Received: 13 March 2023 | Accepted: 29 March 2023

DOI: 10.1002/jvc2.154

SYSTEMATIC REVIEW

A systematic review of isotretinoin dosing in acne vulgaris

Aoife U. Daly1,2 | Rui Baptista Gonçalves2 | Eva Lau2 | Joanne Bowers2 |

Naayema Hussaini3 | Maria Charalambides4 | Jack Coumbe5 |
Carsten Flohr6 | Alison M. Layton2

1
School of Medicine, Dentistry and
Biomedical Sciences, Queens University Abstract
Belfast, Belfast, Northern, Ireland How does low‐dose oral isotretinoin compare with recommended and high‐
2
Dermatology Department, Harrogate dose oral isotretinoin in terms of efficacy, adverse effect profile, duration of
and District NHS Foundation Trust,
Harrogate, England remission, economic profile and rate and severity of relapse? A systematic
3
School of Medicine, Trinity Biomedical literature search of EMBASE, MEDLINE, PubMed and The Cochrane Library
Sciences Institute, Trinity College Dublin, from 1983 to July 2022 was conducted to identify randomised control trials
Dublin, Ireland
(RCTs), cohort studies and cross‐sectional studies investigating the treatment
4
Birmingham Medical School, College of
Medical and Dental Sciences, University
of acne vulgaris with oral isotretinoin. This systematic review of the literature
of Birmingham, Birmingham, England sought to explore and compare the use of different isotretinoin dosing
5
Henriette Raphael House, King's College regimens. Primary outcomes were efficacy, relapse, and safety profiles of oral
London, Guy's Campus, London, England
isotretinoin of varying doses. Secondary outcomes included adverse events and
6
St John's Institute of Dermatology, Guy's
economic considerations. The quality of studies, including risk of bias was
and St Thomas' NHS Foundation Trust,
London, England assessed using GRADE (Grading of Recommendations, Assessment, Develop-
ment and Evaluations). A total of 32 studies were included. Severe acne
Correspondence
Aoife U. Daly, School of Medicine,
responds better to conventional or high fixed daily doses of isotretinoin. In
Dentistry and Biomedical Sciences, cases of mild to moderate acne, where oral isotretinoin was prescribed,
Queens University Belfast, University Rd, clearance rates were comparable with low, conventional or high dosage
Belfast BT7 1NN, Northern Ireland.
Email: adaly27@qub.ac.uk regimens. Despite this, relapse was more frequent in those treated with a
lower dose. The severity of mucocutaneous adverse effects worsens as the dose
Funding information of isotretinoin is increased. Comparison between studies was challenging due
None to declare
to differing methods of assessment, outcome measures and duration of follow‐
up. This review highlights the need for an adequately powered RCT comparing
low, conventional and high doses of oral isotretinoin to establish optimal
dosing for treatment and prevention of relapse in acne vulgaris.

KEYWORDS
acne, acne vulgaris, isotretinoin

This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
© 2023 The Authors. JEADV Clinical Practice published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.

432 | wileyonlinelibrary.com/journal/jvc2 JEADV Clin Pract. 2023;2:432–449.


A SYSTEMATIC REVIEW OF ISOTRETINOIN DOSING IN ACNE VULGARIS
I N T R O D U C TI O N
Acne vulgaris (syn acne) is a very common chronic
inflammatory skin disease affecting an estimated 9.4% of
the world's population.1 Acne is a disease of the
pilosebaceous follicle and predominantly affects the face,
chest and back. The main aetiological factors relate to an
androgen‐mediated increase in sebum production, al-
tered keratinisation within the intrafollicular duct,
colonisation with Cutibacterium acnes (C.acnes) and
inflammatory changes. The disease manifests as sebor-
rhoea, closed and open comedones, papules, pustules
and nodules. Acne, and the scarring that can result from
it, can have a profound impact on psychosocial aspects as
well as health‐related quality of life for patients.2,3
Multiple treatment options exist, ranging from topical
treatments such as benzoyl peroxide, retinoids or
antibiotics used as monotherapy or fixed combination
products for mild, moderate and, in some cases, severe
disease, as well as oral antibiotics used in combination
with topical agents for more moderate–severe disease.4
Hormonal treatments can be considered in adult females
including the oral contraceptive pill5 and oral spirono-
lactone.6 Oral isotretinoin is recommended for severe
forms of acne including acne with evidence of and/or at
risk of permanent scarring that has failed adequate
courses of standard therapy with systemic antibiotics and
topical therapy.4,7
Oral isotretinoin (13‐cis‐retinoic acid) is a synthetic
Vitamin A analogue, which is involved in sebaceous
gland apoptosis and shrinkage via p21 protein expression
and decreased cyclin D.8,9 13‐cis‐retinoic acid has been
found to have antiandrogenic effects via oxidation
processes10 and reduces insulin‐like growth factor 1,
insulin‐like growth factor‐binding protein 3, luteinising
hormone, prolactin, adrenocorticotropic hormone and
free T3.11 Oral isotretinoin is highly lipophilic and taking
the medication with a fatty meal can enhance absorption
by 60%.12 It is associated with adverse effects including
increased serum triglycerides, deranged liver function
tests (LFTs), xerosis of the skin and mucous membranes
and teratenogenicity.13–15 Although it remains contro-
versial and no causal relationship has been firmly
established, a range of neuropsychiatric effects have
been described, and isotretinoin may induce changes in
brain functioning.16
Current UK recommendations and evidence‐based
guidelines suggest oral isotretinoin should be prescribed
at a dose of between 0.5 and 1.0 mg/kg/day with a desired
cumulative dose of between 120 and 150 mg/kg.4 This is
corroborated in the indication by the European Medi-
cines Agency and the European Evidence‐Based Guid-
ance that isotretinoin should be started at a dose of
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| 433
between 0.3 and 0.5 mg/kg.17 Although these dosage
regimens have been established as an effective treatment
for severe acne and acne unresponsive to more conven-
tional therapies, there is debate about optimum dosing
regimens. There have been reports in recent years
suggesting that lower dosing regimens are effective,
better tolerated13–15,18 and more economical.15,19,20 How-
ever, the comparable efficacy, prevalence of adverse
events and long‐term remission of lower doses compared
with higher dosing regimens is still unclear.13,14
This systematic review seeks to evaluate, through the
available literature, treatment of acne by comparing the
use of different dosing regimens of oral isotretinoin.
Primary outcomes were efficacy, relapse, and safety
profiles of oral isotretinoin of varying doses. Secondary
outcomes sought to examine side effects and adverse
events of low‐dose isotretinoin compared with standard
dosing regimens.
ME T H OD S
Systematic searches were performed on EMBASE, MED-
LINE, PubMed and The Cochrane Library, from 1983
(year in which isotretinoin was licensed for medical use
in the European Union) to July 2022 to identify English‐
language studies that presented data on differing doses of
isotretinoin and its efficacy and safety for treating acne
vulgaris. Our strategy searched for the words “isotreti-
noin” OR “roaccutane” within the title or abstract OR
“ISOTRETINOIN” in the subject heading. The previous
terms were combined with the following “acne” terms:
“acne” within the title or abstract OR exp ACNE. And
combined with the following “dosage” terms: “DRUG
DOSAGE COMPARISON” in the subject heading OR
(high ADJ3 dos* OR low ADJ3 dos* OR conventional
ADJ3 dos*) in the title or abstract.
This study was registered on PROSPERO (CRD42021
215665). Figure 1 shows the results of the reviewing
process as a PRISMA21 flowchart. Further details of the
search strategy, study selection and risk of bias assess-
ment can be found in Supporting Information:
Appendix 1.
The following data were extracted from each included
study: first author, year, study design, number of
participants and their characteristics (including age,
ethnicity, sex), dose per day (mg), duration of treatment,
number of isotretinoin courses, cumulative dose (mg),
definitions of efficacy, efficacy rate, relapse and relapse
rate, site of acne, acne grading system used, acne
severity, dietary factors, adverse side effects, including
biochemical, cheilitis, acne flare and mood disturbance,
follow‐up period, economic considerations. A summary
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434 | DALY ET AL.

F I G U R E 1 Study flow diagram. *Inclusion criteria. Studies were included where acne vulgaris was treated with oral isotretinoin of any
dose to establish: efficacy of treatment, relapse rates or safety profiles. Prospective and retrospective cohorts, cross‐sectional and case‐control
studies published in peer‐reviewed journals published in English were all included. 1982–2022. Abstract publications, conference abstracts
and letters to the editor were excluded.

of key data is displayed in Table 1. The quality of studies
was assessed using GRADE (Grading of Recommenda-
tions, Assessment, Development and Evaluations)47 and
an overall quality score given (summarised in Table 2).
RESU LTS
In this review, 32 studies were included, with a total sample
size of 5245 patients with mild to very severe acne vulgaris
(Table 1). Of these, 15 were randomised controlled trials
(RCT), 10 were prospective noncomparative studies, 2 were
prospective comparative studies, and 5 were retrospective,
noncomparative series. When assessing clinical severity of
acne 10 studies focused on mild–moderate acne, 12 on
moderate to severe and 5 on severe only. Three studies
included a wider range, from mild to severe, whereas one
focused solely on resistant acne.
The grading systems adopted were inconsistent across
the studies: 9 studies used GAGS (Global Acne Grading
System) as an assessment scale, 8 used the Leeds Revised
photometric Grading System, 2 the Pochi scale, 1 IGA
(Investigator Global Assessment) and the remaining 12
used various acne scale based on lesion counting.
 T A B L E 1 Summary of all studies included: Design, isotretinoin dosing, number of participants, groups included, key results including efficacy and relapse rates, as well as definition of
relapse and follow‐up time.
Follow up
duration
References Study type Dosing N Dose groups of isotretinoin Efficacy rate Relapse rate Relapse definition posttreatment
Agarwal et al.22 RCT Conventional versus 120 A. 1 mg/kg/day A: 96.03% 0% Emergence of 2 months
intermittent and/ B. 1 mg/kg/day alternate day B: 90.33% pretreatment
or low doses C. 1 mg/kg/day 1 week/4 weeks C: 76.85% acne score
D. 20 mg alternate days 16 weeks D: 93.89%
(treatment duration 24 weeks) (efficacy defined as
reduction in total
acne load)
Ahmad23 RCT Conventional OD 58 A. 0.5–1 mg/kg/day once A: median GAGS decrease Not assessed N/A None
versus divided daily dose from 34 to 0
dosing B. 0.5–1 mg/kg/day dived doses B: median GAGS decrease
(mean treatment duration from 31 to 0
22 weeks)
Akman et al.24 RCT Fixed versus 66 A. 0.5 mg/kg/day of isotretinoin Significantly decreased 14% (all in Emergence of 1 year
intermittent first 10 days of each month global grade in all Group A) pretreatment
A SYSTEMATIC REVIEW OF ISOTRETINOIN DOSING IN ACNE VULGARIS

conventional for 6 months groups p < 0.001 acne score

dose B. 0.5 mg/kg of isotretinoin each
day for 1st month then the
first 10 days of each month
for 5 months
C. 0.5 mg/kg/day isotretinoin
daily for 6 months
Amichai et al.19 Prospective Low dose 638 All received 20 mg/day daily for Group 1. 94.8% achieved Group 1. 3.9% Not defined 4 years
noncom- 6 months significant Group 2. 5.9%
parative Group 1. Ages 12–20 years improvement or (No statistically
Group 2. Ages 21–35 years complete remission significant
Group 2. 92.6% achieved difference
significant p = 0.35)
improvement or
complete remission
(No statistically significant
difference p = 0.36)
Bellosta et al.25 Prospective Conventional dose 60 0.5 mg/kg/day in divided doses Statistically significant 5% Not defined 1 year
noncom- divided for 12–20 weeks reduction in pustules at
parative 2 weeks and nodules at
|

4 weeks (p = 0.01)
435

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 436

TABLE 1 (Continued)
|

Follow up
duration
References Study type Dosing N Dose groups of isotretinoin Efficacy rate Relapse rate Relapse definition posttreatment
26
Blasiak et al. Prospective High 180 A: cumulative dose <220 mg/kg 97.4% reported Relapse ‐ Group A Relapse‐ treatment 1 year
observa- cumulative dose B: cumulative dose >220 mg/kg improvement 47.4%, Group with any
tional B 26.9% prescription
(Statistically medication
significant other than
p < 0.3) isotretinoin
Retrial ‐ Group A retrial‐ retreatment
0%, Group with isotretinoin
B 1.72%
Borghi et al.48 Prospective Low 150 0.2 mg/kg/day increased by 5 mg Aim of the study was to 9.35%. When Emergence of acne 2 years
noncom- cumulative dose fortnightly until maximum determine relapse rate divided into >0.5 Leeds Acne
parative dose tolerated mean cumulative groups of Grade or
dose of 80.92 mg/kg cumulative requiring
dose <40 mg/ systemic
kg, 40–79 mg/ treatment
kg, 80–119
mg/kg and
>120 mg/kg
there was no
statistically
significant
difference
Boyraz and Prospective Fixed versus 60 A: 20 mg daily 100% improvement in both Group A 0% Not defined 6 months
Mustak53 observa- intermittent B: 0.5–0.8 mg/kg/day for 1 week groups at 8 months Group B % 10%
tional low dose every month
Cyrulnik et al.27 Retrospective High dose 80 Mean daily dose 1.6 mg/kg/day 80% of patients had no 12.50% Further course of 3 years
noncom- active disease at 150 isotretinoin
parative days of treatment required
Del Rosso Prospective Conventional dose 201 0.5 mg/kg/day for 4 weeks then aim of the study was to Retreatment with The point at which 2 years
et al.50 noncom- lidose‐ 1 mg/kg/day for 16 weeks of determine relapse rates isotretinoin patient required
parative isotretinoin lidose‐isotretinoin 4.2% retreat- any form of acne
ment with any treatment, topical
acne therapy or oral, OTC
15.1% (topical,
oral, OTC)
DALY
ET AL.

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 TABLE 1 (Continued)

Follow up
duration
References Study type Dosing N Dose groups of isotretinoin Efficacy rate Relapse rate Relapse definition posttreatment
28
Dhaked et al. RCT Low dose daily 240 A: 20 mg daily Decrease in acne load from 0% Emergence of near 3 months
versus B: 20 mg alternate days baseline Group A: pretreatment
alternate days 98.99%, Group B: severity of acne
97.69% (p < 0.01) in treated
patients within
12 weeks of
follow up
El‐Sherif et al.29 RCT Low dose versus low 55 Group 1 20 mg OD >50% reduction of lesions in 21.9% in Group 1, Not defined 6 months
intermittent dose Group 2 20 mg alternate days both groups 39.1% in Group
2. (Not
statistically
significant)

Faghihi et al.30 RCT Low versus 60 A: 0.25 mg/kg/day Both groups showed Not assessed Not defined 6 months
conventional B: 0.5 mg/kg/day significant difference in
dose improvement of severity
A SYSTEMATIC REVIEW OF ISOTRETINOIN DOSING IN ACNE VULGARIS

of acne at baseline,6 and

12 months but no
significance when
comparing both gorups
(p > 0.005)
Ghaffarpour Retrospective Conventional dosing 132 Mean daily dose 0.56 mg/kg/day Mean improvement 18.35% (9.17% Not defined Mean 4.4 years
et al.31 noncom- mean duration 6.6 months of 96.7% required
parative further course
isotretinoin)

Goulden et al.32 Prospective Intermittent 80 0.5 mg/kg/day for 1 week every 4 Both total acne grades and 39% Acne grade >0.25 at 1 year
noncom- conventional weeks for 6 months inflamed lesion count any single
parative dose significantly reduced affected area and
(p < 0.0001), acne lesion count >5
resolved in 88%
Hermes et al.33 Retrospective Low dose 94 mean daily dose 31.4 mg or Clinical improvement 4‐ Relapse rate Not defined Range of 1–6
noncom- isotretinoin 0.43 mg/kg point scale ‐ very good, overall 33% of years
parative Incremental started at 10 mg/day then good, satisfactory, not which 21.3%
increase increased by 10 mg weekly satisfactory required
until dose of 50 mg/day if 62.8% very good, 31.9% retreatment
tolerated (treated until 1 good, 5.3% satisfactory with
isotretinoin
|

month after clearance)

(Continues)
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 438

TABLE 1 (Continued)
|

Follow up
duration
References Study type Dosing N Dose groups of isotretinoin Efficacy rate Relapse rate Relapse definition posttreatment
34
Hafeez et al. RCT Low versus 140 Group A 20 mg/day A 50%, B 71.4% (p = 0.009) Not assessed N/A None
conventional Group B 80 mg/day
dose (mean treatment duration 8.3
months)
Kapadia et al.35 RCT Low versus 60 A: 20 mg/day 100% improvement in both Not assessed N/A None
conventional B: 40 mg/day groups at 6 months
(treatment duration 6 months)
Kaymak et al.51 Prospective, Intermittent dosing 60 A: mild acne (Leeds 82.9% complete resolution Not assessed N/A None
noncom- 0.75–1):0.5 mg/kg/day
parative B: moderate acne (Leeds
1.25–1.5): 0.6–0.75 mg/kg/day
for 1 week out of every 4 for 24
weeks
Lee et al.36 RCT Conventional fixed 60 A: 0.5–0.7 mg/kg daily differences in GAGS score, Group A 13%, Moderate or severe 1 year
versus low dose conventional significant between A Group B 18%, acne according to
fixed versus B: 0.25–0.4 mg/kg daily low dose and C (p < 0.001) B and Group C 56% GAGS score
conventional C: 0.5–0.7 mg/kg daily for 1 week C (<0.044), not
intermittent every 4 weeks intermittent significant between A
Treated for 6 months and B

Mandekou‐ Prospective Low versus 64 A: 0.15–0.40 mg/kg/day low, Group A 69%, Group Group A 9.37%, When acne severe 7 years
Lefaki interven- conventional mean daily dose 0.24 mg/ B 91% Group B 3.1% enough to
et al.37 tional kg/day No significant difference require any form
B: 0.5–1.0 mg/mg/day high, between groups of oral treatment
0.67 mg/kg/day (χ2 = 1.002)
Mean duration treatment Group
A 8 months Group B 5.7
months
Niazi and RCT Low dose daily 60 A: 20 mg/day Group A ‐ efficacy 90%, Not assessed N/A 1 year
Shehzad52 versus B: 20 mg alternate days mean percentage
alternate days decrease in GAGS
73.95 ± 14.04
Group B ‐ efficacy 86.7%,
mean percentage
DALY
ET AL.

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 TABLE 1 (Continued)

Follow up
duration
References Study type Dosing N Dose groups of isotretinoin Efficacy rate Relapse rate Relapse definition posttreatment
decrease in GAGS
66.57 ± 14.97
no significance‐ p > 0.05
Rademaker RCT Low dose 60 A: 5 mg daily for 32 weeks Significant differences in Not assessed N/A 2.5 months
et al.49 B: placebo for 16 weeks, then lesion count 3.6 versus
5 mg open‐label isotretinoin 7.2 after 16 weeks on
daily for 16 weeks iso compared with
placebo p < 0.0001
DLQI showed significant
difference between
groups at Week 16
(p < 0.001) but no
difference by Week 32.
Rademaker38 Retrospective Effects of daily and 1453 Total: mean dose Study group: 95.5% clear 22.40% Defined as further 1–5 years
A SYSTEMATIC REVIEW OF ISOTRETINOIN DOSING IN ACNE VULGARIS

data cumulative dose 44.2 m ± 19.8 = 0.66 mg/ after 1 course course of
analysis on relapse kg ± 0.32 isotretinoin.
control: 42.7 ± 20.1 = 0.58 mg/ Restarted at
kg ± 0.32 patient request
study: 49.2 ± 17.9 = 0.71 mg/
kg ± 0.30
Rao et al.39 Prospective Low dose 50 20 mg/day (0.3–0.4 mg/kg/day) for At end of 12 weeks, 6% of 4% Recurrence of GAGS 6 months
noncom- 3 months patients clear, 90% had grade 1 or more
parative >75% clearance and 4%
had 50%–75%
clearance
Overall efficacy 90%
Rasi et al.40 Retrospective Low dose 146 20 mg/day until a cumulative dose 96.4% complete clearance 7.90% Not defined 5 years
noncom- of 120 mg/kg given
parative

Sardana et al.41 Prospective Low‐dose 320 20 mg alternate days with topical Very good response (greater 16.39% Emergence of 6 months
noncom- alternate days clindamycin 1% gel BD for 6 than 80% improvement) pretreatment
parative months in 68.2% severity of acne

(Continues)
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 440

TABLE 1 (Continued)
|

Follow up
duration
References Study type Dosing N Dose groups of isotretinoin Efficacy rate Relapse rate Relapse definition posttreatment
42
Shetti et al. RCT Low‐dose fixed 100 A: 20 mg OD for 4 months Group A = 86%, Relapse rate higher Not defined 8 months
versus low‐dose B: 20 mg OD 1 week every 4 Group B = 70% in Group B not
intermittent weeks for 4 months (difference in GAGS significant
significant p < 0.005)
Strauss et al.43 RCT Low versus 150 A: 0.1 mg/kg/day Improvement of lesion Group A 30.0%, Not defined 12–18 month
conventional B: 0.5 mg/kg/day count with all groups Group B
higher and C: 1 mg/kg/day for up to 20 p < 0.01 at all treatment 31.4%, Group
lower‐end range weeks or when 70%–80% of and posttreatment C 6.7%
lesions had resolved periods for face and 42% of patients in
trunk Group A
require
retreatment
compared
with 10% in
Group C
Ullah et al.44 Prospective Low dose 30 Isotretinoin 20 mg/doxycycline 85.71% complete clearance Not assessed N/A None
observa- isotretinoin + 100 mg BD alternate days up to at 3 months‐ significant
tional doxycycline 6 months (p < 0.01), a further
alternate days 10.71% clear at 5 months

Van der Meeren RCT Conventional doses 58 A: 0.5 mg/kg/day ‐ 31 patients No significant correlation not recorded N/A Up to 15 months
et al.45 versus each other B: 1.0 mg/kg/day ‐ 27 patients for between two doses and
6 months clinical efficacy after 12
weeks (p > 0.05)
46
Yap Prospective Fixed low dose 150 10 mg/day fixed‐dose until All patients achieve 4% Requiring topical or 1 year
noncom- cumulative dose of complete clearance of oral treatment
parative 90–110 mg/kg acne lesions (mean
duration 24 weeks)

Abbreviations: BD, twice daily; DLQI, Dermatology Life Quality Index; GAGS, Global Acne Grading System; OD, once daily; OTC, over the counter; N/A, not applicable; RCT, randomised controlled trial.
DALY
ET AL.

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 TABLE 2 GRADE evidence profile for the 32 studies included in the systematic review.
Other considerations
Dose‐
Risk Publication Large Plausible response
References Study design of bias Inconsistency Indirectness Imprecision bias effect confounding gradient N Score
28
Dhaked et al. RCT Serious Not serious Not serious Not serious None None None None 240 Low
Shetti et al.42 RCT Serious Not serious Not serious Not serious None None None None 100 Low
23
Ahmad RCT Serious Not serious Not serious Not serious None None None None 58 Low
44
Ullah et al. Observational study Serious Not serious Serious Serious None None None None 30 Low
30
Faghihi et al. RCT Serious Not serious Not serious Not serious None None None None 40 Low
Niazi and RCT Serious Not serious Not serious Not serious None None None None 60 Low
Shehzad52
Boyraz and RCT Serious Not serious Not serious Not serious None None None None 60 Low
Mustak53
Lee et al.36 RCT Serious Not serious Not serious Not serious None None None None 40 Low
40
Rasi et al. Retrospective Serious Not serious Serious Serious None None None None 146 Low
A SYSTEMATIC REVIEW OF ISOTRETINOIN DOSING IN ACNE VULGARIS

noncomparative
Sardana et al.41 Prospective Serious Not serious Serious Not serious None None None None 320 Low
noncomparative
Blasiak et al.26 Prospective interventional Serious Not serious Not serious Not serious None None None None 180 low
Cyrulnik et al.27 Retrospective Serious Not serious Not serious Not serious None None None None 80 Low
noncomparative
Bellosta et al.25 Prospective Serious Not serious Not serious Not serious None None None None 60 Low
noncomparative
Hermes et al.33 Retrospective Serious Not serious Serious Serious None None None None 94 Low
noncomparative
Ghaffarpour Retrospective Serious Not serious Not serious Not serious None None None None 134 Low
et al.31 noncomparative study
38
Rademaker Retrospective data analysis Serious Not serious Serious Not serious None None None None 1219 Low
Mandekou Lefaki Prospective interventional Serious Not serious Not serious Not serious None None None None 64 Low
et al.37
Borghi et at.48 Prospective Serious Not serious Not serious Not Serious None None None None 150 Low
noncomparative
|

(Continues)
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 442

TABLE 2 (Continued)
|

Other considerations
Dose‐
Risk Publication Large Plausible response
References Study design of bias Inconsistency Indirectness Imprecision bias effect confounding gradient N Score
19
Amichai et al. Prospective Serious Not serious Not serious Not serious None None None None 638 Low
noncomparative
Agarwal et al.22 RCT Serious Not serious Not serious Not serious None None None None 120 Low
46
Yap Prospective Serious Not serious Not serious Not serious None None None None 150 Low
noncomparative
Rao et al.39 Prospective Serious Not serious Not serious Not serious None None None None 50 Low
noncomparative
Rademaker RCT serious Not serious Not serious Not serious None None None None 60 Low
et al.49
Strauss et al.43 RCT Serious Not serious Not serious Not serious None None None None 150 Low
Kapadia et al.35 RCT Serious Not serious Not serious Not serious None None None None 60 Low
Goulden et al.32 Prospective Serious Not serious Not serious Not serious None None None None 80 Low
noncomparative cohort
Del Rosso et al.50 Prospective Serious Not serious Not serious Not serious None None None None 201 Low
noncomparative cohort
Kaymak et al.51 RCT Serious Not serious Not serious Not serious None None None None 60 Low
24
Akman et al. RCT Serious Not serious Not serious Not serious None None None None 66 Low
29
El‐Sherif et al. RCT Serious Not serious Not serious Not serious None None None None 75 Low
34
Hafeez et al. RCT Serious Not serious Not serious Not serious None None None None 140 Low
Abbreviation: RCT, randomised controlled trial.
DALY
ET AL.

27686566, 2023, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/jvc2.154, Wiley Online Library on [23/01/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

A SYSTEMATIC REVIEW OF ISOTRETINOIN DOSING IN ACNE VULGARIS
In the large majority of the studies, low dose was
defined as 0.1–0.5 mg/kg/day or a cumulative dose
<120 mg/kg. Conventional dose was defined as either
0.5–1 mg/kg/day or cumulative dose 120–150 mg/kg and
high dose >1 mg/kg/day or cumulative dose >150 mg/kg.
This constitutes a pharmacological conundrum as
low daily dosage may still result in high cumulative
dose if the duration of treatment spans across
multiple months. As such, studies that focused on
cumulative dosing will be analysed separately.
Intermittent dosing regimens varied but included
alternate day regimens, as well as 0.5–0.8 mg/kg/day 1
week or 10 days per month, for 4 or 6 months.
Duration of treatment ranged from 16 weeks22 to
24 months.46 Follow‐up as a means of assessing relapse
ranged from 10 weeks49 to 7 years.37
The primary outcome describing success of treatment
was defined as the percentage decrease in acne severity
(n = 15) or improvement of the acne grading score (n = 7)
or described as ‘clear or almost clear’ in eight studies.
Two studies did not define any outcome measures.
Relapse was also captured in 23 studies. The
definition of relapse varied but could be summarised
into two large groups: relapse as emergence of pretreat-
ment acne scores (with variable indicative thresholds) or
relapse as the need for treatment with oral or systemic
medication.
ISOTRETINOIN DOSING
REGIMENS
Low dose
A total of eight studies focused solely on assessing the
efficacy of low‐dosing regimens alone. Amichai et al.19
found that a dose of 20 mg/day for 6 months regimen had
no statistical difference between two age groups with
respect to improvement (p = 0.36) or relapse rate
(p = 0.35). Rao et al.39 also used 20 mg/day for 3‐month
period and reported that 90% had >75% clearance.
Similarly, another40 retrospective study confirmed
96.4% clearance rate, which was achieved at a mean
time of 4.5 months, with a 7.9% relapse rate in their
5‐year follow‐up period. Ullah et al.44 found that 85.71%
had achieved complete clearance at 3 months (p < 0.01)
with a 20 mg dose on alternate days combined with
doxycycline 100 mg twice daily. Another study46 used a
lower dose of 10 mg/day alongside topical clindamycin.
All patients achieved complete clearance of acne lesions
after a mean period of 24 weeks. However, those with
more severe acne required a higher cumulative dose
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| 443
(p < 0.001) and longer duration of treatment to achieve
clearance (p < 0.001).
Golden et al.32 used low‐dose intermittent isotreti-
noin (0.5 mg/kg for 1 week in 4 for 6 months) and
achieved clearance in 88% of subjects despite reporting
higher relapse rates at 12 months in those with
predominantly truncal acne (p < 0.01), those with more
severe acne initially (p < 0.0001) and those with higher
sebum excretion rates (p < 0.001).
Low dose versus conventional regimens
One study30 compared low (0.25 mg/kg/day) versus
conventional (0.5 mg/kg/day) dose (alongside a 2‐week
regimen of azithromycin and 1 week of prednisolone),
demonstrating nonsignificant improvement of acne
severity in all groups.
Similarly, there was no significant difference in
GAGS score and lesion count between conventional
daily and low daily dosing at 24 weeks in a different
study.36 It also found a similar efficacy between low and
conventional doses but significantly reduced efficacy in
the intermittent group. Another trial34 also showed a
statistically significant increased efficacy in those taking
a dose of 80 mg/day compared with 20 mg/day.
The study by Strauss et al.43 compared three groups:
low, conventional 0.5 mg/kg and conventional 1 mg/kg.
All demonstrated a reduction in number of flares after
20 weeks, with no differences between dosages (p < 0.01).
Kapadia et al.35 reported that patients treated with
higher doses achieved clearance faster than those treated
with lower doses, but all achieved clearance at 24 weeks
(p > 0.5). However, in a different study,43 although
clearance was similar in all groups, the number of
relapses was higher (42% vs. 10%) in the group receiving
0.1 mg/kg/day.
Three studies used a different approach: two studies
started at a lower dose and then offered weekly
increments until the highest dose tolerated was
reached,33,48 and the other study reached a dose of
1 mg/kg/day.50 Borghi et al.48 treated patients for 1
month after complete clearance and noted a relapse rate
of 9.35%. In contrast, another study50 using a target
cumulative dose between 120 and 150 mg/kg for 20
weeks regardless of whether clearance had occurred, had
a relapse rate of 7.8%.
Four studies30,34,36,37,43 demonstrated no statistical
difference in clinical efficacy between the low dose
versus conventional dose at the end of the treatment
period (24–30 weeks), with a similar number and timing
of relapses in each group.

444 | DALY
Low dose versus intermittent doses
Low dose daily versus intermittent
(alternate days)
One study41 used a dose of 20 mg on alternate days
achieving very good results (more than 80% resolution of
baseline acne) in 68.2% of patients, despite a failure of
treatment in 12.46% and a relapse rate of 16.4%.
When comparing this intermittent dosing regimen to
a standard 20 mg fixed daily dose, two studies have
offered further insight: a daily fixed dose provided more
rapid response22,52 but there was no difference in overall
efficacy at the end of treatment. One study52 reported
that those with severe acne responded better to a daily
treatment at 36 weeks (p < 0.001).
Low dose daily versus intermittent
(1 week per month)
Three studies29,42,53 compared a daily 20 mg dose to a
1‐week per month regimen. No statistically significant
difference was noted, although faster clinical response
and lower relapse was found in the groups using a daily
regimen.
Daily conventional versus intermittent
conventional doses
Five studies compared conventional daily dose with
intermittent conventional dose: four studies included
moderate acne (one examined mild, moderate and severe
acne, one examined moderate to severe, one included
mild to moderate and one just focused on moderate
disease) and two studies included severe acne.
One prospective study examined an intermittent
regimen. The authors found that a regimen of 0.5 mg/
kg/day for 1 week every 4 weeks for 6 months achieved a
satisfactory response in 88% (p < 0.0001). Despite this,
there was a reported 9% treatment failure rate, and 39%
of the lesions relapsed after 12 months.32
The remaining studies offered a comparative analysis
between intermittent and conventional daily regimens,
which was found to be around 20% more efficacious and
with a quicker response than the intermittent option.
Another study24 showed that, whilst acne was
significantly reduced in all groups (p < 0.001), only those
with severe acne were found to have responded to the
different regimens (p = 0.0013). This suggests that a fixed
daily dose may be better at treating severe acne, whereas
intermittent doses can be used to treat moderate acne.
27686566, 2023, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/jvc2.154, Wiley Online Library on [23/01/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
ET AL.
A fixed daily dose may also be preferable, as relapse was
only found in those receiving an intermittent dose.24,36
Daily conventional doses compared with
each other
Two studies compared daily dosing regimens where
patients received doses at either end of the conventional
range of 0.5 and 1 mg/kg. One study45 compared doses of
0.5–1 mg/kg/day and found no difference in clearance
between groups, despite finding a statistically significant
increased frequency of side effects in the 1 mg/kg/day
group (p = 0.002).
Another study35 compared three groups, two of
which were also on 0.5 and 1 mg/kg/day and found an
increased rate of side effects in the 1 mg/kg/day group
(p < 0.05). Those in the 0.5 mg/kg group had double the
recurrence rates (20%) of those in the 1 mg/kg group
(10%). Both studies only included patients with either
acne conglobata45 or severe nodulocystic acne43 which
may affect the comparability of these studies.
Conventional doses given in divided doses
Three studies looked at conventional doses divided in
two and given twice instead of once daily.23,25,50 One
compared once daily to twice daily dosing of conven-
tional doses and did not find any difference between
reduced global acne scores (p = 0.8) but highlighted that
side effects were more common in those receiving once
daily dosing (p = 0.001).23 Another found twice daily
dosing of 0.5 mg/kg/day resulted in significant improve-
ment of nodular, pustular and cystic lesions.25 The third
used lidose‐isotretinoin twice daily starting at 0.5 mg/kg
for the first 4 weeks and then increasing to a dose of
1 mg/kg for the remaining 16 weeks of treatment. It
demonstrated statistically significant improvement in
mean acne lesion count but did not compare this to
standard isotretinoin or once daily dosing.50
High dose regimens
Only one study27 looked at high daily doses. Participants
were given a mean dose of 1.6 mg/kg/day of isotretinoin
with a cumulative dose of 290 mg/kg. All patients cleared
with this regimen, with a relapse rate of 12.5%. This
included patients who had required previous courses of
isotretinoin, a group that was mostly excluded from other
studies. When these patients are removed from this
sample, the relapse rate falls to 8.7%.

A SYSTEMATIC REVIEW OF ISOTRETINOIN DOSING IN ACNE VULGARIS
Cumulative dosing considerations
Borghi et al.48 pointed out that those with acne in more
than three bodily areas required higher cumulative doses.
Hermes et al.33 found no statistical significance between
patient demographics, type of acne, duration of treat-
ment or cumulative dose and relapse rate. This study had
the highest relapse rate of the three, with 33% mean
relapse rate—although relapse was determined by new
emergence of acne of greater than 0.5 grade, which was a
lower threshold than most of the other studies.
Another study26 used standard daily doses of
isotretinoin until 1 month after no new lesions occurred,
then divided them into groups of those that received
more or less than 220 mg/kg as a cumulative dose. They
found that relapse was higher (47.4%) in those taking the
lower cumulative doses (<220 mg/kg) compared with
those who received higher cumulative doses (26.9%)
(>220 mg/kg) (p = 0.03). However, this study defined
relapse as requirement of any further prescribed treat-
ment including topical treatments. When patients
requiring a further course of isotretinoin were identified,
these were only two, and belonged to the group with
higher cumulative dose.
With respect to adverse effects, one comparative
study found no statistically significant difference in
deranged LFTs and different cumulative doses.26 Simi-
larly, no significant difference was found in triglycerides
between those that received more or less than 220 mg
cumulative dose of isotretinoin.26 One study demon-
strated a dose‐dependent increase in lipids and triglycer-
ides43 and one study reported a significantly higher rate
of retinoid dermatitis in their group that received more
than 220 mg of isotretinoin as a cumulative dose
compared with less than 220 mg.26
ADVERSE EFFECTS
Biochemical
Most studies reported some derangement in LFTs or
lipids on blood monitoring. The frequency of LFTs
above the upper limit of normal ranged from 0%32,35 to
22%.27 AST was most frequently found to be abnormal
but a rise in transaminases was transient and resolved
on cessation of isotretinoin. No statistically significant
difference in ALT rises was found in a study of two
groups receiving 0.1 and 0.5 mg/kg/day, despite there
being a significant difference in the group receiving
1 mg/kg/day.43 Similarly, one study only reported
deranged LFTs in the 1 mg/kg/day treatment group22
and the study using the highest dose of isotretinoin at
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| 445
1.6 mg/kg/day also reported the highest rate of ALT
derangement at 22%.27
Lipids
Studies measured various lipid profiles including serum
lipids, cholesterol and triglycerides. Triglycerides were
most frequently elevated. Three studies reported normal
lipid profiles despite differing doses of isotretinoin.32,35,38
18.8% of patients receiving 1.6 mg/kg/day of isotretinoin
in the highest dosing study developed abnormal
triglycerides.27
Mucocutaneous side effects
Cheilitis and xerosis were the most common side effects
and were reported in all studies. Several studies
demonstrated a dose‐dependent relationship between
cheilitis and isotretinoin.24,29,36,43,45 Acne flare was
identified as a side effect in four studies.33,37,46,51 One
study found 15.6% of participants experienced acne flare
in their lower dose group (0.15–4.0 mg/kg day of
isotretinoin) compared with 25% in their conventional
dosing group.37 Hermes et al.33 found 27% of patients had
an acne flare but this was not related to dose. Another
study46 reported 5.3% of patients experienced an acne
flare on a low‐dose regimen of 10 mg of isotretinoin per
day. Long‐term follow‐up to assess if side effects other
than flares were persistent after cessation of isotretinoin
was only performed by one study26 that found 20.7% of
patients continued to have cheilitis and 17.2% had xerosis
a year after treatment.
Mood disturbance
In seven studies, patients reported psychiatric or psycho-
logical symptoms whilst taking isotretinoin.26,31,35,38,40,46,51
Reported symptoms included irritability, nervousness or
anxiousness and depressive symptoms, with a frequency
ranging from 0% to 7.34% across all studies. Only 24
participants out of the total of over 5050 across all studies
developed mood disturbance. Most studies did not enquire
specifically about mood changes, but the three that
did, reported no form of mood disturbance in their
sample,19,27,39 including the study that used the highest
recorded dose.27 One study26 divided their patients into
groups who had received a cumulative dose of more or less
than 220 mg/kg and reported mood disturbance in 2.6% of
their participants, despite there being no statistically
significant difference between the two groups. In addition,

446 | DALY
even very low doses of isotretinoin of 5 mg a day, resulted
in improvements in Dermatology Quality of Life Index
(DLQI) scores.38
ECONOMIC CONSIDERATIONS
Most studies overlooked the economic impact of the
dosing regimens used. A comparative study in which
patients with moderate acne were given 20 mg daily of
isotretinoin found their results were comparable with
standard doses of isotretinoin in other studies, at a
lower cost.19
Another comparative study demonstrated a mean
cost of isotretinoin treatment of €376.69 versus €684.45 in
their two treatment groups. However, although the cost
of treatment was lower in the group receiving the lower
dose (mean dose of 0.24 mg/kg) compared with the
recommended dose (mean dose 0.67 mg/kg), it did not
result in greater resolution of acne (68.8% compared with
87.5%, respectively).37 Another study reported a 20%
saving using an intermittent regimen of 0.5 mg/kg 1
week per month, for 6 months, compared with daily
dosing.32
DISCUSSION
This systematic review has examined studies conducted
over 50 years to clarify whether there is an optimal
isotretinoin dosing regimen to achieve efficacy and
sustained improvement in treating acne vulgaris. It also
sought to establish if low‐dose regimens are as clinically
effective, lead to fewer adverse effects and result in
sustained improvement when compared with high‐dose
regimens.
Thirty‐two studies were identified and critically
appraised regarding study design, number of participants
and their characteristics, dose, duration of treatment,
number of isotretinoin courses, cumulative dose, defini-
tions of efficacy, efficacy and relapse, site of acne, acne
grading system used, acne severity, dietary factors,
adverse side effects, including biochemical, cheilitis and
mood disturbance, follow‐up period, economic consider-
ations and study quality score.
The review of these published studies has demon-
strated several issues or omissions which hinders
comparison between studies and interpretation of results.
GRADE assessment revealed all studies had a serious
risk of bias and a low overall assessment score. With
respect to study design, 10 different grading systems have
been used to define treatment outcomes which has
resulted in inconsistency when comparing the clinical
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ET AL.
efficacy of low or intermittent regimens to high‐dose
isotretinoin treatment.
Dosage regimens were variable across studies.
Although isotretinoin is licenced for severe acne, the
grade of acne across studies included mild, moderate and
severe disease and the definition of relapse was either not
clearly defined or inconsistent across studies. Relapse
rates may be influenced by multiple factors including the
severity of acne, younger age of onset, hyperandrogen-
ism, smoking, cessation of treatment before acne
clearance and excessive seborrhoea. It was not clear
from these studies whether these prognostic risk factors
were taken into consideration. Previous large studies
have specifically analysed relapse rates and found
conflicting results: one study reported relapse rates
greater in those taking isotretinoin, but those in the
study appear to have been treated with a subtherapeutic
dose.54 Another large cohort study showed that relapse
was linked to young age and facial acne grade greater
than 3, while mean daily dose and total cumulative dose
had no prognostic value for relapse after isotretinoin‐
induced clearing.55
The studies were carried out across 16 different
countries, and most did not break down results by ethnic
group. Many studies were not controlled and/or did not
use a comparator and many were underpowered. Only
three studies32,37,56 considered the economic impact of
different dosing regimens, which have important impli-
cations for national health services, insurance companies
and self‐funded patients. Patient reported outcome
measures were not employed, which would have been
useful to elicit the patients' perspective on their
treatment efficacy. Patient acceptability and adherence
to longer courses of isotretinoin has not been adequately
explored either.
Oral isotretinoin is known to be highly lipophilic,
however, none of the studies controlled for dietary
factors and many of the studies were not adequately
powered to allow for differences between the different
generic formulations that may have been dispensed.
With respect to adverse effects, data were not
collected in a consistent manner. When this was
recorded, it only identified the more common reported
adverse effects. The duration of long‐term follow‐up was
variable between none23,34,35,44,51 and 7 years,37 and long‐
term adverse effects were only recorded in one study.26
Fifteen studies provided follow‐up of a year or less and
this was often self‐reported via survey.
Notwithstanding this, there were several consistent
results throughout. First, daily dosing regimens resulted
in better efficacy than intermittent dosing regimens in
severe acne. Second, patients with more severe acne
responded better to conventional or high fixed‐dose

A SYSTEMATIC REVIEW OF ISOTRETINOIN DOSING IN ACNE VULGARIS
regimens of isotretinoin. Third, the severity of some
common, particularly mucocutaneous, side effects were
dose‐dependent and adopting a low‐dose regimen
avoided some of the mucocutaneous side effects which
are associated with standard or high‐dose isotretinoin.
Fourth, relapse rates were higher in patients assigned to
low‐dose and intermittent‐dosing regimens when com-
pared with those on high‐dose and conventional regi-
mens. Fifth, low dose extended courses of isotretinoin,
providing they are continued until clearance or near
clearance, appear to have a similar efficacy to conven-
tional doses of isotretinoin. Finally, higher cumulative
doses were not associated with increased efficacy in
studies of mild to moderate acne in which isotretinoin
was being used off‐license.
CONCLUSION
This systematic review has identified some trends across
studies. Daily dosing was better than intermittent dosing
and in severe disease. Low doses resulted in fewer
mucocutaneous adverse effects and less initial acne flare.
Relapse rates were lower in patients taking higher
dosages. However, low‐dose extended courses of isotreti-
noin, providing they are continued until clearance or
near clearance, appear to have a similar efficacy to
conventional doses of isotretinoin. Higher cumulative
doses of isotretinoin were not associated with increased
efficacy in studies of mild to moderate acne in which
isotretinoin was being used off‐license, however, it was
not clear if this was the case in severe disease.
Despite these trends, the overarching conclusion
demonstrates the need for a well‐designed randomised
controlled study which is adequately powered to answer
the question: can a low‐dose oral isotretinoin regimen for
severe acne result in similar efficacy, reduced adverse
effects and long‐term resolution when compared with a
conventional dosing regimen?
AUTHOR CONTRIBUTIONS
Study conception and design: Alison M. Layton, Carsten
Flohr. Preliminary searches: Naayema, Jack Coumbe,
Maria Charalambides. Final search strategy: Aoife U.
Daly, Rui Baptista Gonçalves, Eva Lau, Joanne Bowers,
Alison M. Layton. Data collection: Aoife U. Daly, Rui
Baptista Gonçalves, Eva Lau, Joanne Bowers. Analysis
and interpretation of results: Aoife U. Daly, Rui Baptista
Gonçalves, Eva Lau, Joanne Bowers, Alison M. Layton.
Draft manuscript preparation: Aoife U. Daly, Rui Baptista
Gonçalves, Alison M. Layton. All authors reviewed the
results and approved the final version of the manuscript.
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| 447
AC KNOW LEDGEM ENTS
The authors would like to thank Helen Weir and Daniel
Park, Librarians at Harrogate District General Hospital,
for her greatly appreciated support throughout this
project with the search strategy and data extraction.
The authors declare no funding for this article.
C O NF L I C T O F I N T E R E S T S TA T E M E N T
All authors declare no conflict of interest.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are
available in the supplementary material of this article.
ETHICS STATEMENT
Not applicable.
ORC ID
Rui Baptista Gonçalves https://orcid.org/0000-0002-
4373-5379
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SU PPOR T ING INF OR MATI ON
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article.
How to cite this article: Daly AU, Baptista
Gonçalves R, Lau E, Bowers J, Hussaini N,
Charalambides M, et al. A systematic review of
isotretinoin dosing in acne vulgaris. JEADV Clin
Pract. 2023;2:432–449.
https://doi.org/10.1002/jvc2.154