What Is the Risk of Relapse and Retrial With Isotretinoin for Acne?

April 4, 2025

Isotretinoin has been a life-changing treatment for acne for decades. In patients with severe acne, those who have had suboptimal response to other conventional treatments, or those with scarring acne, isotretinoin has shown significant effectiveness as a long-lasting treatment. Many patients who use isotretinoin are able to achieve acne remission, making it a popular treatment option despite its associated adverse effects. However, some patients with acne who have used isotretinoin continue to struggle with the disease and may experience acne relapse or require further isotretinoin treatment.

New research sought to analyze the rate of acne relapse with isotretinoin and identify factors associated with this outcome in patients who have completed a first course of the drug.¹

“It’s a medicine that many people do experience long-term clearance with, but some people have acne that comes back and requires additional treatment,” said dermatologist John Barbieri, MD, MBA, in an interview with Dermatology Advisor. Dr Barbieri is the primary author of the study and director of the Advanced Acne Therapeutics Clinic at Brigham and Women’s Hospital.

Acne Clearance

Isotretinoin treats the main causes of acne. It shrinks oil glands in the skin, as blocked oil glands may result in the growth of acne bacteria such as Cutibacterium acnes. Additionally, the drug decreases sebum production from the oil glands. Isotretinoin also mitigates hyperkeratinization and decreases inflammation.^2,3

We found the beneficial effects of cumulative dose on preventing recurrence start to go away as you reach really high doses of more than 220 mg/kg. More is not infinitely better.

Although some data have indicated that the long-term clearance rate following a course of isotretinoin may be lower than previously reported — particularly in younger patients who are more likely to relapse — a study found that 61% of patients experienced acne clearance with a single course of isotretinoin, 39% of patients experienced acne relapse within the first 18 months of treatment, and 23% required an additional course of the drug.⁴ Further research on the risk of acne relapse has shown that women had a higher rate of relapse. Additionally, 22.5% of patients required subsequent treatment with a systemic medication and 8.2% required retrial with isotretinoin in Dr Barbieri’s study.¹

“Despite the reports of relapses, this conventional regimen is still highly effective while at the same time causing several dose-related side effects. Therefore, micro-dose, mini-dose, low-dose, and intermittent treatment regimens with better tolerance and lower incidence of adverse effects have been introduced,” wrote authors of a review on the dermatologic uses of oral isotretinoin.⁴

Effective Regimen

The standard dosage of isotretinoin is 0.5 to 1 mg/kg/day, with a standard cumulative dosage of 120 to 150 mg/kg during the course of treatment. However, many different dosing approaches are used in clinical practice and there is no consensus on which approach is best.⁴

A prospective, observational study involving 116 patients with acne that was resistant to other treatments demonstrated that 1 year after completing isotretinoin treatment, patients receiving isotretinoin 220 mg/kg or greater had a significantly lower risk of relapse. Patients in the study were divided into 2 groups based on their cumulative dosing: less than 220 mg/kg or 220 mg/kg and greater. Retinoid dermatitis was the only adverse effect that was significantly more common in the high-dose group.⁵

“This study suggests that significantly higher doses of isotretinoin are effective for treating acne and decreasing relapse rates without increasing adverse effects,” wrote the authors.⁵

The results of Dr Barbieri’s study further built on these prior findings regarding cumulative dosing. In his retrospective cohort study based on claims data,¹ Dr Barbieri found that, “220 mg/kg is better than 150 mg/kg, but the variable for mg/kg itself is no longer significant at cumulative doses greater than 220 mg. So up to 220 mg/kg, each mg/kg of increasing cumulative dose is associated with lower rates of recurrence, but not greater than 220 mg/kg.”

Dr Barbieri continued, “We found the beneficial effects of cumulative dose on preventing recurrence start to go away as you reach really high doses of more than 220 mg/kg. More is not infinitely better.”

Personalized Approach

Dr Barbieri notes that a big takeaway of his study was the valuable data given to clinicians for individualizing their patients’ acne regimens.

Dr Barbieri typically likes to start isotretinoin treatment with a dosage of 0.3 to 0.5 mg/kg/day and then increase the dose over the next few months based on adverse effects and patient goals. He aims for a clinical target of clear skin for at least 2 to 3 months and a cumulative dose of at least 120 to 150 mg/kg.

“What I recommend is an individual daily dose based on patient preference for adverse effects. Lower doses for less adverse effects,” he said.

If the patient prefers a lower adverse effect profile, the lower dose is continued for between 6 and 12 months. However, if the patient is less bothered by adverse effects and desires a quicker treatment, they can try a higher dose for between 5 and 8 months.

Adverse Effects

Higher doses of isotretinoin come with an increased risk of adverse effects. Cheilitis is the most common dose-dependent adverse effect and occurs in approximately 90% of patients taking the medication. Other common adverse effects include xerosis, xerostomia, rhinitis sicca, and photosensitivity. Isotretinoin can also cause myalgia and arthralgia.²

Hypertriglyceridemia and increased liver function tests may occur, thus laboratory testing should be monitored throughout treatment.²

Patients should be advised to don sun protection and use skin moisturizers during treatment. Avoidance of skin resurfacing procedures, such as waxing, laser therapy, or dermabrasion, during treatment and for at least 6 months after isotretinoin treatment is also necessary.²

Further, Dr Barbieri suggests that his patients take omega-3 fatty acids to minimize dryness while on isotretinoin. Although the mechanism for the beneficial effects of omega-3 fatty acids in combatting dryness is unclear, some researchers have hypothesized that the beneficial effects may be due to anti-inflammatory properties that lead to a reduction in inflammatory gene expression and transepidermal water loss.⁶

Moreover, the principal concern regarding the adverse effects associated with isotretinoin is severe birth defects. Due to this risk of teratogenicity, the drug is only approved for marketing under a restricted distribution risk evaluation and mitigation strategy (REMS), called the iPLEDGE REMS.⁷ Through the use of iPLEDGE REMS, the Food and Drug Administration (FDA) aims to prevent fetal exposure as well as to educate practitioners, pharmacists, and patients on the serious risks and safe-use conditions associated with isotretinoin. All FDA-approved isotretinoin products are included in this system, which provides a centralized location to manage patient risk regardless of the isotretinoin product being used.⁸

For those struggling with adverse effects, Dr Barbieri recommends reducing the isotretinoin dosage being used.

Future Research

While recent literature has advanced our understanding on the risk of acne relapse and isotretinoin retrial, this research is not without its limitations. The assumption that filled prescriptions for acne treatment reflect the recurrence of acne, as well as the inability to determine a patient’s clinical status of acne at the time of isotretinoin discontinuation are limitations of Dr Barbieri’s study.¹ Additional research is needed on other serious adverse effects, such as mood changes or sexual dysfunction.³ Further still, other isotretinoin research is limited by a lack of randomized, controlled trials.⁴

Dr Barbieri concluded, “Doing more studies that are prospective with long-term follow-up are needed to complement the research findings thus far.”

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