High Dose vs. Low Dose Isotretinoin

Background on Isotretinoin Dosing for Acne

Oral isotretinoin is indicated for severe acne, treatment resistant moderate acne, or acne that causes scarring or psychological distress.^[1] Standard dosing is 0.5-1 mg/kg/day for 15-20 weeks.^[1] The American Academy of Dermatology’s current guidelines indicate that low-dose (0.25-0.4 mg/kg/day) isotretinoin can effectively treat acne and limit medication-induced adverse effects, but that intermittent dosing is not recommended.^[1] Cumulative doses over 120 mg/kg are associated with a lower relapse rate, a dose-dependent effect that increases with higher dosing up to 150 mg/kg and beyond 200 mg/kg, although the benefit seems to increase only slightly past 150 mg/kg (Table 1).^[2]

An important point of distinction is the difference between the daily dose and the cumulative dose:

• Daily dose refers to the dose of isotretinoin taken on a daily basis and is calculated as mg/day
• Cumulative dose is the total dose of isotretinoin over the entire treatment period and is calculated as mg/kg

Typical Adverse Effects with Isotretinoin

Isotretinoin has several potential side effects that should be reviewed by the treating dermatologist or other physician:

Strong evidence for side effects: ^[1,3]

• Cheilitis
• Xeroderma and xerostomia, mucocutaneous irritation
• Epistaxis
• Teratogenicity (this is a concern regardless of dosing)
• Elevated serum triglycerides, cholesterol, and transaminases
• Staphylococcus aureus colonization and minor skin infections
• Joint pain
• Pyogenic granuloma (typically periungual)^[4]

Other Concerns: ^[1,3]

• Inflammatory bowel disease: The American Academy of Dermatology states that the “evidence is insufficient to prove either an association or a causal relationship between isotretinoin use and inflammatory bowel disease.”^[5]
• Depression and suicidal ideation: studies do not show an evidence-based connection between mood disturbance and isotretinoin use; however, depression and anxiety and suicidal ideation are prevalent, especially in adolescents. As isotretinoin is often prescribed in this demographic, evaluating mood symptoms is an important step in acne treatment.^[1]

What’s the Evidence for Low Dose and High Dose Isotretinoin?

Low dose: intermittent vs. continuous

A randomized trial in India assessed outcomes in 234 patients given 20 mg of isotretinoin daily (Group A) versus every other day (Group B) for 24 weeks and followed patients for 12 weeks after treatment.^[7] No patients had a flare of their acne upon treatment initiation. The mean decrease in acne load was 98.99% in Group A and 97.69% in Group B (p < 0.016) at the end of treatment, and 96.03% in Group A and 92.82% in Group B 12 weeks later. The most common adverse effects were cheilitis (Group A: 97.46%; Group B: 95.69%; p = 0.7) and dry skin (Group A: 16.9%; Group B: 10.3%; p = 0.21). There were no side effects that warranted cessation of treatment. The frequency of adverse effects was slightly higher with daily dosing than every other day dosing; however, the difference was not significant (p > 0.50).

Researchers concluded that for moderate acne, a regimen of isotretinoin 20 mg every other day may be favorable as compared to daily dosing. However, for severe acne, 20 mg daily worked faster than every other day. This study compared daily dosing regimens; the cumulative dose was not specifically compared.

Conclusion: When using low doses of isotretinoin, every other day dosing works just as well as daily dosing in the long term, though results will be reached faster with daily dosing.

Conventional dose vs. low dose

A clinical trial in Iran evaluated 60 patients with moderate to severe acne given either 0.5 mg/kg/day or 0.25 mg/kg/day over 6 months with re-evaluation 6 months after treatment cessation.^[8] There was no significant difference in mean severity of acne in either group, before treatment, at 6 months of treatment or at 6 months post-treatment. There were fewer side effects in the low dose group and greater patient satisfaction, indicating it may be the preferred treatment regimen.

Conclusion: When comparing low versus high daily doses of isotretinoin, lower daily dosing of isotretinoin was just as effective even though the total cumulative dose was lower in the lower daily dose group.

Continuous standard dose vs. continuous low dose vs. intermittent dose

A randomized, controlled study in Korea compared 60 patients with moderate acne treated with isotretinoin 0.5-0.7 mg/kg daily (Group A-daily standard dose), 0.25-0.4 mg/kg daily (Group B-daily low dose) or 0.5-0.7 mg/kg for 1 week out of every 4 weeks (Group C-intermittent dose).^[9] Groups A and B were treated for 24 weeks continuously and Group C was treated for 6 out of 24 weeks. The average cumulative dose of isotretinoin was 90 mg/kg for Group A and 61 mg/kg for Group B.^[9] Subjects were also evaluated one year after treatment completion. There was no significant difference identified between Groups A and B in number of non-inflammatory lesions or global acne grading scores, indicating they had similar efficacy. Group C performed significantly worse in both categories. Patient satisfaction was significantly higher in group B (‘daily low dose’) as compared to groups A and C. Side effects occurred most often in Group A (‘daily standard dose’). One year later, the rates of acne relapse were significantly lower in groups A (13%) and B (18%) as compared to group C (56%).

Conclusion: Overall, a daily low dose of isotretinoin appeared superior to the daily standard dose or intermittent dosing of isotretinoin for the combination of efficacy, patient satisfaction, and reduced side effects in treating moderate acne.

Overall Conclusion on Isotretinoin Dosing for Acne

A review evaluating low dose isotretinoin < 0.5 mg/kg for 6-7 months estimated an average efficacy of 90% for treating mild to moderate acne with comparable relapse rates to the standard 1 mg/kg/day dosing.^[10] With fewer side effects, which may improve patient tolerance and compliance, this may be the optimal dosage goal. Nonetheless, many of the studies excluded those with severe acne, compared dosing regimens using small sample sizes, and varied in study methods, so further evaluations are warranted. 

Practical Tips

1. Low dose isotretinoin (0.25-0.4 mg/kg/day) can be an effective alternative in treating moderate acne and is associated with fewer adverse medication effects than standard dose isotretinoin (0.5-1 mg/kg/day).
2. Intermittent dosing (i.e. 1 week per month) of isotretinoin is not recommended due to reduced efficacy, but every-other day regimens may still be effective.
3. Most investigations of low dose isotretinoin excluded patients with severe acne, so standard dosing regimens are currently recommended for severe acne patients.