|Systematic (IUPAC) name|
|Licence data||US FDA:link|
|Pregnancy cat.||X (AU) X (US)|
|Legal status||Prescription Only (S4) (AU) POM (UK) ℞-only (US)|
|Excretion||Renal and fecal|
|CAS number||4759-48-2 |
|Mol. mass||300.44 g/mol|
| (what is this?) (verify)|
Isotretinoin, INN, ( /ˌaɪsoʊtrɨˈtɪnoʊ.ɨn/) is a medication used mostly for cystic acne. It is also a chemotherapy treatment used in brain, pancreatic and other cancers. It is used to treat harlequin-type ichthyosis, a usually lethal skin disease, and lamellar ichthyosis. Its effects are systemic and nonselective. It is a retinoid, meaning it is related to vitamin A, and is found in small quantities naturally in the body.
Isotretinoin's best-known and most dangerous side effect is birth defects. This is because of the molecule's close resemblance to retinoic acid, a natural vitamin A derivative which controls normal embryonic development. In the United States a special prodecure is required to obtain the pharmaceutical (see below).
In 2009, Roche decided to pull Accutane off the US market after juries had awarded millions of dollars in damages to former Accutane users over inflammatory bowel disease claims. Among others, actor James Marshall sued Roche over Accutane-related disease that resulted in removal of his colon.
The most common brands are Roaccutane (Hoffman-La Roche, known as Accutane in the United States before July 2009), Amnesteem (Mylan), Claravis (Barr), Isotroin (Cipla) or Sotret (Ranbaxy).
Due to side-effects and high cost, isotretinoin is used primarily for severe cystic acne and acne that has not responded to other treatments. Acne treatment usually begins with topical medications (e.g., benzoyl peroxide and adapalene), followed by oral antibiotics and isotretinoin as a last resort.
Isotretinoin's main indication is for the treatment of severe cystic acne vulgaris. Many dermatologists also support its use for treatment of lesser degrees of acne that prove resistant to other treatments, or that produce physical or psychological scarring.
It is also somewhat effective for hidradenitis suppurativa and some cases of severe acne rosacea. It can also be used to help treat harlequin ichthyosis, lamellar ichthyosis and is used in xeroderma pigmentosum cases to relieve keratoses. Isotretinoin has been used to treat the extremely rare condition fibrodysplasia ossificans progressiva. It is also used for treatment of neuroblastoma, a form of nerve cancer.
Isotretinoin therapy has furthermore proven effective against genital warts in experimental use, but is rarely used due to potentially severe side effects. In a small-scale study, low dose oral isotretinoin showed considerable efficacy; Isotretinoin may represent an efficacious and safe alternative systemic form of therapy for RCA of the cervix. Not many studies have been conducted to further confirm its effectiveness. In most countries this therapy is currently unapproved and only used if other therapies failed.
In the United Kingdom, this drug may be prescribed only by or under the supervision of a consultant dermatologist. Because severe cystic acne has the potential to cause permanent scarring over a short period, restrictions on its more immediate availability have proved contentious. Similar restrictions are common in most Australian states – in New South Wales and Victoria, for instance, the prescriber must be a Fellow of the Australasian College of Dermatologists (FACD). In New Zealand, isotretinoin can be prescribed by any doctor, but is subsidised only if prescribed by a vocationally registered general practitioner or dermatologist.
Since 1 March 2006, the dispensing of isotretinoin in the United States has been controlled by an FDA-mandated website called iPLEDGE – dermatologists are required to register their patients before prescribing and pharmacists are required to check the website before dispensing the drug. The prescription may not be dispensed until both parties have complied. A physician may not prescribe more than a 30-day supply. A new prescription may not be written for at least 30 days. Pharmacies are also under similar restriction. There is also a seven-day window between the time the prescription is written and the time the medication must be picked up at the pharmacy. If the original prescription is lost, or pick-up window is missed, the patient must requalify to have another prescription written. Doctors and pharmacists must also verify written prescriptions in an online system before patients may fill the prescription. Due to its teratogenic effects, women with the potential to bear children must commit to the use of two forms of contraception simultaneously for the duration of isotretinoin therapy, as well as for the month immediately preceding and the month immediately following therapy.
In Mexico, Colombia and Brazil use of the drug is restricted and an official identification and patient signature is required by the pharmacies.
The dose of isotretinoin patients receive is dependent on their weight and the severity of the condition. High-dose treatments are administered between 0.5 mg/kg/day to 2 mg/kg/day (usually at 0.5 to 1 mg/kg/day, divided into two doses), for a total treatment of four to six months. In some rare cases where the patient's acne is severe or unresponsive, the initial course may last up to nine months. A second course may be used at least eight weeks following the cessation of the initial course if severe acne recurs. Efficacy appears to be related to the cumulative dose of isotretinoin taken, with a total cumulative dose over each course of 120–150 mg/kg used as a guideline. Shorter, higher dose treatments or uninterrupted double courses should be used only as a last resort, due to adverse side effects.
Nearly all patients achieve initial clearing of acne during high-dose isotretinoin therapy. Furthermore, about 40% observe complete and long-term remission of the disease following one course of isotretinoin, while another 40% eventually develop less severe recurrent acne, which is treatable with less invasive medications. The remaining 20% relapse significantly enough to warrant an additional course of isotretinoin. Each additional course, however, has a higher probability of cure.
Lower-dosage treatments, such as 10–20 mg/day (approximately half the high dosage treatments above), are also highly effective, with greatly diminished side effects. However, such lower dosage courses may be associated with higher relapse rates, requiring additional courses, especially if not taken for sufficient time.
Isotretinoin is marketed under many brand names by various manufacturers. Some brands of oral isotretinoin include: Accure (Alphapharm), Accutane and Roaccutane (Roche), Aknenormin (Hermal), Amnesteem (Mylan), Ciscutan (Pelpharma), Claravis (Barr), Clarus (Prepharm), Isohexal (Hexal Australia), Istretinoin-A (Pharmathen), Isosupra (SMB Laboratories), Isotane (Pacific Pharmaceuticals), Isotroin (Cipla), Oratane (Douglas Pharmaceuticals), Atretin (Lafrancol), Nimegen (Medica Korea), Acnotin (Mega Lifesciences), Ruatine (United Pharmaceutical)and Sotret (Ranbaxy).
It is also available as a 0.05% topical preparation, marketed by Stiefel under the trade name Isotrex or Isotrexin (with erythromycin), Sotret Gel from Ranbaxy and Isotroin Gel from Cipla. In Russia Ретиноевая мазь 0.05% and 0.1%.
Increasingly higher dosages will result in higher toxicity, resembling vitamin A toxicity. Following are adverse drug reactions from Roches UK product information for Roaccutane as of October 2010.
The most common side effects are mucocutaneous and ocular in nature (i.e., cheilitis, ocular sicca, and decreased dark adaptation). It can also cause xerosis. Patients should be made aware of these side effects before taking isotretinoin and also that use of moisturizers and eye drops can help to mitigate them. Sometimes, however, the dose needs to be decreased to reduce the induction of side effects.
In a study from 2011, twenty male patients all developed heart hypertrophy and hypovolemia after 10 weeks of isotretinoin treatment with 0.5 mg/kg/day.
During a prospective study in Mexico that evaluated the efficacy and safety of isotretinoin in acne, six male patients reported difficulties in maintaining adequate penile erection, in addition to depression, suggesting a potential link between isotretinoin and risk of erectile dysfunction.
Research suggests vitamin E supplementation in the form of alpha-tocopherol reduces the toxicity of isotretinoin treatment in subjects with cancer and myelodysplastic syndrome. In contrast, a randomized study in 82 subjects taking isotretinoin (1 mg/kg/day) for acne vulgaris found no difference in the incidence or severity of side effects in the group taking an additional 800 IU/day of vitamin E in the form of d-l-alphatocopherol.
Permanent side effects
The following adverse effects have been reported to persist in some patients even after discontinuing therapy:
The U.S. Food and Drug Administration's (FDA) medication guide for Accutane states the drug "may stop long bone growth in teenagers who are still growing." Several reports state that premature epiphyseal closure can occur in acne patients receiving recommended doses of Accutane, and has been seen after only 5 months of treatment with a dose of 0.5 mg/kg in a 16 year old boy. In a retrospective cohort done in 2011, advanced bone age was observed in 29% of children who had received isotretinoin with an accumulative dose of 13440 mg/m² body surface area for treatment of neuroblastoma as compared to none in the group treated without isotretinoin. These effects are seen because isotretinoin like all retinoids (including excessive vitamin a intake) negatively impairs chondrogenesis (formation of new cartilage), with diminishing cartilage in the epiphyseal plate to ossify, growth slows down and subsequently stops when all remaining cartilage has been ossified. Since the age until complete ossification of bones normally varies between individuals (17–20 years for upper limbs, 18–23 years for lower limbs) and since many are prescribed Accutane in their late teens when growth still occurs, but has begun decelerating, there is a risk that deceleration of growth from use of isotretinoin is mistakenly seen as the normal deceleration of growth. It is also worth noting that stunted growth of long bones and other bones with epiphyseal plates that are not affecting an individuals height, for example the clavicles, scapula and sternum is almost impossible to detect since no measurements of these bones are done. The effect of multiple courses of Accutane on epiphyseal closure is unknown.
One study in 2007 also found a significant decrease of growth hormone (GH) levels from 0.9 mU/L to 0.3 mU/L after three months of isotretinoin treatment. And a study in 2010 found that isotretinoin treatment decreases insulin-like growth factor-1 (IGF-1) levels. IGF-1 is produced in the liver as response to growth hormone and is the primary mediator of GH.
Inflammatory bowel disease
Several scientific studies have posited isotretinoin as a possible cause of Crohn's disease and ulcerative colitis in some individuals. Several trials over inflammatory bowel disease claims have been held in the United States thus far, with many of them resulting in multimillion dollar judgments against the makers of isotretinoin. And in 2009 Roche decided to pull Accutane off the market, claiming at the time that the move was to stem the tide of Accutane lawsuits. As of January 2012, there were an additional 6,000 cases pending.
Teratogenicity (birth defects)
Isotretinoin is a teratogen and is highly likely to cause birth defects if taken during pregnancy. A few of the more common birth defects this drug can cause are hearing and visual impairment, missing or malformed earlobes, facial dysmorphism, and mental retardation. Isotretinoin is classified as FDA Pregnancy Category X and ADEC Category X, and use is contraindicated in pregnancy.
The manufacturer recommends pregnancy be excluded in female patients two weeks prior to commencement of isotretinoin, and they should use two simultaneous forms of effective contraception at least one month prior to commencement, during, and for at least one month following isotretinoin therapy.
In the U.S., more than 2,000 women have become pregnant while taking the drug between 1982 and 2003, with most pregnancies ending in abortion or miscarriage. About 160 babies with birth defects were born. As a consequence, the iPLEDGE program was introduced by the U.S. FDA on 12 August 2005 in an attempt to ensure female patients receiving isotretinoin do not become pregnant. As of 1 March 2006, only prescribers registered and activated in iPLEDGE are able to prescribe isotretinoin, and only patients registered and qualified in iPLEDGE will be able to have isotretinoin dispensed. This excludes women not of child-bearing age and men.
Patients receiving isotretinoin therapy are not permitted to donate blood during and for at least one month after discontinuation of therapy due to its teratogenicity.
Since the 1980s, scientific research has suggested a relationship between isotretinoin administration and the onset of psychological symptoms including depression, suicidal ideation, and psychosis. And several recent studies have shown a link between isotretinoin and clinical depression.
In a study in 2006, it was demonstrated for the first time that isotretinoin administration enhances depression-related behaviors in mice. The mechanism by which this occurs was not elucidated, although altered neuronal gene regulation and changes in hippocampal neurogenesis were thought to be involved.
Various case reports of depression, suicidal ideation, suicide attempt, and suicide in patients treated with isotretinoin have been reported to the U.S. FDA Adverse Events Reporting System, with 431 cases reported between 1982 and May 2001 – of these, 37 patients had committed suicide.
Studies have shown that patients with acne, the population group eligible to receive isotretinoin therapy, have an increased risk of clinical depression compared with the general population. Chee Hong describes isotretinoin-related depression as "an idiosyncratic side-effect", claiming, often anxiety can bring on acne and depression, creating more anxiety. Correspondingly, treatment of severe acne with isotretinoin has been shown to reduce anxiety and depression, for tests have shown acne to be a main depressant in most tested patients' lives.
Studies showing changes in brain
In 2004, two studies showed that Accutane in mice significantly reduces cell proliferation in the hippocampus and the subventricular zone, suppresses hippocampal neurogenesis, and severely disrupts the capacity of the mice to learn a spatial radial maze task.
In 2005, psychiatrist Dr. Doug Bremner found decreased orbitofrontal cortex function on brain imaging in patients treated with Accutane (isotretinoin). Bremner's study, which used positron emission tomography (PET), found that patients treated with isotretinoin experienced an average 21% decrease in orbifrontal-lobe brain activity. However, there were no changes in the depressive state of the patients that could be measured with the Hamilton depression scale. Bremner's findings have prompted members of the scientific community to call for more studies regarding isotretinion's links to depression and suicidal behavior.
In 2007, one in vitro study demonstrated that isotretinoin reduced available serotonin in synapses by increasing 5-HT1A receptors and serotonin transporter protein levels.
In 2008, a study showed that isotretinoin alters the morphology of serotonergic neurons in rats, which are thought to be associated with depressive symptoms.
In 2009, it was shown that isotretinoin given to mice alters metabolism in raphe nuclei and disrupts functional connectivity between the raphe nuclei and the hippocampal formation, which the researchers thought may contribute to the observed increase in depression-related behaviors.
in 2010, one in vitro study showed that isotretinoin lead to a decrease of hypothalamic cells and that it may contribute to the increased depression-related behaviors observed in mice given isotretinoin.
Mechanism of action
Isotretinoin's exact mechanism of action is unknown but several studies have shown that isotretinoin induces apoptosis (cell death) in various cells in the body such as cells in meibomian glands, hypothalamic cells, hippocampus cells and important for treatment of acne, in sebaceous gland cells.
One study found that isotretinoin significantly changed the expression of hundreds of genes in skin after 8 weeks of therapy.
Isotretinoin is also one of several drugs discussed in a recent study examining epigenetic side effects (for example DNA methylation) of common pharmaceuticals that leads to silencing of genes.
One study suggests the drug amplifies production of neutrophil-gelatinase-associated lipocalin (NGAL) in the skin, which has been shown to reduce sebum production by inducing apoptosis in sebaceous gland cells, while exhibiting an antimicrobial effect on Propionibacterium acnes. The drug decreases the size and sebum output of the sebaceous glands. Isotretinoin's combined impact on several of acne's contributory factors distinguishes it from alternative remedies, such as antibiotics, and accounts for its greater efficacy in severe, nodulocystic cases.
The effect on sebum production can be temporary and remission of the disease can be "complete and prolonged."
Isotretinoin has been speculated to down-regulate the telomerase enzyme and hTERT, inhibiting "cellular immortalization and tumorigenesis."
Isotretinoin has also been proved, according to a 2007 study, to inhibit the action of the metalloprotease MMP-9 (gelatinase) in sebum, without any influence in the action of TIMP1 and TIMP2 (tissue inhibitors of metalloproteases). It is already known that metalloprotases play an important role in the pathogenesis of acne, thus the inhibition of their action by isotretinoin is an additional mechanism of action that contributes to the efficacy of Isotretinoin.
Isotretinoin, when administered orally, is best absorbed when taken after a high-fat meal, as it has a high level of lipophilicity. In a crossover study, the peak plasma concentration was found to be more than doubled when taken after a high-fat meal versus a fasted condition. Isotretinoin is primarily (99.9%) bound to plasma proteins, mostly albumin. At least three metabolites have been detected in human plasma after oral administration: 4-oxo-isotretinoin, retinoic acid, and 4-oxo-retinoic acid. Isotretinoin also oxidizes, irreversibly, to 4-oxo-isotretinoin. The metabolites of isotretinoin are excreted through both urine and feces. The mean elimination half-life is 21 hours, with a standard deviation from this mean of 8.2 hours.
An early treatment of acne first used during the 1930s was high doses of the fat-soluble vitamin A (retinoic acid). At these dosage levels (sometimes 500,000 IU per day), sebum production is notably reduced, thwarting acne, but overly dry hair is a negative side effect, and such high doses can lead to vitamin A toxicity. Use of animal-based vitamin A at nutritive levels (where the upper limit dosage is 10,000 IU daily), taken over the course of a year, has also been shown to reduce acne.
Building on the discovery that vitamin A can inhibit sebum production at toxic dosages, the retinoic acid derivative isotretinoin (13-cis-retinoic acid) was developed in 1982 by Hoffmann-La Roche. Dr. Gary Peck is credited with discovering its use for the treatment of cystic acne, as well as disorders of keratinization, such as lamellar ichthyosis, Darier's disease, and pityriasis rubra pilaris. In addition, he demonstrated its chemopreventive properties in patients with basal cell nevus syndrome, also known as nevoid basal cell carcinoma syndrome and Gorlin's syndrome. In fact, within one year of attaining the U.S. patent for discovering the use of isotretinoin in the treatment of acne, he received the Inventor's Award from the US Department of Commerce and a Meritorious Service Medal from the US Public Health Services in 1983. In 2003, he was honored with The Discovery Award by the Dermatology Foundation in "recognition of extraordinary scientific accomplishments that have had a profound influence on the specialty of dermatology and have gained the respect and admiration of the world scientific community".
Dosage requirements of isotretinoin have been disputed. After a 1984 study funded by Roche, relatively high dosages of isotretinoin became mainstream in treatment in the United States. Lower dosages were found to be effective in treatment by independent research (see dosage section).
From the time of its introduction, the drug was known to have teratogenic potential, and pregnancies with the drug were strongly discouraged. When they occurred, they were found to have approximately 30% rates of congenital malformation, versus a 3–5% baseline risk. Beginning in 1998, prescriptions of the drug came under scrutiny, as fewer than half of prescribers were testing for pregnancy, usually relying on less-sensitive urine tests. On the grounds that pregnancies by women taking the drug had been underreported by the manufacturer between 1982 and 2000, and that, once generic manufacturers entered the market risk management was no longer centralized, the FDA instituted restrictions on prescribing and dispensing the drug, first with the "System to Manage Accutane Related Teratogenicity" (SMART) in 2000, and subsequently the iPLEDGE program in 2006. A retrospective cohort study recently found that pregnancy rates were quite high during the period (one per 30 women per year), and 84% of pregnancies were ended by induced abortion.
In February 2002, Roche's patents for isotretinoin expired, and there are now many other companies selling cheaper generic versions of the drug. On June 29, 2009, Roche Pharmaceuticals, the original creator and distributor of isotretinoin, officially discontinued both the manufacture and distribution of their Accutane brand in the United States due to what the company described as business reasons related to low market share (below 5%), coupled with the high cost of defending personal-injury lawsuits brought by some patients prescribed the drug. Generic isotretinoin will remain available in the United States through various manufacturers. Roche USA continues to defend Accutane and claims to have treated over 13 million patients since its introduction in 1982. F. Hoffmann-La Roche Ltd. apparently will continue to manufacture and distribute Roaccutane outside of the United States.
Isotretinoin is available over the internet from countries where it can be dispensed without a prescription. This presents a dilemma for acne sufferers residing in countries with highly regulated medical and pharmaceutical industries (FD&C Act), as private importation might violate existing statutes.
- ^ isotretinoin – Definitions from Dictionary.com
- ^ Feeley, Jef (2011-03-11). "Roche Accutane Acne Drug Caused 'Tragedy' for Actor, Brian Dennehy Says". Bloomberg. http://www.bloomberg.com/news/2011-03-10/roche-s-accutane-caused-tragedy-for-actor-brian-dennehy-says.html.
- ^ a b Rossi S (2006). Australian medicines handbook 2006. Adelaide, S. Aust: Australian Medicines Handbook Pty Ltd. ISBN 0-9757919-2-3.
- ^ a b c d Klasco RK, editor. Drugdex system, vol. 128. Greenwood Village (CO): Thomson Micromedex; 2006.
- ^ Strauss, J; Krowchuk, D; Leyden, J; Lucky, A; Shalita, A; Siegfried, E; Thiboutot, D; Vanvoorhees, A et al. (2007). "Guidelines of care for acne vulgaris management". Journal of the American Academy of Dermatology 56 (4): 651–63. doi:10.1016/j.jaad.2006.08.048. PMID 17276540.
- ^ Georgala, S; Katoulis, AC; Georgala, C; Bozi, E; Mortakis, A (2004). "Oral isotretinoin in the treatment of recalcitrant condylomata acuminata of the cervix: A randomised placebo controlled trial". Sexually Transmitted Infections 80 (3): 216–8. doi:10.1136/sti.2003.006841. PMC 1744851. PMID 15170007. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1744851/.
- ^ Sehgal, Virendra N.; Srivastava, Govind; Sardana, Kabir (2006). "Isotretinoin - unapproved indications/uses and dosage: A physician's reference". International Journal of Dermatology 45 (6): 772–7. doi:10.1111/j.1365-4632.2006.02830.x. PMID 16796650.
- ^ Joint Formulary Committee. British National Formulary. 47th ed. London: British Medical Association and Royal Pharmaceutical Society of Great Britain. ISBN 0-85369-584-9
- ^ James, Michael (1996). "Isotretinoin for severe acne". The Lancet 347 (9017): 1749–50. doi:10.1016/S0140-6736(96)90814-4. PMID 8656912.
- ^ Pharmaceutical Services Branch. Guide to poisons and therapeutic goods legislation for medical practitioners and dentists. Sydney: NSW Department of Health; 2006.
- ^ "iPledge (About iPledge)". https://www.ipledgeprogram.com/AboutiPLEDGE.aspx.
- ^ United States Pharmacopeia Staff. Consumer Reports Complete Drug Reference. Yonkers, NY: Consumer Reports Books, 1995. Pg 998.
- ^ a b James, William D. (2005). "Acne". New England Journal of Medicine 352 (14): 1463–72. doi:10.1056/NEJMcp033487. PMID 15814882.
- ^ Amichai, Boaz; Shemer, Avner; Grunwald, Marcelo H. (2006). "Low-dose isotretinoin in the treatment of acne vulgaris". Journal of the American Academy of Dermatology 54 (4): 644–6. doi:10.1016/j.jaad.2005.11.1061. PMID 16546586.
- ^ Seukeran, DC; Cunliffe, WJ (1998). "Acne vulgaris in the elderly: the response to low-dose isotretinoin". British Journal of Dermatology 139 (1): 99–101. doi:10.1046/j.1365-2133.1998.02321.x. PMID 9764156.
- ^ Shahidullah, Mohammed; Tham, Siew NEE; Goh, Chee-Leok (1994). "Isotretinoin therapy in acne vulgaris: a 10-year retrospective study in Singapore". International Journal of Dermatology 33 (1): 60–3. doi:10.1111/j.1365-4362.1994.tb01500.x. PMID 8112947.
- ^ Hermes, B.; Praetel, C.; Henz, B.M. (1998). "Medium dose isotretinoin for the treatment of acne". Journal of the European Academy of Dermatology and Venereology 11 (2): 117–21. doi:10.1111/j.1468-3083.1998.tb00763.x. PMID 9784036.
- ^ Lin, Ja-Liang; Shih, I-Hsin; Yu, Chun-Chen (1999). "Hemodialysis-Related Nodulocystic Acne Treated with Isotretinoin". Nephron 81 (2): 146–50. doi:10.1159/000045270. PMID 9933749.
- ^ Ertl, GA; Levine, N; Kligman, AM (1994). "A comparison of the efficacy of topical tretinoin and low-dose oral isotretinoin in rosacea". Archives of dermatology 130 (3): 319–24. doi:10.1001/archderm.130.3.319. PMID 8129410.
- ^ Connie L. Barnes, Angie L. Osborne. "Isotretinoin Uses and Effects". U.S. Pharmacist. Archived from the original on 2007-12-25. http://web.archive.org/web/20071225182847/http://www.uspharmacist.com/oldformat.asp?url=newlook/files/Feat/apr00iso.cfm&pub_id=8&article_id=508.
- ^ Zouboulis, Christos C. (2006). "The Truth behind This Undeniable Efficacy – Recurrence Rates and Relapse Risk Factors of Acne Treatment with Oral Isotretinoin". Dermatology 212 (2): 99–100. doi:10.1159/000090646. PMID 16484812.
- ^ Haryati, Indra; Jacinto, Sylvia S. (2005). "Profile of acne patients in the Philippines requiring a second course of oral isotretinoin". International Journal of Dermatology 44 (12): 999–1001. doi:10.1111/j.1365-4632.2005.02284.x. PMID 16409263.
- ^ Azoulay, L.; Oraichi, D.; Bérard, A. (2007). "Isotretinoin therapy and the incidence of acne relapse: A nested case–control study". British Journal of Dermatology 157 (6): 1240–8. doi:10.1111/j.1365-2133.2007.08250.x. PMID 17970803.
- ^ Layton, A.M.; Dréno, B.; Gollnick, H.; Mobaken, H.; Shear, N. (2009). "Isotretinoin therapy and the incidence of acne relapse: A nested case-control study". British Journal of Dermatology 160 (1): 217–8; author reply 218–9. doi:10.1111/j.1365-2133.2008.08935.x. PMID 19067687.
- ^ http://www.lakemedelsverket.se/upload/nyheter/2010/UK%20Roaccutan%20SPC%20Oct%202010.pdf
- ^ Scheinfeld, N; Bangalore, S (2006). "Facial edema induced by isotretinoin use: A case and a review of the side effects of isotretinoin". Journal of drugs in dermatology 5 (5): 467–8. PMID 16703787.
- ^ Soriano, Eline A.; Azevedo, Paula S.; Miot, Hélio A.; Minicucci, Marcos F.; Pansani, Mariele C.; Matsubara, Luiz S.; Okoshi, Katashi; Zornoff, Leonardo A.M. et al. (2011). "Cardiac remodeling induced by 13-cis retinoic acid treatment in acne patients". International Journal of Cardiology. doi:10.1016/j.ijcard.2011.05.048. PMID 21663986.
- ^ Tirado Sánchez, A; León Dorantes, G (2005). "Erectile dysfunction during isotretinoin therapy". Actas urologicas espanolas 29 (10): 974–6. PMID 16447596.
- ^ Dimery, IW; Hong, WK; Lee, JJ; Guillory-Perez, C; Pham, F; Fritsche Jr, HA; Lippman, SM (1997). "Phase I trial of alpha-tocopherol effects on 13-cis-retinoic acid toxicity". Annals of oncology 8 (1): 85–9. PMID 9093712. http://annonc.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=9093712.
- ^ Besa, Emmanuel C.; Abrahm, Janet L.; Bartholomew, Mary J.; Hyzinski, Martin; Nowell, Peter C. (1990). "Treatment with 13-cis-retinoic acid in transfusion-dependent patients with myelodysplastic syndrome and decreased toxicity with addition of alpha-tocopherol". The American Journal of Medicine 89 (6): 739–47. doi:10.1016/0002-9343(90)90215-Y. PMID 2252043.
- ^ Kus, Sadiye; Gun, Dilek; Demircay, Zeynep; Sur, Haydar (2005). "Vitamin E does not reduce the side-effects of isotretinoin in the treatment of acne vulgaris". International Journal of Dermatology 44 (3): 248–51. doi:10.1111/j.1365-4632.2004.02072.x. PMID 15807739.
- ^ Mollan, SP; Woodcock, M; Siddiqi, R; Huntbach, J; Good, P; Scott, RA (2006). "Does use of isotretinoin rule out a career in flying?". The British journal of ophthalmology 90 (8): 957–9. doi:10.1136/bjo.2006.092833. PMC 1857209. PMID 16723361. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1857209/.
- ^ a b Fraunfelder, FT; Fraunfelder, FW; Edwards, R (2001). "Ocular side effects possibly associated with isotretinoin usage". American journal of ophthalmology 132 (3): 299–305. doi:10.1016/S0002-9394(01)01024-8. PMID 11530040.
- ^ Pittsley, Richard A.; Yoder, Frank W. (1983). "Retinoid Hyperostosis". New England Journal of Medicine 308 (17): 1012–4. doi:10.1056/NEJM198304283081707. PMID 6403861.
- ^ Pennes, DR; Ellis, CN; Madison, KC; Voorhees, JJ; Martel, W (1984). "Early skeletal hyperostoses secondary to 13-cis-retinoic acid". American Journal of Roentgenology 142 (5): 979–83. PMID 6609585.
- ^ Tangrea, JA; Kilcoyne, RF; Taylor, PR; Helsel, WE; Adrianza, ME; Hartman, AM; Edwards, BK; Peck, GL (1992). "Skeletal hyperostosis in patients receiving chronic, very-low-dose isotretinoin". Archives of dermatology 128 (7): 921–5. doi:10.1001/archderm.1992.01680170053004. PMID 1626958.
- ^ Novick, Nelson Lee; Lawson, William; Schwartz, Ira S. (1984). "Bilateral nasal bone osteophytosis associated with short-term oral isotretinoin therapy for cystic acne vulgaris". The American Journal of Medicine 77 (4): 736–9. doi:10.1016/0002-9343(84)90376-0. PMID 6237578.
- ^ Ginarte, M; Peteiro, C; Toribio, J (1999). "Keloid formation induced by isotretinoin therapy". International Journal of Dermatology 38 (3): 228–9. PMID 10208624.
- ^ a b Lambert, Robert W.; Smith, Ronald E. (1989). "Effects of 13-Cis-Retinoic Acid on the Hamster Meibomian Gland". Journal of Investigative Dermatology 92 (3): 321–5. doi:10.1111/1523-1747.ep12277122. PMID 2918239.
- ^ a b Kremer, Israel; Gaton, Dan D.; David, Michael; Gaton, Edith; Shapiro, Amiram (1994). "Toxic Effects of Systemic Retinoids on Meibomian Glands". Ophthalmic Research 26 (2): 124–8. doi:10.1159/000267402. PMID 8196934.
- ^ a b Nelson, Amanda M; Gilliland, Kathryn L; Cong, Zhaoyuan; Thiboutot, Diane M (2006). "13-cis Retinoic Acid Induces Apoptosis and Cell Cycle Arrest in Human SEB-1 Sebocytes". Journal of Investigative Dermatology 126 (10): 2178–89. doi:10.1038/sj.jid.5700289. PMID 16575387.
- ^ a b Nelson, A.M.; Cong, Z.; Gilliland, K.L.; Thiboutot, D.M. (2011). "TRAIL contributes to the apoptotic effect of 13-cis retinoic acid in human sebaceous gland cells". British Journal of Dermatology 165 (3): 526–33. doi:10.1111/j.1365-2133.2011.10392.x. PMC 3166444. PMID 21564055. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3166444/.
- ^ label. (PDF) . Retrieved on 2010-11-13.
- ^ Milstone, LM; McGuire, J; Ablow, RC (1982). "Premature epiphyseal closure in a child receiving oral 13-cis-retinoic acid". Journal of the American Academy of Dermatology 7 (5): 663–6. doi:10.1016/S0190-9622(82)70148-3. PMID 6958690.
- ^ Lawson, Jack P.; McGuire, Joseph (1987). "The spectrum of skeletal changes associated with long-term administration of 13-cis-retinoic acid". Skeletal Radiology 16 (2): 91–7. doi:10.1007/BF00367754. PMID 3107131.
- ^ Marini, JC; Hill, S; Zasloff, MA (1988). "Dense metaphyseal bands and growth arrest associated with isotretinoin therapy". American journal of diseases of children 142 (3): 316–8. PMID 3422785.
- ^ David, M; Hodak, E; Lowe, NJ (1988). "Adverse effects of retinoids". Medical toxicology and adverse drug experience 3 (4): 273–88. PMID 3054426.
- ^ Montag, M; Reiser, M; Hamm, H; Traupe, H; Vogt, HJ (1988). "Skeletal changes following long-term treatment with retinoids". Der Radiologe 28 (7): 320–5. PMID 3045876.
- ^ Török, L; Galuska, L; Kása, M; Kádár, L (1989). "Bone-scintigraphic examinations in patients treated with retinoids: a prospective study". The British journal of dermatology 120 (1): 31–6. doi:10.1111/j.1365-2133.1989.tb07762.x. PMID 2534736.
- ^ Orfanos, CE (1989). "Retinoide: der neue Stand. Erhaltungstherapie, Resorptionsstörungen bei 'non-responders', Interaktionen und Interferenzen mit Medikamenten, Behandlung von Kindern und Knochentoxizität, Acitretin und 13-cis-Acitretin [Retinoids: the new status. Maintenance therapy, disorders of resorption in 'non-responders', interactions and interferences with drugs, treatment of children and bone toxicity, acitetin and 13-cis-acitretin]" (in German). Hautarzt 40 (3): 123–9. PMID 2523875.
- ^ Standeven, AM; Davies, PJ; Chandraratna, RA; Mader, DR; Johnson, AT; Thomazy, VA (1996). "Retinoid-induced epiphyseal plate closure in guinea pigs". Fundamental and applied toxicology 34 (1): 91–8. doi:10.1006/faat.1996.0179. PMID 8937896.
- ^ Steele, RG; Lugg, P; Richardson, M (1999). "Premature epiphyseal closure secondary to single-course vitamin A therapy". The Australian and New Zealand journal of surgery 69 (11): 825–7. PMID 10553976.
- ^ Digiovanna, JJ (2001). "Isotretinoin effects on bone". Journal of the American Academy of Dermatology 45 (5): S176–82. doi:10.1067/mjd.2001.113721. PMID 11606950.
- ^ Luthi, François; Eggel, Yan; Theumann, Nicolas (2011). "Premature epiphyseal closure in an adolescent treated by retinoids for acne: An unusual cause of anterior knee pain". Joint Bone spine. doi:10.1016/j.jbspin.2011.11.001. PMID 22154700.
- ^ Hobbie, Wendy L.; Mostoufi-Moab, Sogol; Carlson, Claire A.; Gruccio, Denise; Ginsberg, Jill P. (2011). "Prevalence of advanced bone age in a cohort of patients who received cis-retinoic acid for high-risk neuroblastoma". Pediatric Blood & Cancer 56 (3): 474–6. doi:10.1002/pbc.22839. PMID 21072832.
- ^ De Luca, F.; Uyeda, JA; Mericq, V; Mancilla, EE; Yanovski, JA; Barnes, KM; Zile, MH; Baron, J (2000). "Retinoic Acid is a Potent Regulator of Growth Plate Chondrogenesis". Endocrinology 141 (1): 346–53. doi:10.1210/en.141.1.346. PMID 10614657.
- ^ Student Investigation 6.1. Predicting Height from the Length of Limb Bones
- ^ Heliövaara, Maikki K.; Remitz, Anita; Reitamo, Sakari; Teppo, Anna-Maija; Karonen, Sirkka-Liisa; Ebeling, Pertti (2007). "13-cis-Retinoic acid therapy induces insulin resistance, regulates inflammatory parameters, and paradoxically increases serum adiponectin concentration". Metabolism 56 (6): 786–91. doi:10.1016/j.metabol.2007.02.002. PMID 17512311.
- ^ Karadag, A.S.; Ertugrul, D.T.; Tutal, E.; Akin, K.O. (2009). "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?". British Journal of Dermatology 162 (4): 798–802. doi:10.1111/j.1365-2133.2009.09618.x. PMID 20128787.
- ^ Feily, A; Namazi, MR (2011). "Decrease of insulin growth factor-1 as a novel mechanism for anti-androgen effect of isotretinoin and its reported association with depression in some cases". Journal of drugs in dermatology 10 (7): 793–4. PMID 21720662.
- ^ Crockett, Seth D; Porter, Carol Q; Martin, Christopher F; Sandler, Robert S; Kappelman, Michael D (2010). "Isotretinoin Use and the Risk of Inflammatory Bowel Disease: A Case–Control Study". The American Journal of Gastroenterology 105 (9): 1986–93. doi:10.1038/ajg.2010.124. PMC 3073620. PMID 20354506. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3073620/.
- ^ Reddy, Deepa; Siegel, Corey A.; Sands, Bruce E.; Kane, Sunanda (2006). "Possible Association Between Isotretinoin and Inflammatory Bowel Disease". The American Journal of Gastroenterology 101 (7): 1569–73. doi:10.1111/j.1572-0241.2006.00632.x. PMID 16863562.
- ^ Passier, JL; Srivastava, N; Van Puijenbroek, EP (2006). "Isotretinoin-induced inflammatory bowel disease". The Netherlands Journal of Medicine 64 (2): 52–4. PMID 16517990. http://www.njmonline.nl/njm/getarticle.php?v=64&i=2&p=52.
- ^ Borobio, E; Arín, A; Valcayo, A; Iñarrairaegui, M; Nantes, O; Prieto, C (2004). "Isotretinoína y colitis ulcerosa [Isotretinoin and ulcerous colitis]" (in Spanish). Anales del Sistema Sanitario de Navarra 27 (2): 241–3. doi:10.4321/S1137-66272004000300009. PMID 15381956.
- ^ Reniers, Denise E; Howard, John M (2001). "Isotretinoin-Induced Inflammatory Bowel Disease in an Adolescent". The Annals of Pharmacotherapy 35 (10): 1214–6. doi:10.1345/aph.10368. PMID 11675849.
- ^ Voreacos, David (May 30, 2007). "Roche Found Liable in First Of 400 Suits Over Accutane". The Washington Post. Bloomberg News. http://www.washingtonpost.com/wp-dyn/content/article/2007/05/29/AR2007052901946.html. Retrieved April 30, 2012.
- ^ Tesoriero, Heather Won (April 23, 2008). "Jury Awards $10.5 Million Over Accutane". The Wall Street Journal. http://online.wsj.com/article/SB120890352155036159.html. Retrieved April 30, 2012.
- ^ http://www.lawyersandsettlements.com/articles/accutane-inflammatory-bowel-disease-ibd/accutane-inflammatory-bowel-disease-ibd-35-16353.html
- ^ http://accutanecrohns-disease.com/2012/01/history-mass-tort-accutane-lawyers/
- ^ Roche Products Pty Ltd. Roaccutane (Australian Approved Product Information). Dee Why (NSW): Roche; 2005.
- ^ BNF, edition 57
- ^ a b O'Reilly, Kally C; Shumake, Jason; Gonzalez-Lima, F; Lane, Michelle A; Bailey, Sarah J (2006). "Chronic Administration of 13-Cis-Retinoic Acid Increases Depression-Related Behavior in Mice". Neuropsychopharmacology 31 (9): 1919–27. doi:10.1038/sj.npp.1300998. PMID 16395305.
- ^ O'Donnell, James (2003). "Overview of Existing Research and Information Linking Isotretinoin (Accutane), Depression, Psychosis, and Suicide". American Journal of Therapeutics 10 (2): 148–59. doi:10.1097/00045391-200303000-00012. PMID 12629595.
- ^ Bremner, J. Douglas (2003). "Does isotretinoin cause depression and suicide?" (PDF). Psychopharmacol Bull 37 (1): 64–78. PMID 14561949. http://www.roaccutaneaction.com/Studies/2003_Bremner.pdf.
- ^ Wysowski, Diane K.; Pitts, Marilyn; Beitz, Julie (2001). "An analysis of reports of depression and suicide in patients treated with isotretinoin". Journal of the American Academy of Dermatology 45 (4): 515–9. doi:10.1067/mjd.2001.117730. PMID 11568740.
- ^ Gupta, MA; Gupta, AK (1998). "Depression and suicidal ideation in dermatology patients with acne, alopecia areata, atopic dermatitis and psoriasis". British Journal of Dermatology 139 (5): 846–50. doi:10.1046/j.1365-2133.1998.02511.x. PMID 9892952.
- ^ Niemeier, V.; Kupfer, J.; Demmelbauer-Ebner, M.; Stangier, U.; Effendy, I.; Gieler, U. (1998). "Coping with Acne vulgaris". Dermatology 196 (1): 108–15. doi:10.1159/000017842. PMID 9557243.
- ^ Hong Ng, Chee; Schweitzer, Isaac (2003). "The association between depression and isotretinoin use in acne". Australian and New Zealand Journal of Psychiatry 37 (1): 78–84. doi:10.1046/j.1440-1614.2003.01111.x. PMID 12534661.
- ^ Rubinow, David R.; Peck, Gary L.; Squillace, Kathleen M.; Gantt, Gail G. (1987). "Reduced anxiety and depression in cystic acne patients after successful treatment with oral isotretinoin". Journal of the American Academy of Dermatology 17 (1): 25–32. doi:10.1016/S0190-9622(87)70166-2. PMID 2956296.
- ^ Chia, C. Y.; Lane, W; Chibnall, J; Allen, A; Siegfried, E (2005). "Isotretinoin Therapy and Mood Changes in Adolescents with Moderate to Severe Acne: A Cohort Study". Archives of Dermatology 141 (5): 557–60. doi:10.1001/archderm.141.5.557. PMID 15897376.
- ^ a b Sakai, Yasuo; Crandall, James E.; Brodsky, Jacob; McCaffery, Peter (2004). "13-cisRetinoic Acid (Accutane) Suppresses Hippocampal Cell Survival in Mice". Annals of the New York Academy of Sciences 1021: 436–40. Bibcode 2004NYASA1021..436S. doi:10.1196/annals.1308.059. PMID 15251924.
- ^ a b Crandall, James; Sakai, Yasuo; Zhang, Jinghua; Koul, Omanand; Mineur, Yann; McCaffery, Peter; Dowling, John E. (2004). "13-cis-Retinoic Acid Suppresses Hippocampal Cell Division and Hippocampal-Dependent Learning in Mice". Proceedings of the National Academy of Sciences 101 (14): 5111–6. Bibcode 2004PNAS..101.5111C. doi:10.1073/pnas.0306336101. JSTOR 3371827. PMC 387382. PMID 15051884. //www.ncbi.nlm.nih.gov/pmc/articles/PMC387382/.
- ^ Bremner, J. D.; Fani, N; Ashraf, A; Votaw, JR; Brummer, ME; Cummins, T; Vaccarino, V; Goodman, MM et al. (2005). "Functional Brain Imaging Alterations in Acne Patients Treated with Isotretinoin". American Journal of Psychiatry 162 (5): 983–91. doi:10.1176/appi.ajp.162.5.983. PMID 15863802.
- ^ O'Reilly, K. C.; Trent, S.; Bailey, S. J.; Lane, M. A. (2007). "13-cis-Retinoic Acid Alters Intracellular Serotonin, Increases 5-HT1A Receptor, and Serotonin Reuptake Transporter Levels in Vitro". Experimental Biology and Medicine 232 (9): 1195–203. doi:10.3181/0703-RM-83. PMID 17895527.
- ^ Ishikawa, Junko; Sutoh, Chihiro; Ishikawa, Akinori; Kagechika, Hiroyuki; Hirano, Hitoshi; Nakamura, Shoji (2008). "13-cis-retinoic acid alters the cellular morphology of slice-cultured serotonergic neurons in the rat". European Journal of Neuroscience 27 (9): 2363–72. doi:10.1111/j.1460-9568.2008.06191.x. PMID 18445226.
- ^ O'Reilly, Kally C.; Shumake, Jason; Bailey, Sarah J.; Gonzalez-Lima, F.; Lane, Michelle A. (2009). "Chronic 13-cis-retinoic acid administration disrupts network interactions between the raphe nuclei and the hippocampal system in young adult mice". European Journal of Pharmacology 605 (1–3): 68–77. doi:10.1016/j.ejphar.2008.12.037. PMID 19168052.
- ^ a b Griffin, Jennifer N.; Pinali, Daniel; Olds, Kaylan; Lu, Na; Appleby, Lindsay; Doan, Louis; Lane, Michelle A. (2010). "13-Cis-retinoic acid decreases hypothalamic cell number in vitro". Neuroscience Research 68 (3): 185–90. doi:10.1016/j.neures.2010.08.003. PMID 20708044.
- ^ Nelson, Amanda M; Zhao, Wei; Gilliland, Kathryn L; Zaenglein, Andrea L; Liu, Wenlei; Thiboutot, Diane M (2009). "Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action". Dermato-endocrinology 1 (3): 177–87. doi:10.4161/derm.1.3.8258. PMC 2835911. PMID 20436886. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2835911/.
- ^ Csoka, AB; Szyf, M (2009). "Epigenetic side-effects of common pharmaceuticals: a potential new field in medicine and pharmacology". Medical hypotheses 73 (5): 770–80. doi:10.1016/j.mehy.2008.10.039. PMID 19501473.
- ^ Wachter, Kerri (2009). "Isotretinoin's Mechanism of Action Explored". Skin & Allergy News 40 (11): 32. doi:10.1016/S0037-6337(09)70553-4.
- ^ Isotretinoin’s Mechanism of Action Elucidated. Medconnect (2009-08-28). Retrieved on 2010-11-13.
- ^ Nelson, Amanda M.; Zhao, Wei; Gilliland, Kathryn L.; Zaenglein, Andrea L.; Liu, Wenlei; Thiboutot, Diane M. (2008). "Neutrophil gelatinase–associated lipocalin mediates 13-cis retinoic acid–induced apoptosis of human sebaceous gland cells". Journal of Clinical Investigation 118 (4): 1468–78. doi:10.1172/JCI33869. PMC 2262030. PMID 18317594. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2262030/.
- ^ a b Peck, Gary L.; Olsen, Thomas G.; Yoder, Frank W.; Strauss, John S.; Downing, Donald T.; Pandya, Mangala; Butkus, Danute; Arnaud-Battandier, Jeanne (1979). "Prolonged Remissions of Cystic and Conglobate Acne with 13-cis-Retinoic Acid". New England Journal of Medicine 300 (7): 329–33. doi:10.1056/NEJM197902153000701. PMID 153472.
- ^ Roche Laboratories (September 2007). "Accutane (Isotretinoin Capsules)". FDA-Approved Official Product Label (U.S. Food and Drug Administration) NDA 018-662 S-058. http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/018662s060lbl.pdf. Retrieved 05/02/2011.
- ^ Farrell, Lawrence N.; Strauss, John S.; Stranieri, Anna M. (1980). "The treatment of severe cystic acne with 13-cis-retinoic acidEvaluation of sebum production and the clinical response in a multiple-dose trial". Journal of the American Academy of Dermatology 3 (6): 602–11. doi:10.1016/S0190-9622(80)80074-0. PMID 6451637.
- ^ Jones, H; Blanc, D; Cunliffe, WJ (1980). "13-Cis Retinoic Acid and Acne". The Lancet 316 (8203): 1048–9. doi:10.1016/S0140-6736(80)92273-4. PMID 6107678.
- ^ Pendino, Frédéric; Flexor, Maria; Delhommeau, François; Buet, Dorothée; Lanotte, Michel; Ségal-Bendirdjian, Evelyne (2001). "Retinoids Down-Regulate Telomerase and Telomere Length in a Pathway Distinct from Leukemia Cell Differentiation". Proceedings of the National Academy of Sciences 98 (12): 6662–7. Bibcode 2001PNAS...98.6662P. doi:10.1073/pnas.111464998. JSTOR 3055868. PMC 34517. PMID 11371621. //www.ncbi.nlm.nih.gov/pmc/articles/PMC34517/.
- ^ Φαχαντίδης, Παναγιώτης Ε. (2007). "Η επίδραση της ισοτρετινοϊνης και των αναστολέων της 5α-αναγωγάσης στις μεταλλοπρωτεάσες του συνδετικού ιστού σε ασθενείς με ακμή [The influence of isotretinoin and 5-a reductase inhibitors in metaloproteases of connective tissue in patients with ance]" (in Greek). Aristotle University of Thessaloniki. http://invenio.lib.auth.gr/record/103970.
- ^ Toyoda, M.; Nakamura, M.; Makino, T.; Kagoura, M.; Morohashi, M. (2002). "Sebaceous glands in acne patients express high levels of neutral endopeptidase". Experimental Dermatology 11 (3): 241–7. doi:10.1034/j.1600-0625.2002.110307.x. PMID 12102663.
- ^ a b Bérard, A; Azoulay, L; Koren, G; Blais, L; Perreault, S; Oraichi, D (2007). "Isotretinoin, pregnancies, abortions and birth defects: a population-based perspective". British Journal of Clinical Pharmacology 63 (2): 196–205. doi:10.1111/j.1365-2125.2006.02837.x. PMC 1859978. PMID 17214828. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1859978/.
- ^ Holmes, SC; Bankowska, U; MacKie, RM (1998). "The prescription of isotretinoin to women: is every precaution taken?". British Journal of Dermatology 138 (3): 450–5. doi:10.1046/j.1365-2133.1998.02123.x. PMID 9580798.
- ^ "Roche Discontinues and Plans to Delist Accutane in the U.S." (Press release). Genentech. June 29, 2009. http://www.gene.com/gene/products/information/accutane/. Retrieved November 12, 2010.