Isotretinoin Best Practices: New Formulations, Avoiding Relapses, and More

One of the challenges of isotretinoin use for clinicians is ensuring adequate absorption by patients, which can be tricky because of the drug’s lipophilic nature. Two new formulations of isotretinoin could help overcome this hurdle, Joshua Zeichner, MD, told attendees during the “Acne Boot Camp” session at the American Academy of Dermatology (AAD) 2023 Annual Meeting, held March 17-21, in New Orleans, Louisiana.¹

Joshua Zeicher, MD

Zeichner, associate professor of dermatology at Mount Sinai in New York, New York, focused his talk on the basics of isotretinoin use, the challenges that come with treatment, new formulation options for clinicians, best practices to avoid relapses of a patient’s acne, ongoing studies on inflammatory bowel disease (IBD) and isotretinoin use, and the connection between acne and mental health.

Reaching Target Absorption for Isotretinoin

Adequate absorption is always a concern, Zeichner said, and isotretinoin is meant to be administered along with a high-fat, high-calorie meal, which the US Food and Drug Administration considers to be between 800 and 1000 calories with high fat equating to 50% of total caloric intake.

However, that can present a challenge when American Dietetic Association data show that > 50% of teenage boys and > 66% of teenage girls report skipping breakfast regularly. Zeichner advised clinicians to use skin and lip dryness as a marker of whether patients are adequately absorbing isotretinoin. If patients on the drug are not presenting with dry skin and/or lips, they are either not taking their medication or not absorbing it entirely.

New Formulations

Two newer formulations of isotretinoin seek to solve this conundrum. First, Zeichner reviewed “lidose” isotretinoin, which relies on a technology called hot melt extrusion to enhance solubility from a lipid matrix, thereby boosting absorption regardless of whether the patient has eaten a high-fat meal.

A 2019 phase 4 open-label study² offered some real-world data to support the use of lidose isotretinoin and was the first to study administration in a fasted state. Investigators sought to determine safety and efficacy in patients with severe recalcitrant nodular acne across 21 sites in the United States. The study was organized into a 20-week active treatment period followed by a 104-week posttreatment observation period, with a primary end point of the proportion of patients who required re-treatment with oral isotretinoin.

During weeks 1-4, patients started with 0.5 mg/kg per day administered as 2 doses without food. During weeks 5-20, patients received a stable dose of 1 mg/kg per day given as 2 doses without food.

During the 2-year posttreatment observation period, Zeichner said, 95% of patients did not require re-treatment with isotretinoin, and 82% did not require re-treatment with any over-the-counter or prescription acne medication.

"These numbers are much better than what we've seen before and really have to do, in my mind, with absorption of the drug because remember, [it's] lidose technology in the fasted state,” Zeichner said.

The other newer formulation Zeichner discussed was micronized low-dose isotretinoin, which reduces the size of the drug particles down to micrometer size, effectively boosting the rate of drug dissolution.

Navigating Relapses

Zeichner also discussed how to handle patient relapses after isotretinoin use. The risk factors for relapse include male gender, trunk involvement, macrocomedo predominance, ovarian dysfunction, longer use of isotretinoin therapy, and younger age. But another avoidable risk factor to remember is insufficient initial dosing.

According to Zeichner, 63% of prescribers currently dose isotretinoin twice daily because the drug exposure is greater compared with with once-a-day dosing. The traditional dosing to reach the target treatment goal is a total dose of 120-150 mg/kg (usually started as 0.5 mg/kg for the first month, and then 1 mg/kg thereafter). Zeichner advises clinicians to only discontinue therapy once the patient’s skin is clear. He typically treats 1 month past the last pimple.

Is There a Connection Between IBD and Isotretinoin?

The lecture also briefly touched on whether there is an association between IBD and isotretinoin, which a number of studies have sought to determine. A few studies have hinted at slight increases in rates of IBD among patients using isotretinoin, but clinicians often point to a French nationwide case-control study³ in 2014 that examined 7600 cases of IBD (0.3% exposed to isotretinoin) and 30,000 matched controls (0.4% exposed to isotretinoin). Investigators there determined that isotretinoin exposure is not associated with ulcerative colitis and, in fact, exposure to the drug actually had a bit of a protective effect against Crohn’s disease.

“Of course, I discuss this with all of my patients before putting them on this drug,” Zeichner said. “And, as I'm sure you know, it's a consent form that you need to sign as part of the iPLEDGE program, but I do educate my patients on this specific study.”

Mental Health Implications

Because of the enormous toll of acne on mental health, the use of isotretinoin can play a key role in enhancing patients’ self-image and confidence. A 2021 study⁴ that analyzed a large commercial insurance claims database found that, compared with the general population, patients with acne prescribed isotretinoin were less likely to engage in suicidal behavior.

“I personally can say that I have seen this drug completely change patients’ lives,” Zeichner said. “I have seen patients lose significant amounts of weight. I have seen patients gain self confidence that we never knew that they had. I have seen patients come off psychiatric medication.”

References:

1. Zeichner J. Isotretinoin boot camp. Presented at American Academy of Dermatology 2023 Annual Meeting; March 17-21, 2023; New Orleans, LA.
2. Del Rosso JQ, Stein Gold L, Segal J, Zaenglein AL. An Open-label, Phase IV Study Evaluating Lidose-isotretinoin Administered without Food in Patients with Severe Recalcitrant Nodular Acne: Low Relapse Rates Observed Over the 104-week Post-treatment Period. J Clin Aesthet Dermatol. 2019;12(11):13-18.
3. Racine A, Cuerq A, Bijon A, et al. Isotretinoin and risk of inflammatory bowel disease: a French nationwide study. Am J Gastroenterol. 2014;109(4):563-569. doi:10.1038/ajg.2014.8
4. Ugonabo N, Love E, Wong PW, et al. Psychiatric disorders and suicidal behavior in patients with acne prescribed oral antibiotics versus isotretinoin: Analysis of a large commercial insurance claims database. J Am Acad Dermatol. 2021;85(4):878-884. doi:10.1016/j.jaad.2021.01.107