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Accutane (isotretinoin)

Everything You Need to Know About Isotretinoin, Including User Reviews

Last updated: September 29, 2018

Article Summary

Accutane is the most well-known brand name of the oral medication known as isotretinoin. It is powerful, and for people with severe, widespread, deeply scarring acne, it can be a godsend. However, Accutane is like a nuclear option for acne. It affects the entire body and creates permanent changes to the body and the skin. Permanently changing your body is a huge decision and should not be entered into lightly. 

EXTREME CAUTION!: ACCUTANE (ISOTRETINOIN) CAUSES SEVERE BIRTH DEFECTS AND FETAL DEATH.

 
 

What Is Accutane?

Accutane (isotretinoin), or Roaccutane as it is known 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 Accutane is a systemic medication that affects every bodily system and can cause lifelong side effects to the user. Accutane need not be paired with other medications.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


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.

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.1-2

    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.

    Over the past 2 wk, how often have you been bothered by any of the following problems? Not at all Several days More than half the days Nearly every day
    1. Little interest or pleasure in doing things 0 1 2 3
    2. Feeling down, depressed, or hopeless 0 1 2 3
    3. Trouble falling or staying asleep, or sleeping too much 0 1 2 3
    4. Feeling tired or having little energy 0 1 2 3
    5. Poor appetite or overeating 0 1 2 3
    6. Feeling bad about yourself–or that you are a failure or have let yourself or your family down 0 1 2 3
    7. Trouble concentrating on things, such as reading the newspaper or watching television 0 1 2 3
    8. Moving or speaking so slowly that other people could have noticed? Or the opposite–being so fidgety or restless that you have been moving around a lot more than usual. 0 1 2 3
    9. Thoughts that you would be better off dead or of hurting yourself in some way 0 1 2 3


    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."

     







     

     

    The Experts at Acne.org

    Our team of medical doctors, biology & chemistry PhDs, and acne experts work hand-in-hand with Dan (Acne.org founder) to provide the most complete information on all things acne. If you find any errors in this article, kindly use this Feedback Form and let us know.

    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).
    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).
    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).
    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).
    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).
    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).
    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).
    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).
    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).
    10. Ellis, C. N. & Krach, K. J. Uses and complications of isotretinoin therapy. J. Am. Acad. Dermatol. 45, S150–157 (2001).
    11. Demircay, Z., Kus, S. & Sur, H. Predictive factors for acne flare during isotretinoin treatment. Eur. J. Dermatol. 18, 452–456 (2008).
    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).
    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).
    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).
    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).
    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).
    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).
    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).
    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).
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    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).
    2. Honein, M. A., Paulozzi, L. J. & Erickson, J. D. Continued occurrence of Accutane-exposed pregnancies. Teratology 64, 142–147 (2001).
    3. Brelsford, M. & Beute, T. C. Preventing and managing the side effects of isotretinoin. Semin. Cutan. Med. Surg. 27, 197–206 (2008).
    4. Berard, A. et al. Isotretinoin, pregnancies, abortions and birth defects: a population-based perspective. Br. J. Clin. Pharmacol. 63, 196–205 (2007).
    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).
    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).
    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).
    8. McLane, J. Analysis of common side effects of isotretinoin. J. Am. Acad. Dermatol. 45, S188–194 (2001).
    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).
    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).
    11. DiGiovanna, J. J. Isotretinoin effects on bone. J. Am. Acad. Dermatol. 45, S176–182 (2001).
    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).
    13. Eksioglu, E. et al. Sacroiliitis and polyneuropathy during isotretinoin treatment. Clin. Exp. Dermatol. 33, 122–124 (2008).
    14. De Francesco, V., Stinco, G. & Campanella, M. Acute arthritis during isotretinoin treatment for acne conglobata. Dermatology 194, 195 (1997).
    15. Bewley, A. P., Rankin, E. C., Levell, N. J. & Robinson, T. W. Isotretinoin causing acute aseptic arthropathy. Clin. Exp. Dermatol. 20, 279 (1995).
    16. Kaplan, G. & Haettich, B. Rheumatological symptoms due to retinoids. Baillieres Clin. Rheumatol. 5, 77–97 (1991).
    17. Hughes, R. A. Arthritis precipitated by isotretinoin treatment for acne vulgaris. J. Rheumatol. 20, 1241–1242 (1993).
    18. Lehucher Ceyrac, D. Acute arthritis after isotretinoin. Dermatology 198, 406–407 (1999).
    19. Kaymak, Y. Creatine phosphokinase values during isotretinoin treatment for acne. Int. J. Dermatol. 47, 398–401 (2008).
    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).
    21. Sundstrom, A. et al. Association of suicide attempts with acne and treatment with isotretinoin: retrospective Swedish cohort study. BMJ 341, c5812 (2010).
    22. Laroche, M. L., Macian-Montoro, F., Merle, L. & Vallat, J. M. Cerebral ischemia probably related to isotretinoin. Ann. Pharmacother. 41, 1073–1076 (2007).
    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).
    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).
    25. Ozdemir, M. A. et al. Isotretinoin-induced agranulocytosis. Pediatr. Dermatol. 24, 425–426 (2007).
    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).
    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).
    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).
    29. Neudorfer, M. et al. Ocular adverse effects of systemic treatment with isotretinoin. Arch. Dermatol. 148, 803–808 (2012).
    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).
    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).
    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).
    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).
    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).
    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).


    Pregnancy and Accutane

    1. CDC. Epidemiologic Notes and Reports Isotretinoin -- A Newly Recognized Human Teratogen. Morbidity and Mortality Weekly Report 33, 171–173 (1986).
    2. Hull, P. R. & D'Arcy, C. Acne, depression, and suicide. Dermatol Clin 23, 665–674 (2005).
    3. Magin, P., Pond, D. & Smith, W. Isotretinoin, depression and suicide: a review of the evidence. Br. J. Gen. Pract. 55, 134–138 (2005).
    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).
    5. Henry, D. et al. Occurrence of pregnancy and pregnancy outcomes during isotretinoin therapy. CMAJ 188, 723–730 (2016).
    6. Zomerdijk, I. M. et al. Isotretinoin exposure during pregnancy: a population-based study in The Netherlands. BMJ Open 4, e005602 (2014).
    7. Berard, A. et al. Isotretinoin, pregnancies, abortions and birth defects: a population-based perspective. Br. J. Clin. Pharmacol. 63, 196–205 (2007).
    8. Collins, M. K. et al. Compliance with pregnancy prevention measures during isotretinoin therapy. J. Am. Acad. Dermatol. 70, 55–59 (2014).
    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).


    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).
    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).
    3. Hull, P. R. & D'Arcy, C. Acne, depression, and suicide. Dermatol. Clin. 23, 665–674 (2005).
    4. Magin, P., Pond, D. & Smith, W. Isotretinoin, depression and suicide: a review of the evidence. Br. J. Gen. Pract. 55, 134–138 (2005).
    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).
    6. Sundstrom, A. et al. Association of suicide attempts with acne and treatment with isotretinoin: retrospective Swedish cohort study. BMJ 341, c5812 (2010).
    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).
    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).
    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).
    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).
    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).
    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).
    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).
    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).
    15. Nevoralova, Z. & Dvorakova, D. Mood changes, depression and suicide risk during isotretinoin treatment: a prospective study. Int. J. Dermatol. 52, 163–168 (2013).
    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).
    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).
    18. Wysowski, D. K., Pitts, M. & Beitz, J. Depression and suicide in patients treated with isotretinoin. N. Engl. J. Med. 344, 460 (2001).
    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).
    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).
    21. Strahan, J. E. & Raimer, S. Isotretinoin and the controversy of psychiatric adverse effects. Int. J. Dermatol. 45, 789–799 (2006).
    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).
    23. Wolverton, S. E. & Harper, J. C. Important controversies associated with isotretinoin therapy for acne. Am. J. Clin. Dermatol. 14, 71–76 (2013).
    24. Misery, L. et al. [Isotretinoin and adolescent depression]. Ann. Dermatol. Venereol. 139, 118–123 (2012).
    25. Thiboutot, D. & Zaenglein, A. Isotretinoin and affective disorders: thirty years later. J. Am. Acad. Dermatol. 68, 675–676 (2013).


    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).
    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).
    4. ABSORICA [prescribing information]. (Ranbaxy Laboratories I., Jacksonville, FL, 2012).

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