Isotretinoin

What isotretinoin is

Isotretinoin is a form of vitamin A acid (13-cis-retinoic acid) and is taken as a capsule. It is prescription-only and has been used against severe acne since the 1980s. In the EU, the summary of product characteristics was harmonized in a referral procedure in 2003 and tightened in 2018 after a review of all retinoids.

What is rated is the state of knowledge. Isotretinoin has been widely used for decades and is closely monitored by regulators; the randomized trials, however, are often small, rarely placebo-controlled and mostly at high risk of bias. Increasingly, it is also being used at a low continuous dose for mild to moderate acne. That is not approved.

How it works

According to the Cochrane review, isotretinoin is the only acne drug that targets all the main causes of acne. Other agents such as antibiotics or topically applied drugs each address only individual factors.

Retinoids also interfere with the development of the embryo. The malformations after isotretinoin typically affect the face and ears, heart, thymus and nervous system and resemble those from animal experiments; a disturbance of neural crest cells is considered a possible mechanism. How psychiatric and sexual side effects arise has not been clarified. For sexual dysfunction, the safety committee of the European Medicines Agency names a drop in blood testosterone as a possible mechanism.

What the studies show

The Cochrane review

Costa 2018 (Cochrane) analyzed 31 randomized trials with 3,836 participants aged 12 to 55, with a mean treatment duration of 19.7 weeks. Twelve trials were funded by manufacturers, and all but three had a high risk of bias in at least one domain. Compared with oral antibiotics plus topical treatment, there was no difference in the number of inflammatory lesions, RR 1.01 (3 trials, 400 participants, very low quality of evidence). The physician’s global assessment was possibly 15 percent better, RR 1.15, but milder side effects such as dry skin, cheilitis and nausea were 67 percent more frequent. In a study with 150 participants with severe acne, there was a clear dose dependency.

Low, conventional and intermittent dose

Lee 2011 (Br J Dermatol) randomized 60 patients with moderate acne to 0.5 to 0.7 mg/kg daily, 0.25 to 0.4 mg/kg daily, or 0.5 to 0.7 mg/kg for only one week in four, each over 24 weeks. The conventional and the low dose worked equally well, the intermittent regimen less well. Patients were most satisfied with the low dose, and side effects occurred more often with the conventional dose. One year after the end of treatment, 2 of 16, 3 of 17 and 9 of 16 patients had relapsed.

What the meta-analysis on the low dose says

Al Muqarrab 2022 (Dermatol Ther) pooled studies on low-dose isotretinoin in adults with mild to moderate acne, an off-label use. The authors rate the quality of evidence as low. For response, the conventional dose performed better overall than the low daily dose, and sustained remission was more likely under the conventional dose. The low daily dose, in turn, was more effective than intermittent dosing.

Psychiatric disorders and suicide

Tan 2024 (JAMA Dermatol) analyzed 25 studies with 1,625,891 participants, randomized and observational. The absolute one-year risk of suicide, suicide attempt, suicidal ideation and self-harm was below 0.5 percent in each case, and 3.83 percent for depression. The risk of all psychiatric disorders was not increased, RR 1.08 (0.99 to 1.19). Suicide attempts 2 to 4 years after treatment tended to be less frequent than in non-users, RR 0.92 after 2, 0.86 after 3 and 0.85 after 4 years. The authors nonetheless recommend monitoring mental health during treatment.

Malformations

Lammer 1985 (NEJM) examined 154 pregnancies with isotretinoin exposure: 95 terminations, 26 children without major malformations, 12 miscarriages and 21 malformed children. In a prospectively followed subgroup of 36 pregnancies there were 8 miscarriages, 23 healthy and 5 malformed children. The relative risk for selected major malformations was 25.6 (11.4 to 57.5).

Where the data stop

• High-quality comparative trials. The Cochrane review rates the evidence for most endpoints as low. Whether isotretinoin reduces inflammatory lesions more than antibiotics plus topical treatment remains uncertain.
• The low continuous dose. It rests on small studies; the conventional dose more often led to sustained remission. For purely cosmetic use without acne, the sources analyzed here contain no studies.
• Causality of psychiatric side effects. In 2018 the EMA could not establish a causal relationship, and the British medicines regulator MHRA reached the same conclusion in 2023. Population-level data do not rule out individual reactions.
• Sexual complaints after stopping. Whether and how often sexual dysfunction persists after the end of treatment is not answered by the studies analyzed here. A similar debate exists for finasteride.

Status, approval and legal

Oral isotretinoin is prescription-only in Germany. According to the harmonized EU summary of product characteristics, the indication is severe acne that does not respond to oral antibiotics and topical treatment. The approved dosage starts at 0.5 mg per kg of body weight daily, with a range of 0.5 to 1.0 mg/kg; a course usually lasts 16 to 24 weeks, and the cumulative dose is 120 to 150 mg/kg. Use at a low continuous dose for mild to moderate acne is not approved.

For women of childbearing potential, a pregnancy prevention program applies, which the EMA updated in 2018: pregnancy tests before, during and after treatment, at least one effective method of contraception and a form with which the physician and patient confirm that information was provided. According to the summary of product characteristics, contraception is used from one month before until one month after treatment.

In the United Kingdom, additional rules have applied since October 2023: for under-18s, two independent prescribers must agree, and mental health and sexual function are assessed before prescribing.

Safety

The greatest risk is harm to the unborn child. Pregnancy must therefore be ruled out before, during and until one month after treatment. The most common side effects are mild, above all dry skin and lips, cheilitis and nausea. In the trials analyzed by Cochrane, one serious event occurred, a Stevens-Johnson syndrome.

The summary of product characteristics lists depression, psychotic symptoms and, rarely, suicide attempts and suicides. In 2018 the EMA found contradictory data and no established causal relationship, but pointed out that severe skin diseases themselves increase the risk of psychiatric disorders; patients should be informed about possible changes in mood and behavior and monitored. Sexual dysfunction, including erectile dysfunction and reduced libido, has been included in the European product information since 2017.

Sources

• Costa CS et al., Cochrane Database Syst Rev 2018 – oral isotretinoin for acne, 31 RCTs with 3,836 participants
• Lee JW et al., Br J Dermatol 2011 – conventional, low and intermittent dose compared, RCT with 60 patients
• Al Muqarrab F, Almohssen A, Dermatol Ther 2022 – meta-analysis of low-dose isotretinoin in mild to moderate acne
• Tan NKW et al., JAMA Dermatol 2024 – meta-analysis on suicide and psychiatric disorders, 25 studies with 1,625,891 participants
• Lammer EJ et al., N Engl J Med 1985 – retinoic acid embryopathy, 154 pregnancies under isotretinoin
• EMA – review of retinoid-containing medicines 2018: pregnancy prevention program and warning on psychiatric disorders
• EMA/CPMP – isotretinoin, Article 29 referral, harmonized summary of product characteristics 2003
• EMA/CMDh – oral isotretinoin, PSUSA assessment 2017: sexual dysfunction as a side effect
• MHRA, October 31, 2023 – isotretinoin: two prescribers for under-18s, assessment of mental health and sexual function
• German Ordinance on Prescription-Only Medicines (AMVV), Annex 1 (prescription-only substances)