Prevalence of adverse events varies with the different oral isotretinoin brands in acne treatment: a retrospective observational study

Oral isotretinoin remains the most effective treatment for acne. The aim of this retrospective single-center cohort study was to estimate the prevalence of adverse events with the different oral isotretinoin brands used in acne treatment. The population consisted of all patients who consulted for acne between January 2015 and January 2020. The inclusion criterion was the initiation of treatment with oral isotretinoin. The exclusion criteria were the use of two or more brands during the same course of treatment and previous treatment with oral isotretinoin. Statistical analysis was carried out using Chi-square and Mann–Whitney tests. We analyzed 468 patients of whom 68.6% were female. The median age was 21 years. The median weight was 65 kg. The treatment was Roaccutane®, Curacné®, Acnotren®, Isosupra®, Contracné®, or Acnogen® in 44.2%, 28%, 14.5%, 10.5%, 1.7% and 0.4% of cases, respectively. Xerosis was the most frequently reported side effect regardless of the brand. The highest frequencies of hypercholesterolemia (25.6%) and eczema (13%) were noted with Roaccutane®; hypertriglyceridemia (16.8%), epistaxis (9.9%) and fatigue (3.1%) with Curacné®; excessive sweating (4.1%) and headache (4.1%) with Isosupra®; and abnormal liver function tests (11%) with Acnotren®. We found a significant correlation mainly between abnormal ASAT and Acnotren® (p = 0.009), hypercholesterolemia and Roaccutane® [OR = 1.652 (95% CI 1.056–2.585)], hypertriglyceridemia and higher body weight (p = 0.004). Factors related to the drug brand and to characteristics of acne patients could explain the variability in the prevalence of some adverse events.


Introduction
Oral isotretinoin, or 13-cis-retinoic acid, remains the most effective treatment for acne. By the guidelines of the American Academy of Dermatology, it is recommended for nodular, treatment-resistant, scarring, or psychosocially distressing acne [1]. As a prodrug derived from vitamin A, it is converted in the cell into active metabolites which bind to nuclear receptors RAR and RXR inducing the transcription of target genes, in particular those of the FoxO proteins which in turn modulate the expression of other genes [2]. The clinical effect is often a healing or a prolonged remission, explained by the apoptosis of sebocytes, the increase in epidermal turnover, the decrease in colonization by Cutibacterium acnes, and a non-specific anti-inflammatory action [3,4]. The effectiveness depends on the dose and duration of treatment. With the exception of teratogenicity, adverse events are dose-dependent and resolve without sequelae upon discontinuation of the drug. The most frequent are mucocutaneous, notably dry lips, xerosis, facial erythema, epistaxis, cheilitis, and itching [5,6]. Myalgias, tiredness, and headache were also common [6]. Less common adverse events, reported in less than 10% of patients, included abnormal bloodwork, vision changes, hair loss, abdominal pain, menstrual irregularities, and other miscellaneous manifestations [6,7]. Some side effects remain speculative like inflammatory bowel disease, mood changes, and changes in bone mineralization [8][9][10]. There was no report of serious adverse events [11]. Discontinuation following a side effect occurred only in 0.14% of treated patients [6].
Although the proprietary drug and its generics have different aspects, they meet the same efficacy and quality standards. Generics cost less and those of oral isotretinoin are widely prescribed for acne. Several studies have evaluated the adverse events of oral isotretinoin in the treatment of acne. Apart from two clinical trials that compared the safety of micronized and Lidose formulas to standard isotretinoin, no study analyzed the frequency of adverse events across the different brands [12,13]. Taylor et al. have studied through different tests the pharmaceutical quality of 14 generics compared to the brand Roaccutane ® and have found significant variability in the molecular size that might have consequences for the safety and efficacy of the product, assuming for example that a patient treated with the same dose of a smaller-particle-size isotretinoin product will have higher plasma concentrations of isotretinoin and its metabolites, and probably, more intense effect or adverse events than Roaccutane ® [14].
We aimed in this study to estimate the prevalence of adverse events with the different oral isotretinoin brands, the proprietary drug and its generics, used in acne treatment.

Study setting, objectives, and eligibility criteria
We conducted this analytical retrospective single-center cohort study at our tertiary care university hospital, primarily to analyze the prevalence of adverse events with the different oral brands of isotretinoin used in acne treatment and secondarily to identify features eventually associated with a given adverse event. The population consisted of all patients who consulted our department for acne between January 2015 and January 2020. The inclusion criterion was the initiation of treatment with oral isotretinoin. The exclusion criteria were the use of two or more brands during the same course of treatment and previous treatment with oral isotretinoin. Thus, those who had another course of oral isotretinoin during the study period were included only in their first course.

IRB approval
The study was approved by the institution's IRB committee (Reference Number: Tfem/2022/78) to collect the information from the patients' files in our dermatology department. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki.

Data collection
We checked out patients' files and collected the following data: age, sex, ethnicity, weight, relevant medical history, doxycycline intake in the previous 3 months, concomitant treatments, acne type and site, oral isotretinoin brand, the starting daily dose, the total dose received, the treatment course duration, the season when treatment was started, the reported clinical adverse events, and the values of the different laboratory assessments.

Outcomes
The adverse events are usually monitored and detected clinically during the patient's regular visits and through monthly blood tests. In daily practice, there are no checklists to fill but the adverse events are assessed through subjective reports of patients and physician clinical assessment. Unless infected or symptomatic, dry lips are not considered an adverse event since they are constantly seen in most patients; severe cheilitis was computed as irritative dermatitis.
Liver enzymes ASAT and ALAT, as well as total cholesterol and triglycerides, were tested in the serum of patients on a monthly basis, at least for the first 3 months of treatment. CPK and cell blood count were tested in case of fatigue or muscle pain. Abnormalities in bloodwork (High ASAT, high ALAT, high CPK, hypercholesterolemia, hypertriglyceridemia, and anemia) were recorded if they occurred at least in one blood test. Whenever the abnormality occurred more than once, the highest value was kept.

Sample size
Study size determination did not rely on pre-specified statistical assumptions for the outcomes but was intended to be optimal by including all the eligible patients while respecting the inclusion/exclusion criteria.

Statistical methods
Patients who have received more than one course during the 5 years were counted twice or more, accordingly.
The categorical variables were presented as percentages and were analyzed using the Chi-square test. The continuous variables were presented as median and interquartile ranges; they were analyzed using the Mann-Whitney test.
The statistical analyses were run using SPSS software (IBM Corp. Released 19, SPSS Statistics for Windows Version 26.0, Armonk, NY). The statistical code and the
Chi-square tests did not show a significant correlation between the presence of at least one adverse event and a given isotretinoin brand (data not shown).
Chi-square tests for categorical variables and Mann-Whitney tests for continuous variables did not show a significant correlation between the presence of at least one adverse event and any of the patient's characteristics (age, sex, weight, relevant medical history, doxycycline in the previous 3 months, concomitant treatment, season at treatment initiation), neither in the group of all patients nor in the subgroups of the different isotretinoin brands (data not shown).
Finally, we analyzed through Chi-square tests for categorical variables and Mann-Whitney tests for continuous variables, if any of the different adverse events was significantly correlated to any isotretinoin brand or any patient's characteristic. We found a significant correlation only in the following tests (data not shown): • Abnormal ASAT (p = 0.009) with Acnotren ® ; abnormal ASAT (p < 0.001) and abnormal ALAT (p < 0.001) with concomitant treatment with inositol-folic acid.

Discussion
Our study exposes the frequencies of the adverse events reported with the different brands of oral isotretinoin. To the best of our knowledge, this is the first study with such an objective. Among the significant correlations found, we mainly report hypercholesterolemia with Roaccutane ® , an increase of aspartate aminotransferase with Acnotren ® , menstrual disorders, mood disorders, and weight gain with Contracné ® . These findings can help the clinician in screening the adverse events according to the patient profile and the chosen brand of oral isotretinoin. Our results emerge from a medium-sized cohort of patients treated in a real-life setting. We have exhaustively collected the clinical characteristics of the patients, as well as the reported clinical and biological adverse events. The sample size led to robust statistical results.
Some limitations need to be considered when interpreting our results. The study was retrospective and conducted in one center. Evidence quality decreased due to the possibility of memory and reporting biases. The majority of patients (70%) were treated with either Roaccutane ® or Curacné ® ; thus, other brands might have been under-represented in the analysis. Because of the real-life setting, the starting doses, the daily doses, and the treatment duration may have shown some dissimilarities, but this was not limited to any brand. We should have also added data about the efficacy of the treatment; however, the files lacked a standardized assessment form for efficacy. The multivariate analysis could not be included in the model.
Of 3525 patients retrospectively analyzed over 5 years on the adverse effects of isotretinoin, Brzezinski et al. also found a majority of women, but of younger age and of longer treatment duration. The prevalence of the different adverse events was frequently much higher than that computed in our study; thus, xerosis was reported in 94%, epistaxis in 47%, pruritus in 38%, fatigue in 20%, headache in 16%, and mood change in 9% of patients. They had even reported hair loss in 4%, abdominal pain in 3%, and visual disturbances in 2.8% of patients, three adverse events not found in our study [6].
Another retrospective review over a 6-year period of 1743 patients treated with isotretinoin for various dermatological conditions also found higher percentages of adverse events in the group treated with doses more than 0.75 mg/kg/day than in the group treated with doses less than 0.25 mg/kg/day; discontinuation because of adverse events occurred in 1.4% of patients. Very uncommon side effects like alopecia, hematuria, acanthosis nigricans, or gingival hyperplasia were also reported [15].
A prospective interventional study on patients treated with isotretinoin for resistant acne found that none of the adverse effects was significantly different between the lower-cumulative dose group (< 220 mg/kg) and the higher-cumulative dose group (≥ 220 mg/kg), except for the retinoid dermatitis that was significantly more common in the high-dose group [16]. Similarly, no correlation was found in our study between the presence of any or a specific adverse event and the starting daily dose or the total cumulative dose of isotretinoin.
The literature provided in recent years several consensus studies and systematic reviews to optimize the use of oral isotretinoin. On the one hand, lowering the initial and daily doses and prolonging the treatment 1 month after acne clearance were suggested not only to improve remission rates and reduce relapse but also to lower the prevalence of adverse events and increase adherence to treatment [1,5,[17][18][19]. On the other hand, monitoring lab abnormalities has been practically limited to triglycerides and ALAT tests before treatment and 2 months later, which improved the quality and cost of care [20][21][22].
In conclusion, factors related to the drug brand of oral isotretinoin and to characteristics of acne patients could explain the variability in the occurrence of some adverse events. Further prospective studies should ensure a clearly reported assessment of adverse events with the different brands of oral isotretinoin.