alternative for patients who require effective treatment but are concerned about the side effects associated with continuous high-dose isotretinoin.

Low fixed-dose vs. low intermittent dose

Studies such as Dhaked et al. [17] and El-Sherif et al. [16] explored the effectiveness of continuous low-dose regimens (e.g., 20 mg/day) versus intermittent low-dose regimens (e.g., 20 mg once daily for 1 week per month). Both studies reported significant reductions in acne severity scores in both treatment groups, with El-Sherif et al. noting a faster reduction in acne lesion counts in the continuous dosing group. However, there were no significant differences in overall outcomes by the end of the treatment period. These findings suggest that while continuous low-dose regimens may offer quicker initial results, intermittent dosing can still provide effective long-term management of acne vulgaris, with the added benefit of reducing cumulative drug exposure and side effects.

Niazi and Shehzad [10] further supported the efficacy of intermittent low-dose dosing, reporting no significant difference in acne severity reduction between daily and alternate-day dosing regimens. The study concluded that alternate-day dosing may be a preferred option for patients with mild to moderate acne who are looking to minimize the risk of side effects without sacrificing treatment efficacy.

High dose vs. low dose

Multiple studies examined the direct comparison between high-dose (e.g., 1 mg/kg/day) and low-dose regimens (e.g., 20 mg/day). For instance, in Syed and Ahmed study [6], the high-dose group achieved a slightly faster rate of acne clearance; however, both dosing strategies were effective in achieving significant reductions in acne severity. Importantly, the high-dose regimen was associated with a higher incidence of adverse effects, particularly cheilitis, xerosis, and other mucocutaneous side effects. Similarly, Faysal et al. [15] found that while high-dose isotretinoin was effective in reducing acne severity, it also led to more frequent and severe side effects compared to the low-dose group.

Safety outcomes

Adverse effects: Across all included studies, common side effects reported included cheilitis, dry skin, and mild elevations in liver enzymes and lipid profiles. High-dose isotretinoin regimens were consistently linked with a higher frequency and severity of side effects. In Akman et al. [21], for example, patients on high-dose isotretinoin experienced cheilitis in up to 98% of cases, compared to significantly lower rates in patients on low-dose or intermittent regimens. Similarly, Syed and Ahmed [6] reported that low-dose regimens were associated with significantly fewer adverse effects, while still providing comparable efficacy in acne lesion reduction.

Lipid and liver function: Several studies, such as Lee et al. [12] and Kassem et al. [19], reported mild elevations in serum lipids (cholesterol and triglycerides) and liver enzymes (ALT and AST) during isotretinoin treatment. These side effects were more pronounced in patients receiving high-dose regimens but generally did not reach clinically significant levels that would necessitate discontinuation of therapy. Niazi and Shehzad [10] observed that even in low-dose groups, mild changes in lipid profiles were recorded, though these were less frequent and less severe compared to high-dose treatments.

Comparison of continuous vs. intermittent regimens

Studies comparing continuous low-dose regimens with intermittent regimens, such as Shetti et al. [8] and Aryal et al. [20], found that while intermittent regimens reduced cumulative drug exposure and the frequency of side effects, they did not compromise treatment efficacy. For example, Shetti et al. [8] reported that both continuous and intermittent low-dose isotretinoin regimens resulted in significant reductions in acne lesion counts, with no statistically significant differences in overall outcomes. Intermittent regimens, however, had the added advantage of reducing the incidence of common side effects such as dry skin and cheilitis.

Discussion

This systematic review highlights important findings regarding the efficacy and safety of different dosing regimens of isotretinoin for treating acne vulgaris. The results from various randomized controlled trials demonstrate that both low-dose and intermittent isotretinoin regimens offer a favourable balance between therapeutic effectiveness and a reduced incidence of side effects compared to conventional high-dose regimens.

The efficacy of low-dose and intermittent isotretinoin regimens was found to be comparable to that of the conventional high-dose regimen (1 mg/kg/day) for acne clearance. For instance, a study by Shetti et al. [8] found that both continuous low-dose (20 mg/day) and intermittent low-dose regimens achieved significant reductions in acne severity, as measured by the Global Acne Grading System (GAGS). While continuous low-dose treatment provided slightly faster results, the overall efficacy of the two approaches was similar after 16 weeks of treatment [8].

Similarly, Syed and Ahmed [6] found no significant differences in the efficacy of low-dose isotretinoin (20 mg/day) compared to high-dose treatment in patients with severe acne. This suggests that low-dose isotretinoin is effective in achieving complete remission of acne lesions, comparable to the conventional dose regimen, which often carries a higher risk of adverse effects.

Moreover, studies comparing intermittent dosing regimens to continuous regimens have yielded promising results. Al-Dhubaibi for example, reported that intermittent isotretinoin (administered daily for 1 week out of every 4 weeks) provided a viable alternative for reducing drug exposure while maintaining effective acne control in patients with mild to moderate acne [22]. This indicates that, for patients who prefer avoiding daily treatment or are prone to side effects, intermittent dosing may offer a safer yet effective alternative.

One of the most notable advantages of low-dose and intermittent isotretinoin regimens is their reduced risk of side effects, particularly mucocutaneous reactions such as cheilitis, xerosis, and dry eyes. In the study by Syed and Ahmed [6], mucocutaneous side effects were significantly more common in patients receiving high-dose isotretinoin (100%) compared to those on low-dose regimens (80%). This finding is echoed in other studies, such as Kothari et al. which demonstrated that side effects were more frequent and severe with conventional dosing regimens compared to low-dose and intermittent regimens [11].

Importantly, laboratory side effects, such as elevations in serum lipids and liver enzymes, were mild and less common in patients treated with lower doses. Rao et al. showed that low-dose isotretinoin (20 mg/day) resulted in only mild changes in lipid profiles, with very few cases of clinically significant elevations in serum cholesterol or triglycerides [23]. These findings suggest that low-dose regimens not only reduce the risk of mucocutaneous side effects but also minimize the potential for serious systemic side effects, making them a safer option for long-term acne management.

The findings from this review underscore the need for a more individualized approach to isotretinoin dosing. For patients with severe or treatment-resistant acne, conventional high-dose isotretinoin may offer faster results but at the expense of increased side effects. On the other hand, low-dose and intermittent regimens are highly effective for moderate to severe acne and significantly reduce the risk of adverse effects, making them an attractive option for long-term therapy.

Given that both efficacy and safety outcomes are optimized with personalized dosing regimens, clinicians should consider patient preferences, acne severity, and tolerance for side effects when selecting an isotretinoin dosing strategy.

Conclusions

Overall, the evidence strongly supports the use of low-dose and intermittent isotretinoin regimens as effective alternatives to high-dose treatments. These regimens not only achieve comparable acne clearance but also reduce the frequency and severity of adverse effects, making them a safer and more tolerable option for many patients. Future research should focus on long-term outcomes and the potential for relapse with different dosing strategies to further inform clinical guidelines for isotretinoin use.

Funding Statement

Funding No external funding.

Ethical approval

Not applicable.

Conflict of interest

The authors declare no conflict of interest.