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Accutane (isotretinoin)

Everything You Need to Know About Isotretinoin

By: Dan Kern, Acne.org Founder & CSO
Last updated: February 17, 2020

The Essential Information

Accutane® is the most well-known brand name of the powerful oral medication derived from vitamin A called isotretinoin.

It is sometimes referred to as the "nuclear option" when it comes to acne treatment because of its ability to provide remission of acne in about 2/3 of people who take a 15-20 week course of the drug, while at the same time causing concerning, potentially lifelong side effects, including severe birth defects.

The FDA has approved isotretinoin only for people with severe, widespread, and scarring acne, but some physicians prescribe it for less severe acne. This is controversial because isotretinoin changes the skin and the body forever. Once you take it, there is no going back. As a real life example, because of the way isotretinoin can permanently alter eyesight, the U.S. military will not allow anyone who has previously taken isotretinoin to be a fighter pilot.

How It Works: It clears acne primarily through permanently reducing skin oil production, but also prevents clogged pores, reduces inflammation, and reduces bacteria.

Side Effects: Because it is an oral medication, it affects the entire body. Dry, cracked lips and skin are expected, and side effects such as nose bleeds, irritated eyes, rashes, fatigue, headaches, joint pain, and insomnia are just a few of the other common side effects. Concerningly, some of these side effects can be lifelong, leaving the user with, for instance, a lifetime of impaired joints, or the need to use lip balm several times a day for the rest of their life.

Pregnancy: EXTREME CAUTION!: ACCUTANE (ISOTRETINOIN) CAUSES SEVERE BIRTH DEFECTS AND FETAL DEATH. Females using isotretinoin must pass two (2) pregnancy tests before taking isotretinoin, and must use at least two (2) forms of birth control while on isotretinoin.

Suicide & Depression: Many people swear that they are more depressed or suicidal while taking isotretinoin, and while the research we have thus far does not show a connection, anyone taking isotretinoin should closely monitor their mental state.

Take with a High-fat Meal: For isotretinoin to get absorbed into the bloodstream, it should be taken with a high-fat meal (20 grams of fat or more).

The Science

What Is Accutane?

Iisotretinoin, originally known for its brand name Accutane, or Roaccutane in parts of the world, was discovered in 1979 when it was first given to patients with severe acne, most of whom reacted with dramatic and permanent clearing of their acne symptoms. It is a vitamin A derivative (13-cis-retinoic acid) that is administered orally in pill form with a meal that contains an adequate amount of fat,1normally for 15-20 weeks (3.5-4.5 months),2although it is also sometimes prescribed at lower dosages for up to six months or longer. It was originally recommended for people with severe acne that did not respond to other treatments,3but has gained in popularity in the past 25 years and is prescribed more and more frequently for less severe acne.4-6This practice is controversial because isotretinoin is a systemic medication that affects every bodily system and can cause lifelong side effects to the user. It need not be paired with other medications, but in cases of extra-severe acne, physicians sometimes prescribe a few weeks of oral corticosteroids to quickly reduce inflammation before beginning a course of isotretinoin.7

How Does Accutane Work?

Exactly how Accutane works on a cellular level is unknown but we do know that it affects four ways that acne develops.

  1. It dramatically reduces the size of the skin's oil glands (35%-58%) and even more dramatically reduces the amount of oil these glands produce (around 80%).8-11
  2. Acne bacteria (P. acnes) live in skin oil. Since oil is dramatically reduced, so is the amount of acne bacteria in the skin.9
  3. It slows down how fast the skin produces skin cells inside the pore, which helps pores from becoming clogged in the first place.11-12
  4. It has anti-inflammatory properties.11-12

How Accutane (isotretinoin) Works

Although acne may get worse within the first month of Accutane use for about 30% of patients, the ultimate results are usually dramatic.13Accutane works to achieve partial or complete clearance of acne in about 95% of people who complete a cycle, regardless of whether they have inflammatory or non-inflammatory acne.14The majority of people who take it experience long-term remission of acne symptoms. Studies show relapse rates between 14.6% to 52%, with a real-world average of about 1/3 of people experiencing a relapse. In these cases sometimes a second course is given.11,7,9,14-19

This relapse rate is dose-dependent. Patients who receive a cumulative dose of 100-120mg/kg see the best results and lowest relapse rates. Patients who receive a lower dose relapse more frequently. Daily dosage depends on how much the patient weighs; 0.5mg-2mg / kg is typical.1,15,17

Other factors that increase the chance of relapse are:

  • male gender
  • severe acne
  • not taking isotretinoin with an adequate amount of dietary fat
  • hormonal imbalances like poly-cystic ovary syndrome (PCOS) in women

Low dosing: Traditionally, most doctors prescribe high doses of at least 1mg/kg / day for relatively short periods of time (15-20 weeks). However, because many people develop severe side effects from Accutane, more recently clinicians started testing lower doses of Accutane administered over a longer period of time. Initial data is showing that patients with mild to moderate acne may be able to achieve long-term remission with significantly lower dosages, and thus suffer fewer side effects,20-22including lower incidence of scarring. For people with more severe acne, staying on a lower dose of Accutane for a longer period of time until the full 120mg/kg cumulative dose is achieved may be a way to produce long-term remission with significantly fewer side effects.The current recommendation based on this initial research is that the cumulative dose - the amount of Accutane that accumulates in the body - is the most important factor that determines the success of the treatment.1

5b22b85a01a25_JC-JournalofClinicalandAes

A good explanation on how to reach a desired cumulative dose of Accutane was published in the Journal of Clinical and Aesthetic Dermatology: "If a patient weighs 70kg, the cumulative total dose target of 120mg/kg for his or her course of therapy would be 8400mg (70kg x 120mg). Considering convenience and the practical consideration of capsule strengths, if the patient was started on 40mg daily (slightly more than 0.5mg/kg / day) for the first month, then increased to 60mg daily (slightly less than 1mg/kg / day) thereafter, it would take five months for the patient to reach the cumulative total dose of 8400mg based on the 120mg/kg target (1200mg [40mg x 30 days/month x 1 month] + 7200mg [60mg x 30 days/month x 4 months]). If the daily dose needs to be lowered due to side effects, the cumulative total dose target can be reached by lengthening the duration of therapy to what is needed to reach 120 to 150mg/kg."1

Intermittent dosing: Intermittent dosing (taking Accutane only one week of every month) also produces fewer side effects but may not work as well. It has been studied twice. In both studies people receiving an intermittent dose ended up receiving a lower cumulative dose, so we do not know if the poorer results are due to the intermittent administration of the drug or the lower cumulative dose. The first study compared an intermittent dose to a regular dose. Researchers gave patients in the intermittent dose group the same dose as patients in the regular dose group but for only one week out of the month. This resulted in only ¼ the cumulative dose after treatment ended. This produced slightly less clearing of acne and more than three times the relapse rate compared to the regular dose group. The second study compared a similar intermittent dose for only one week out of the month to a continuous low-dose every day. While exact numbers were not reported, from what we can glean from the study, this resulted in approximately ½ the cumulative dose for the intermittent group when compared to the continuous low dose group. Both groups in this second study achieved completely clear skin by the end of treatment, but more people relapsed in the intermittent group.21

Accutane Side Effects

Accutane is a systemic medication that affects the entire body. Side effects are numerous and widespread, and affect almost all patients.1-35Side effects can be moderate and reversible, but in some cases can be severe or long term.

Isotretinoin Has Serious Side Effects

Side Effects of Accutane (Isotretinoin)

Local Adverse Events: Occurs in:
Cheilitis (inflammation of the lips)
up to 100%
Dry skin
up to 100%
Skin peeling
up to 92.9%
Dry nose
up to 70%
Facial rash
up to 68%
Nose bleed
up to 66.7%
Pruritus (itchy skin)
up to 57.1%
Irritated/dry eyes
up to 52%
Conjunctivitis (pink eye)
up to 50%
Thirst
up to 35.7%
Fingertip peeling
up to 33%
Rash
up to 30%
Loss of hair
up to 29%
Sore mouth
up to 28.6%
Eczema
up to 12.1%
Fissuring of the skin
up to 6.7%
Crusting lesions
up to 6.7%
General Adverse Events: Occurs in:
Fatigue
up to 27%
Headache
up to 24.1%
Joint pain
up to 24%
Insomnia
up to 22%
Muscle ache or cramps
up to 17%
Nausea
up to 18%
Loss of appetite
up to 17%
Eye pain
up to 16%
Abdominal pain
up to 14%
Sunburn
up to 12%
Malaise
up to 10%
Double vision
up to 7.1%
Mood change
up to 7.1%
Dry hair
up to 6.7%
Ptergium (growth on the eye)
up to 6.7%
Photophobia (sensitivity to bright light)
up to 6.7%
Decreased sweating
up to 6.7%
Hordeolum (red painful bump near eyelid)
up to 1.4%
Chalazion (lump near tear gland of eye)
up to 1.4%
Blepharitis (inflammation of eyelid)
up to 1%
Laboratory Adverse Events: Occurs in:
Increase in cholesterol
up to 57%
Increase in triglycerides
up to 43%
Increase in liver enzymes
up to 24.5%
Other Adverse Events:
Teratogenicity:
Isotretinoin is associated with teratogenicity resulting in severe birth defects and spontaneous abortions.
Depression/Suicide:
To date, no causal association has been found between isotretinoin and depression/suicide.
Inflammatory bowel disease:
To date, no causal association has been found between isotretinoin and inflammatory bowel disease.
Celiac disease:
To date, no causal association has been found between isotretinoin and celiac disease.
Bone density:
To date, no causal association has been found between isotretinoin and problems in bone density in young patients using short term isotretinoin.

Pregnancy and Accutane


Extreme Warning: Accutane Causes Birth Defects

Accutane is the number one teratogen on the market. A teratogen is a medication that interferes with normal development of the fetus and causes birth defects. Shortly after Accutane became available on the market, the Centers for Disease Control (CDC) reported that a large proportion of pregnancies in women who are exposed to Accutane result in spontaneous abortions and birth defects and advised against the use of Accutane by pregnant women.1Birth defects include:

  • skull
  • ear
  • eye
  • facial
  • central nervous system
  • cardiovascular
  • thymus and parathyroid abnormalities
  • death2

Clinical research shows extremely high risk for birth defects if Accutane is taken by pregnant women.3The effects and risks of Accutane on unborn children are so severe that the FDA approved the iPledge program, which requires female patients of childbearing age to commit to using two (2) forms of birth control while on Accutane.4

Accutane Side Effects on the Fetus

However, despite warnings to women not to get pregnant while using Accutane, studies published in Canada, the Netherlands, and the UK report a range of 11-24 per 1000 women getting pregnant while on Accutane.5-7This is lower than the pregnancy rate in the general population of these countries which stands at approximately 50 per 1000 women, but is still unacceptably high, leading to tragic outcomes.

Another study performed in California looked at rates of pregnancy before and after the iPledge program was implemented. Thankfully, they found lower rates of pregnancy among women using Accutane in California, but found that the iPledge program had only modest results. Before iPledge, 3.1 women in California per 1000 taking Accutane got pregnant, and after iPledge this number dropped to 2.7. Researchers stated, "We found that most women on isotretinoin depend on contraceptive methods that require considerable adherence to be effective. Unfortunately, our results suggest that this degree of adherence is unrealistic for many women."8Abstinence, condoms, and the birth control pill were all cited as areas of non-adherence.

The iPledge program. Roche started with a program called SMART (System to Manage Accutane Related Teratogenicity) in 2000, which became the iPLEDGE program in March, 2006. Female patients of childbearing age are required to use two (2) forms of birth control while on Accutane.4,9

iPLEDGE program telephone: 1-866-495-0654. iPLEDGE program website: ipledgeprogram.com

Suicide and Depression

Suicide and Depression

Patients have reported depressive symptoms while taking Accutane since the drug hit the market in 1982. Whether the drug causes these depressive feelings remains a subject of intense debate. There are, after all, millions of people taking the drug, and there are bound to be people experiencing depression amongst them. Despite the confusion around this topic, Roche Pharmaceuticals, the makers of Accutane, added a warning to its label regarding suicide and depression in 1998.

Media coverage on the topic spiked in 2000 when Michigan Congressman Bart Stupak's son BJ committed suicide while on Accutane. Research began in earnest to determine whether there is a causal link between Accutane, suicide, and depression. Quite a few studies have been conducted since. These have included large population-based cohort studies, retrospective analysis studies, relative risk estimates, prospective, observational, and longitudinal studies, and questionnaires performed in the United States and around the world.3-16The first of these studies showed no conclusive evidence linking Accutane with depression or suicide.1-2As the studies mounted, the data continued to show no evidence of a link.7-9,17One study published in The New England Journal of Medicine found "431 cases of depression, suicidal ideation, suicide attempts, or suicide in U.S. patients treated with isotretinoin," within a 10-year period. The article went on to note that the numbers listed do not exceed the U.S. suicide rate.18

If a researcher were to examine the evidence from 2000 until 2005, he or she would likely conclude that there is no evidence linking Accutane with suicide or depression.7-9However, as is often the case, further analysis showed limitations to many of the studies.19-20A general overview published in 2006 by the International Journal of Dermatology noted, "the overall lack of concrete scientific data limits any conclusion that can be drawn about a causal relationship between isotretinoin and psychiatric adverse events."21

Then, in 2006, mice injected with the drug exhibited depression-related behaviour. While animal studies often do not reflect human models, it was marginally intriguing.10But even more provocative was a large cohort case-crossover study published in 2008 by the Journal of Clinical Psychiatry, which was the first controlled study to find a correlation between Accutane, suicide, and depression, albeit relatively minor.11More recent studies have leant more credibility to the argument that Accutane does not negatively affect depression or mood,5,6and several studies show significant improvements to depression, anxiety, and obsessive thoughts,12-16presumably due to the power of Accutane to clear acne and thus increase quality of life.

A review of literature on the link between Accutane in depression in 2015 stated, "The major part of the dermatology community states that there is no causal link between isotretinoin and depression with this postulate: acne causes anxiety and depression; treating acne with isotretinoin is a way to manage depression." However, there is still controversy, with critics pointing out the dermatology community's tendency to not understand depression as well as the psychiatric community. "Literature studies have demonstrated two opposing views as to the role of isotretinoin from two differing clinical specialties. The psychiatric literature…suggests a causal link between isotretinoin and depression. The dermatological literature suggests that acne is an independent risk factor for depression and isotretinoin could be used to improve depression by treating acne and improving self-image. These differing views could be explained by a recruitment bias. Dermatologists may not have been aware of the occurrence of psychiatric disorders."22

The preponderance of the evidence at this point is that Accutane does not appear to be linked with suicide and depression.20,23However, to be safe, it is important for anyone taking Accutane to closely monitor their mental health while on the drug.4,1,24Doctors prescribing Accutane can also check for signs of depression. A paper published in the Journal of the American Academy of Dermatology in 2016 recommends that all patients who are prescribed Accutane be screened for depression. The authors of the paper state, "Regardless of whether depression in these patients is rooted in the underlying acne or its treatment, the prevalence and serious nature of depression, suicide, and suicidal ideation demand attention. Given the chronic nature of acne treatment, dermatologists are uniquely situated to help screen for depression and suicidal ideation. It is our duty to care for all aspects of our patients' health, including their mental health."25The paper also provided a screening tool for depression, which allows physicians to quickly screen patients who are at high risk of developing depression while taking Accutane. The tool consists of a series of questions and if a patient receives a score of 3 or more, he or she should be further examined to determine if they could safely take Accutane.

Take with a High-fat Meal

Take with a High-Fat Meal

Isotretinoin is a fat-soluble molecule, meaning that it is best absorbed into the blood if taken with a meal that contains an adequate amount of fat.1-2According to drug labeling information submitted to the U.S. National Library of Medicine by the makers of Accutane, "Both peak plasma concentration (Cmax) and the total exposure (AUC) of isotretinoin were more than doubled following a standardized high-fat meal when compared with Accutane given under fasted conditions. Therefore, Accutane capsules should always be taken with food. Failure to take Accutane with food will significantly decrease absorption."3This failure to take Accutane with fat-containing meals may account for some of the relapse that we see post-Accutane.

So what kind of meal should be eaten when taking Accutane, and how much dietary fat should it contain? So far only 2 studies have been performed. The first asked participants to ingest approximately 20g of fat (2 poached eggs, toast with margarine, plus 8oz. of skimmed milk), and found that this was enough to approximately double the absorption of Accutane.2The second asked participants to ingest 50g of fat (1 bagel, 2 tablespoons of peanut butter, 5 slices of bacon, 6oz. of apple juice, and 1 donut), and found that this was also enough to approximately double the absorption rate.4Further research is required to determine exactly how much fat one must optimally ingest to reach maximum isotretinoin levels in the blood, but suffice it to say that isotretinoin must be taken with a meal which contains dietary fat to deliver its full potential. Based on the research thus far, it is prudent to ingest at least 20 grams of fat when taking a daily dose of isotretinoin.

One exception - Absorica™: In 2012, the FDA approved a new version of isotretinoin, called isotretinoin-Lidose, for sale in the United States that is marketed under the brand name Absorica. This formulation encapsulates isotretinoin in fat molecules and therefore reduces the need to take it with a fatty meal.1,4The package insert states that Absorica "(1) is bioequivalent with Accutane when both are taken with a high fat meal; (2) has 83% greater absorption than Accutane under fasted conditions; (3) is not interchangeable with generic products of Accutane, and (4) can be dosed without regard to meals." While data does show that absorption of Absorica is significantly greater than absorption of regular isotretinoin on an empty stomach, the claim that Absorica can be dosed without regard to meals may be skewed, since data show that even with Absorica, the amount of isotretinoin in the blood remains significantly higher when taken with a high-fat-containing meal.4

Absorbica (isotretinoin-lidose) Absorbability

Thus, it may also be prudent to take Absorica with a meal which contains an adequate amount of dietary fat. In addition, since there are no generic forms of Absorica, it is considerably more expensive than other forms of isotretinoin.
 
Absorbica: Cost for 30 Days Treatment

History of Accutane

Gerald Peck and co-workers from the NIH (National Institutes of Health) in Bethesda, Maryland first studied isotretinoin in patients with skin cell disorders. They accidentally found that it also worked on patients with severe acne. Isotretinoin was registered in 1979, released in the United States in 1982 as Accutane, and released in Europe in 1985 as Roaccutane.

Roche's patent expired in 2002, and manufacturers began selling generic forms of the drug.

In June, 2009, shortly after a jury awarded $33 million in damages to people who claimed Accutane caused bowel disease, Roche decided to discontinue selling brand name, Accutane. The company cited declining sales as their reason.

Topical Isotretinoin

Topical isotretinoin exists but does not produce the results of oral isotretinoin. It is largely of historical significance in acne treatment.

WARNING: Do Not Buy Accutane on the Internet!

According to the FDA:

  1. "Buying (Accutane) over the Internet bypasses important procedures to ensure that patients can take this drug safely. When these procedures are ignored, isotretinoin can cause serious and harmful side effects."
  2. You should NEVER buy Accutane (isotretinoin) without first seeing your healthcare professional.
  3. You should NEVER take Accutane (isotretinoin) or any of the generic versions of Accutane if you are pregnant or trying to get pregnant or could accidentally become pregnant.
  4. Some websites sell prescription drugs without a prescription. This is illegal and DANGEROUS.

Buying Accutane or any other prescription over the Internet often means you will receive pills that contain little or no active ingredient, or in some cases, a different medication entirely. Buying Accutane over the Internet is not only illegal, it is potentially dangerous and is also a waste of money.4 I agree strongly with the FDA. NEVER buy Accutane over the Internet."

Presentation of bias

As a critical sociology major in college, I learned that it is important for an author to present his or her bias. Because we are human and it is impossible to be completely unbiased, the presentation of bias allows the reader to take the author's bias into account when absorbing content.

My bias: I suffered with moderately severe acne in my adolescence and early adulthood. I took Accutane at age 20 but do not recall the dosage my doctor prescribed. It cleared me up completely within weeks. I transformed from a shy introvert to an outgoing college student. As a result of my skin clearing up, my mental state felt relatively light and good, albeit still somewhat anxious as I had always been. My short-term side effects included severely dry lips, extremely dry skin, dry eyes, and sometimes severe joint pain. I now live with two long-term conditions which may be from taking Accutane or may be coincidence. Since Accutane, whenever I sprint or exert myself in quick bursts my joints react with pain and inflammation, thus limiting my sports endeavors. I also have a mild version of an eye condition called pterygium, which is an irreversible and not-so-attractive growth on the white part of both eyes. My acne relapsed post-Accutane somewhat aggressively to what would be described as moderate acne. I am now able to control my acne symptoms with The Acne.org Regimen."

References:

How Does Accutane Work?

  1. Del Rosso, J. Q. Face to face with oral isotretinoin: a closer look at the spectrum of therapeutic outcomes and why some patients need repeated courses. J. Clin. Aesthet. Dermatol. 5, 17 - 24 (2012). https://www.ncbi.nlm.nih.gov/pubmed/23198008
  2. Ganceviciene, R. & Zouboulis, C. C. Isotretinoin: state of the art treatment for acne vulgaris. J. Dtsch. Dermatol. Ges. 8 Suppl 1, S47 - 59 (2010). https://www.ncbi.nlm.nih.gov/pubmed/20482692
  3. Dreno, B. et al. An expert view on the treatment of acne with systemic antibiotics and/or oral isotretinoin in the light of the new European recommendations. Eur. J. Dermatol. 16, 565 - 571 (2006). https://www.ncbi.nlm.nih.gov/pubmed/17101480
  4. Chen, K., White, T. J., Juzba, M. & Chang, E. Oral isotretinoin: an analysis of its utilization in a managed care organization. J. Manag. Care Pharm. 8, 272 - 277 (2002). https://www.ncbi.nlm.nih.gov/pubmed/14613420
  5. Wysowski, D. K., Swann, J. & Vega, A. Use of isotretinoin (Accutane) in the United States: rapid increase from 1992 through 2000. J. Am. Acad. Dermatol. 46, 505 - 509 (2002). https://www.ncbi.nlm.nih.gov/pubmed/11907498
  6. Rigopoulos, D., Larios, G. & Katsambas, A. D. The role of isotretinoin in acne therapy: why not as first-line therapy? facts and controversies. Clin. Dermatol. 28, 24 - 30 (2010). https://www.ncbi.nlm.nih.gov/pubmed/20082946
  7. Dhir, R., Gehi, N. P., Agarwal, R. & More, Y. E. Oral isotretinoin is as effective as a combination of oral isotretinoin and topical anti-acne agents in nodulocystic acne. Indian J. Dermatol. Venereol. Leprol. 74, 187 (2008). https://www.ncbi.nlm.nih.gov/pubmed/18401903
  8. Nelson, A. M., Gilliland, K. L., Cong, Z. & Thiboutot, D. M. 13-cis Retinoic acid induces apoptosis and cell cycle arrest in human SEB-1 sebocytes. J. Invest. Dermatol. 126, 2178 - 2189 (2006). https://www.ncbi.nlm.nih.gov/pubmed/16575387
  9. Plewig, G., Dressel, H., Pfleger, M., Michelsen, S. & Kligman, A. M. Low dose isotretinoin combined with tretinoin is effective to correct abnormalities of acne. J. Dtsch. Dermatol. Ges. 2, 31 - 45 (2004). https://www.ncbi.nlm.nih.gov/pubmed/16281880
  10. Ellis, C. N. & Krach, K. J. Uses and complications of isotretinoin therapy. J. Am. Acad. Dermatol. 45, S150 - 157 (2001). https://www.ncbi.nlm.nih.gov/pubmed/11606947
  11. Demircay, Z., Kus, S. & Sur, H. Predictive factors for acne flare during isotretinoin treatment. Eur. J. Dermatol. 18, 452 - 456 (2008). https://www.ncbi.nlm.nih.gov/pubmed/18573721
  12. Mandekou-Lefaki, I., Delli, F., Teknetzis, A., Euthimiadou, R. & Karakatsanis, G. Low-dose schema of isotretinoin in acne vulgaris. Int. J. Clin. Pharmacol. Res. 23, 41 - 46 (2003). https://www.ncbi.nlm.nih.gov/pubmed/15018017
  13. Ng, P. P. & Goh, C. L. Treatment outcome of acne vulgaris with oral isotretinoin in 89 patients. Int. J. Dermatol. 38, 213 - 216 (1999). https://www.ncbi.nlm.nih.gov/pubmed/10208621
  14. Quereux, G., Volteau, C., N'Guyen, J. M. & Dreno, B. Prospective study of risk factors of relapse after treatment of acne with oral isotretinoin. Dermatology 212, 168 - 176 (2006). https://www.ncbi.nlm.nih.gov/pubmed/16484824
  15. Haryati, I. & Jacinto, S. S. Profile of acne patients in the Philippines requiring a second course of oral isotretinoin. Int. J. Dermatol. 44, 999 - 1001 (2005). https://www.ncbi.nlm.nih.gov/pubmed/16409263
  16. Akman, A. et al. Treatment of acne with intermittent and conventional isotretinoin: a randomized, controlled multicenter study. Arch. Dermatol. Res. 299, 467 - 473 (2007). https://www.ncbi.nlm.nih.gov/pubmed/17710426
  17. Morales-Cardona, C. A. & Sanchez-Vanegas, G. Acne relapse rate and predictors of relapse following treatment with oral isotretinoin. Actas Dermosifiliogr. 104, 61 - 66 (2013). https://www.ncbi.nlm.nih.gov/pubmed/22795452
  18. Rademaker, M., Wishart, J. M. & Birchall, N. M. Isotretinoin 5 mg daily for low-grade adult acne vulgaris--a placebo-controlled, randomized double-blind study. J. Eur. Acad. Dermatol. Venereol. 28, 747 - 754 (2014). https://www.ncbi.nlm.nih.gov/pubmed/23617693
  19. Boyraz, N. & Mustak, P. K. Comparison of the efficacies of intermittent and continuous low-dose isotretinoin regimens in the treatment of moderate acne vulgaris. Int. J. Dermatol. 52, 1265 - 1267 (2013). https://www.ncbi.nlm.nih.gov/pubmed/23675954
  20. Borghi, A. et al. Low-cumulative dose isotretinoin treatment in mild-to-moderate acne: efficacy in achieving stable remission. J. Eur. Acad. Dermatol. Venereol. 25, 1094 - 1098 (2011). https://www.ncbi.nlm.nih.gov/pubmed/21198947
  21. Rasi, A., Behrangi, E., Rohaninasab, M. & Nahad, Z. M. Efficacy of fixed daily 20 mg of isotretinoin in moderate to severe scar prone acne. Adv. Biomed. Res 3, 103 (2014). https://www.ncbi.nlm.nih.gov/pubmed/24804178
  22. Lee, J. W. et al. Effectiveness of conventional, low-dose and intermittent oral isotretinoin in the treatment of acne: a randomized, controlled comparative study. Br. J. Dermatol. 164, 1369 - 1375 (2011). https://www.ncbi.nlm.nih.gov/pubmed/21114478


Accutane Side Effects

  1. Rademaker, M. Adverse effects of isotretinoin: A retrospective review of 1743 patients started on isotretinoin. Australas. J. Dermatol. 51, 248 - 253 (2010). https://www.ncbi.nlm.nih.gov/pubmed/21198520
  2. Honein, M. A., Paulozzi, L. J. & Erickson, J. D. Continued occurrence of Accutane-exposed pregnancies. Teratology 64, 142 - 147 (2001). https://www.ncbi.nlm.nih.gov/pubmed/11514944
  3. Brelsford, M. & Beute, T. C. Preventing and managing the side effects of isotretinoin. Semin. Cutan. Med. Surg. 27, 197 - 206 (2008). https://www.ncbi.nlm.nih.gov/pubmed/18786498
  4. Berard, A. et al. Isotretinoin, pregnancies, abortions and birth defects: a population-based perspective. Br. J. Clin. Pharmacol. 63, 196 - 205 (2007). https://www.ncbi.nlm.nih.gov/pubmed/17214828
  5. Abroms, L., Maibach, E., Lyon-Daniel, K. & Feldman, S. R. What is the best approach to reducing birth defects associated with isotretinoin? PLoS Med. 3, e483 (2006). https://www.ncbi.nlm.nih.gov/pubmed/17121451
  6. Shin, J. et al. The impact of the iPLEDGE program on isotretinoin fetal exposure in an integrated health care system. J. Am. Acad. Dermatol. 65, 1117 - 1125 (2011). https://www.ncbi.nlm.nih.gov/pubmed/21565419
  7. Goulden, V., Layton, A. M. & Cunliffe, W. J. Long-term safety of isotretinoin as a treatment for acne vulgaris. Br. J. Dermatol. 131, 360 - 363 (1994). https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2133.1994.tb08524.x
  8. McLane, J. Analysis of common side effects of isotretinoin. J. Am. Acad. Dermatol. 45, S188 - 194 (2001). https://www.ncbi.nlm.nih.gov/pubmed/11606952
  9. Burkhart, C. G. Another threat to the availability of isotretinoin: ocular side effects have aviation authorities considering restricting use from (even potential) pilots. Dermatol. Online J. 14, 2 (2008). https://www.ncbi.nlm.nih.gov/pubmed/18718186
  10. Barzilai, A., David, M., Trau, H. & Hodak, E. Seborrheic dermatitis-like eruption in patients taking isotretinoin therapy for acne: retrospective study of five patients. Am. J. Clin. Dermatol. 9, 255 - 261 (2008). https://www.ncbi.nlm.nih.gov/pubmed/18572976
  11. DiGiovanna, J. J. Isotretinoin effects on bone. J. Am. Acad. Dermatol. 45, S176 - 182 (2001). https://www.ncbi.nlm.nih.gov/pubmed/11606950
  12. DiGiovanna, J. J. et al. Effect of a single course of isotretinoin therapy on bone mineral density in adolescent patients with severe, recalcitrant, nodular acne. J. Am. Acad. Dermatol. 51, 709 - 717 (2004). https://jhu.pure.elsevier.com/en/publications/effect-of-a-single-course-of-isotretinoin-therapy-on-bone-mineral-4
  13. Eksioglu, E. et al. Sacroiliitis and polyneuropathy during isotretinoin treatment. Clin. Exp. Dermatol. 33, 122 - 124 (2008). https://www.ncbi.nlm.nih.gov/pubmed/17725657
  14. De Francesco, V., Stinco, G. & Campanella, M. Acute arthritis during isotretinoin treatment for acne conglobata. Dermatology 194, 195 (1997). https://www.ncbi.nlm.nih.gov/pubmed/9094477
  15. Bewley, A. P., Rankin, E. C., Levell, N. J. & Robinson, T. W. Isotretinoin causing acute aseptic arthropathy. Clin. Exp. Dermatol. 20, 279 (1995). https://www.ncbi.nlm.nih.gov/pubmed/7671431
  16. Kaplan, G. & Haettich, B. Rheumatological symptoms due to retinoids. Baillieres Clin. Rheumatol. 5, 77 - 97 (1991). https://www.ncbi.nlm.nih.gov/pubmed/2070429
  17. Hughes, R. A. Arthritis precipitated by isotretinoin treatment for acne vulgaris. J. Rheumatol. 20, 1241 - 1242 (1993). https://www.ncbi.nlm.nih.gov/pubmed/8371229
  18. Lehucher Ceyrac, D. Acute arthritis after isotretinoin. Dermatology 198, 406 - 407 (1999). https://www.ncbi.nlm.nih.gov/pubmed/10449946
  19. Kaymak, Y. Creatine phosphokinase values during isotretinoin treatment for acne. Int. J. Dermatol. 47, 398 - 401 (2008). https://www.ncbi.nlm.nih.gov/pubmed/18377609
  20. Kaymak, Y., Taner, E. & Taner, Y. Comparison of depression, anxiety and life quality in acne vulgaris patients who were treated with either isotretinoin or topical agents. Int. J. Dermatol. 48, 41 - 46 (2009). https://www.ncbi.nlm.nih.gov/pubmed/19126049
  21. Sundstrom, A. et al. Association of suicide attempts with acne and treatment with isotretinoin: retrospective Swedish cohort study. BMJ 341, c5812 (2010). https://www.bmj.com/content/341/bmj.c5812
  22. Laroche, M. L., Macian-Montoro, F., Merle, L. & Vallat, J. M. Cerebral ischemia probably related to isotretinoin. Ann. Pharmacother. 41, 1073 - 1076 (2007). https://www.ncbi.nlm.nih.gov/pubmed/17472998
  23. Zane, L. T., Leyden, W. A., Marqueling, A. L. & Manos, M. M. A population-based analysis of laboratory abnormalities during isotretinoin therapy for acne vulgaris. Arch. Dermatol. 142, 1016 - 1022 (2006). https://www.ncbi.nlm.nih.gov/pubmed/16924051
  24. Karadag, A. S., Ertugrul, D. T., Tutal, E. & Akin, K. O. Short-term isotretinoin treatment decreases insulin- like growth factor-1 and insulin-like growth factor binding protein-3 levels: does isotretinoin affect growth hormone physiology? Br. J. Dermatol. 162, 798 - 802 (2010). https://www.ncbi.nlm.nih.gov/pubmed/20128787
  25. Ozdemir, M. A. et al. Isotretinoin-induced agranulocytosis. Pediatr. Dermatol. 24, 425 - 426 (2007). https://www.ncbi.nlm.nih.gov/pubmed/17845176
  26. Reddy, D., Siegel, C. A., Sands, B. E. & Kane, S. Possible association between isotretinoin and inflammatory bowel disease. Am. J. Gastroenterol. 101, 1569 - 1573 (2006). https://www.ncbi.nlm.nih.gov/pubmed/16863562
  27. Crockett, S. D., Porter, C. Q., Martin, C. F., Sandler, R. S. & Kappelman, M. D. Isotretinoin use and the risk of inflammatory bowel disease: a case-control study. Am. J. Gastroenterol. 105, 1986 - 1993 (2010). https://www.ncbi.nlm.nih.gov/pubmed/20354506
  28. Erturan, I., Naziroglu, M. & Akkaya, V. B. Isotretinoin treatment induces oxidative toxicity in blood of patients with acne vulgaris: a clinical pilot study. Cell Biochem. Funct. 30, 552 - 557 (2012). https://www.ncbi.nlm.nih.gov/pubmed/22517509
  29. Neudorfer, M. et al. Ocular adverse effects of systemic treatment with isotretinoin. Arch. Dermatol. 148, 803 - 808 (2012). https://jamanetwork.com/journals/jamadermatology/fullarticle/1148708
  30. Alhusayen, R. O. et al. Isotretinoin use and the risk of inflammatory bowel disease: a population-based cohort study. J. Invest. Dermatol. 133, 907 - 912 (2013). https://www.ncbi.nlm.nih.gov/pubmed/23096714
  31. Etminan, M., Bird, S. T., Delaney, J. A., Bressler, B. & Brophy, J. M. Isotretinoin and risk for inflammatory bowel disease: a nested case-control study and meta-analysis of published and unpublished data. JAMA Dermatol. 149, 216 - 220 (2013). https://www.ncbi.nlm.nih.gov/pubmed/23426479
  32. Stobaugh, D. J., Deepak, P. & Ehrenpreis, E. D. Alleged isotretinoin-associated inflammatory bowel disease: disproportionate reporting by attorneys to the Food and Drug Administration Adverse Event Reporting System. J. Am. Acad. Dermatol. 69, 393 - 398 (2013). https://www.ncbi.nlm.nih.gov/pubmed/23683730
  33. Gungor, S. & Gokdemir, G. Anal fissure and rectal bleeding as a complication of systemic isotretinoin therapy: dermatologists know this side-effect, what about proctologists? Colorectal Dis. 15, 1187 - 1188 (2013). https://www.ncbi.nlm.nih.gov/pubmed/23701373
  34. Javanbakht, A. M., Pour, H. M. & Tarrahic, M. J. Effects of oral isotretinoin on serum folic acid levels. J. Drugs Dermatol. 11, e23 - 24 (2012). https://www.ncbi.nlm.nih.gov/pubmed/23135667
  35. Akturk, A. S. et al. Effects of isotretinoin on serum vitamin E levels in patients with acne. Int. J. Dermatol. 52, 363 - 366 (2013). https://www.ncbi.nlm.nih.gov/pubmed/23414163


Pregnancy and Accutane

  1. CDC. Epidemiologic Notes and Reports Isotretinoin -- A Newly Recognized Human Teratogen. Morbidity and Mortality Weekly Report 33, 171 - 173 (1986). https://www.cdc.gov/mmwr/preview/mmwrhtml/00000310.htm
  2. Hull, P. R. & D'Arcy, C. Acne, depression, and suicide. Dermatol Clin 23, 665 - 674 (2005). https://www.ncbi.nlm.nih.gov/pubmed/16112443
  3. Magin, P., Pond, D. & Smith, W. Isotretinoin, depression and suicide: a review of the evidence. Br. J. Gen. Pract. 55, 134 - 138 (2005). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1463189/
  4. Kaymak, Y., Taner, E. & Taner, Y. Comparison of depression, anxiety and life quality in acne vulgaris patients who were treated with either isotretinoin or topical agents. Int. J. Dermatol. 48, 41 - 46 (2009). https://www.ncbi.nlm.nih.gov/pubmed/19126049
  5. Henry, D. et al. Occurrence of pregnancy and pregnancy outcomes during isotretinoin therapy. CMAJ 188, 723 - 730 (2016). https://www.ncbi.nlm.nih.gov/pubmed/27114489
  6. Zomerdijk, I. M. et al. Isotretinoin exposure during pregnancy: a population-based study in The Netherlands. BMJ Open 4, e005602 (2014). https://www.ncbi.nlm.nih.gov/pubmed/25392022
  7. Berard, A. et al. Isotretinoin, pregnancies, abortions and birth defects: a population-based perspective. Br. J. Clin. Pharmacol. 63, 196 - 205 (2007). https://www.ncbi.nlm.nih.gov/pubmed/17214828
  8. Collins, M. K. et al. Compliance with pregnancy prevention measures during isotretinoin therapy. J. Am. Acad. Dermatol. 70, 55 - 59 (2014). https://www.ncbi.nlm.nih.gov/pubmed/24157382
  9. Shin, J. et al. The impact of the iPLEDGE program on isotretinoin fetal exposure in an integrated health care system. J. Am. Acad. Dermatol. 65, 1117 - 1125 (2011). https://www.ncbi.nlm.nih.gov/pubmed/21565419


Suicide and Depression

  1. Jacobs, D. G., Deutsch, N. L. & Brewer, M. Suicide, depression, and isotretinoin: is there a causal link? J. Am. Acad. Dermatol. 45, S168 - 175 (2001). https://www.ncbi.nlm.nih.gov/pubmed/11606949
  2. Jick, S. S., Kremers, H. M. & Vasilakis-Scaramozza, C. Isotretinoin use and risk of depression, psychotic symptoms, suicide, and attempted suicide. Arch. Dermatol. 136, 1231 - 1236 (2000). https://www.ncbi.nlm.nih.gov/pubmed/11030769
  3. Hull, P. R. & D'Arcy, C. Acne, depression, and suicide. Dermatol. Clin. 23, 665 - 674 (2005). https://www.ncbi.nlm.nih.gov/pubmed/16112443
  4. Magin, P., Pond, D. & Smith, W. Isotretinoin, depression and suicide: a review of the evidence. Br. J. Gen. Pract. 55, 134 - 138 (2005). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1463189/
  5. Kaymak, Y., Taner, E. & Taner, Y. Comparison of depression, anxiety and life quality in acne vulgaris patients who were treated with either isotretinoin or topical agents. Int. J. Dermatol. 48, 41 - 46 (2009). https://www.ncbi.nlm.nih.gov/pubmed/19126049
  6. Sundstrom, A. et al. Association of suicide attempts with acne and treatment with isotretinoin: retrospective Swedish cohort study. BMJ 341, c5812 (2010). https://www.bmj.com/content/341/bmj.c5812
  7. Chia, C. Y., Lane, W., Chibnall, J., Allen, A. & Siegfried, E. Isotretinoin therapy and mood changes in adolescents with moderate to severe acne: a cohort study. Arch. Dermatol. 141, 557 - 560 (2005). https://www.ncbi.nlm.nih.gov/pubmed/15897376
  8. Hersom, K., Neary, M. P., Levaux, H. P., Klaskala, W. & Strauss, J. S. Isotretinoin and antidepressant pharmacotherapy: a prescription sequence symmetry analysis. J. Am. Acad. Dermatol. 49, 424 - 432 (2003). https://www.ncbi.nlm.nih.gov/pubmed/12963905
  9. Ferahbas, A. et al. A pilot study evaluating anxiety and depressive scores in acne patients treated with isotretinoin. J. Dermatolog. Treat. 15, 153 - 157 (2004). https://www.ncbi.nlm.nih.gov/pubmed/15204147
  10. O'Reilly, K. C., Shumake, J., Gonzalez-Lima, F., Lane, M. A. & Bailey, S. J. Chronic administration of 13-cis- retinoic acid increases depression-related behavior in mice. Neuropsychopharmacology 31, 1919 - 1927 (2006). https://www.ncbi.nlm.nih.gov/pubmed/16395305
  11. Azoulay, L., Blais, L., Koren, G., LeLorier, J. & Berard, A. Isotretinoin and the risk of depression in patients with acne vulgaris: a case-crossover study. J. Clin. Psychiatry 69, 526 - 532 (2008). https://www.ncbi.nlm.nih.gov/pubmed/18363422
  12. Yesilova, Y., Bez, Y., Ari, M., Kaya, M. C. & Alpak, G. Effects of isotretinoin on obsessive compulsive symptoms, depression, and anxiety in patients with acne vulgaris. J. Dermatolog. Treat 23, 268 - 271 (2012). https://www.ncbi.nlm.nih.gov/pubmed/21815780
  13. Ergun, T. et al. Isotretinoin has no negative effect on attention, executive function and mood. J. Eur. Acad. Dermatol. Venereol. 26, 431 - 439 (2012). https://www.ncbi.nlm.nih.gov/pubmed/21545542
  14. Marron, S. E., Tomas-Aragones, L. & Boira, S. Anxiety, depression, quality of life and patient satisfaction in acne patients treated with oral isotretinoin. Acta Derm. Venereol. 93, 701 - 706 (2013). https://www.ncbi.nlm.nih.gov/pubmed/23727704
  15. Nevoralova, Z. & Dvorakova, D. Mood changes, depression and suicide risk during isotretinoin treatment: a prospective study. Int. J. Dermatol. 52, 163 - 168 (2013). https://www.ncbi.nlm.nih.gov/pubmed/23347302
  16. Yesilova, Y., Bez, Y., Ari, M. & Turan, E. Effects of isotretinoin on social anxiety and quality of life in patients with acne vulgaris: a prospective trial. Acta Dermatovenerol. Croat. 20, 80 - 83 (2012). https://www.ncbi.nlm.nih.gov/pubmed/22726279
  17. Cohen, J., Adams, S. & Patten, S. No association found between patients receiving isotretinoin for acne and the development of depression in a Canadian prospective cohort. Can. J. Clin. Pharmacol. 14, e227 - 233 (2007). https://www.ncbi.nlm.nih.gov/pubmed/17556790
  18. Wysowski, D. K., Pitts, M. & Beitz, J. Depression and suicide in patients treated with isotretinoin. N. Engl. J. Med. 344, 460 (2001). https://www.ncbi.nlm.nih.gov/pubmed/11221610
  19. Marqueling, A. L. & Zane, L. T. Depression and suicidal behavior in acne patients treated with isotretinoin: a systematic review. Semin. Cutan. Med. Surg. 26, 210 - 220 (2007). https://www.ncbi.nlm.nih.gov/pubmed/18395669
  20. Wysowski, D. K. & Beitz, J. Methodological limitations of the study Isotretinoin use and risk of depression, psychotic symptoms, suicide, and attempted suicide. Arch. Dermatol. 137, 1102 - 1103 (2001). https://www.ncbi.nlm.nih.gov/pubmed/11493109
  21. Strahan, J. E. & Raimer, S. Isotretinoin and the controversy of psychiatric adverse effects. Int. J. Dermatol. 45, 789 - 799 (2006). https://www.ncbi.nlm.nih.gov/pubmed/16863513
  22. Wysowski, D. K., Pitts, M. & Beitz, J. An analysis of reports of depression and suicide in patients treated with isotretinoin. J. Am. Acad. Dermatol. 45, 515 - 519 (2001). https://www.ncbi.nlm.nih.gov/pubmed/11568740
  23. Wolverton, S. E. & Harper, J. C. Important controversies associated with isotretinoin therapy for acne. Am. J. Clin. Dermatol. 14, 71 - 76 (2013). https://www.ncbi.nlm.nih.gov/pubmed/23559397
  24. Misery, L. et al. [Isotretinoin and adolescent depression]. Ann. Dermatol. Venereol. 139, 118 - 123 (2012). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804262/
  25. Thiboutot, D. & Zaenglein, A. Isotretinoin and affective disorders: thirty years later. J. Am. Acad. Dermatol. 68, 675 - 676 (2013). https://www.ncbi.nlm.nih.gov/pubmed/23522408


Take with a High Fat Meal

  1. Roche Laboratories, I. Accutane (isotretinoin) capsule, liquid filled https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=8655#section-13
  2. Colburn, W. A., Gibson, D. M., Wiens, R. E. & Hanigan, J. J. Food increases the bioavailability of isotretinoin. J. Clin. Pharmacol. 23, 534 - 539 (1983). https://www.ncbi.nlm.nih.gov/pubmed/6582073
  3. Webster, G. F., Leyden, J. J. & Gross, J. A. Comparative pharmacokinetic profiles of a novel isotretinoin formulation (isotretinoin-Lidose) and the innovator isotretinoin formulation: a randomized, 4-treatment, crossover study. J. Am. Acad. Dermatol. 69, 762 - 767 (2013). https://www.ncbi.nlm.nih.gov/pubmed/23953888
  4. ABSORICA [prescribing information]. (Ranbaxy Laboratories I., Jacksonville, FL, 2012). https://www.absorica.com/hcp/references/

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