Isotretinoin
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Clinical data | |
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Pronunciation | See note at tretinoin |
Trade names | Accutane, Roaccutane, others[1] |
AHFS/Drugs.com | Monograph |
MedlinePlus | a681043 |
License data |
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Pregnancy category |
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Routes of administration | By mouth, topical |
ATC code | |
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Pharmacokinetic data | |
Bioavailability | Variable |
Protein binding | 99.9% |
Metabolism | Liver |
Elimination half-life | 10–20 hours |
Excretion | Kidney and feces |
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Isotretinoin, also known as 13-cis-retinoic acid and sold under the brand name Accutane among others, is a medication used to prevent certain skin cancers such as squamous-cell carcinoma and to treat skin diseases like harlequin-type ichthyosis, and lamellar ichthyosis, and severe cystic acne or moderate acne that is unresponsive to antibiotics.[6]: 33 It is a retinoid, meaning it is related to vitamin A, and is found in small quantities naturally in the body. Its isomer, tretinoin, is also an acne drug.
The most common adverse effects are dry lips (
Isotretinoin was patented in 1969 and approved for medical use in 1982.[9] In 2021, it was the 264th most commonly prescribed medication in the United States, with more than 1 million prescriptions.[10][11]
Medical uses
Isotretinoin is used primarily for persistent cystic acne.[12][13][14][15] 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.[16] Isotretinoin is not indicated for treatment of prepubertal acne and is not recommended in children less than 12 years of age.[17]
It is also somewhat effective for
Isotretinoin therapy has furthermore proven effective against
Prescribing restrictions
Isotretinoin is a
In the United States, since March 2006, the dispensing of isotretinoin is run through a website called
In most countries, isotretinoin can only be prescribed by dermatologists or specialist physicians; some countries also allow limited prescription by general practitioners and family doctors. In the United Kingdom
Adverse effects
Increasingly higher dosages will result in higher toxicity, resembling
According to information leaflets[31] | According to studies | |||||
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Type of disorders |
Very common (≥ 1/10) |
Common (≥ 1/100, < 1/10) |
Rare (≥ 1/10 000,< 1/1000) |
Very rare (≤ 1/10 000) |
Unknown Frequency | Frequency |
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Blood and lymphatic system |
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Immune system |
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Psychiatric
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Psychiatric: 25.15%[32] | |||
Nervous system |
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Eye |
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Ear |
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Vascular
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Respiratory, thoracic and |
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Gastrointestinal
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Hepatobiliary
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Skin and
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100%[32] | ||
Musculo-skeletal and |
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and tendons)
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urinary
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Reproductive system and breast disorders |
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General |
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Investigation[clarification needed] |
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Possible permanent effects
The effects of isotretinoin are predominantly permanent. This has been proposed to be due to induction of apoptosis in sebaceous glands, meibomian glands, neuroblastoma cells, hypothalamic cells, hippocampus cells, Dalton's lymphoma ascites cells, B16F-10 melanoma cells, neuronal crest cells, stem cells and others,[33] that it changes epigenetics[34] and shortens telomeres.[35]
Isotretinoin may stop
Isotretinoin is known to cause
Sexual
Isotretinoin is also associated with permanent sexual side effects, namely erectile dysfunction and reduced libido.[45] In October 2017, the UK MHRA issued a Drug Safety Update to physicians in response to reports of these problems.[46] This was in response to an EU review, published in August 2017, which states that a plausible physiological explanation of these side effects "may be a reduction in plasma testosterone".[17] The review also stated that "the product information should be updated to include ‘sexual dysfunction including erectile dysfunction and decreased libido’ as an undesirable effect with an unknown frequency".[47] There have also been reports of spermatogenesis disorders, such as oligospermia. 27 cases of sexual dysfunction report either negative dechallenge or positive dechallenge.[clarification needed][17]
Skin
The most common side effects are mucocutaneous: dry lips, skin and nose. Other common mucocutaneous side effects are inflammation and chapping of the lips (cheilitis), redness of the skin (erythema), rashes, peeling, eczema (dermatitis), itching (pruritus) and nose bleeds (epistaxis).[48] Absence of dryness of the lips is considered an indication of non-compliance with treatment (not taking the drug as advised), as it occurs in almost all people who take it.[48]
Regular use of lip balm and moisturizer is recommended throughout a course of treatment to reduce these problems. The dose may need to be decreased to reduce the severity of these side effects.[49] The skin becomes more fragile—especially to frictional forces—and may not heal as quickly as normal. Wound healing is delayed. For this reason, elective surgery, waxing of hair, tattooing, tattoo removal, piercings, dermabrasion, exfoliation, etc., are not recommended. Treatment of acne scars is generally deferred until 12 months after completion of a course of isotretinoin.
Teratogenicity
Isotretinoin is a
The manufacturer recommends pregnancy be ruled out two weeks prior to commencement of isotretinoin, and women 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.[51]
In the US, around 2000 women became pregnant while taking the drug between 1982 and 2000, with most pregnancies ending in abortion or miscarriage. About 160 babies with birth defects were born. After the FDA put the more strict iPLEDGE program in place for the companies marketing the drug in the US, in 2011, 155 pregnancies occurred (0.12%) among 129,544 women of childbearing potential taking isotrentinoin.[52]
People taking isotretinoin are not permitted to donate blood during and for at least one month after discontinuation of therapy due to its teratogenicity.[53]
Psychological effects
Rare psychological side effects may include depression, worsening of pre-existing depression, aggressive tendencies, irritable mood and anxiety. Very rare effects include abnormal behaviour, psychosis, suicidal ideation, suicide attempts and suicide.[14][54][55][56] In a total of 5577 adverse reactions reported to the UK's MHRA up to 31 March 2017, the plurality (1207, or 22%) concerned psychiatric effects.[57] There were 85 reports of suicidal ideation, 56 of suicide and 43 of suicide attempts.[57]
Isotretinoin decreases the brain metabolism in the orbitofrontal cortex an average of 21%, a brain area known to mediate symptoms of depression.[58]
The association between isotretinoin use and psychopathology has been controversial. Beginning in 1983, isolated case reports emerged suggesting mood change, particularly depression, occurring during or soon after isotretinoin use.[59] A number of studies have been conducted since then of the drug's effect on depression, psychosis, suicidal thoughts and other psychological effects.[59]
Depression and suicidality
Isotretinoin is the only non-psychiatric drug on the FDA's top 10 list of drugs associated with depression[55][60] and is also within the top 10 for suicide attempts.[61] A black box warning for suicide, depression and psychosis has been present on isotretinoin's packaging in the United States since 2005.[60] In March 2018, European Medicines Agency issued a warning on a possible risk of neuropsychiatric disorders (such as depression, anxiety and mood changes) following the use of oral retinoids, including isotretinoin, though the limitations of the available data did not allow them to clearly establish whether this risk was due to the use of retinoids.[50]
A Swedish retrospective cohort study with 5756 patients showed a significantly increased risk of attempted suicides from 6 months after the treatment to around 2 years after the treatment.[62]
In 2012, a systematic review covering all articles in the literature related to isotretinoin, depression and suicide, as well as articles related to class effect, dose response, and biologic plausibility found that the literature reviewed was consistent with an association of isotretinoin administration and depression and with suicide in a subgroup of vulnerable individuals.[54] Following this systematic review, in a 2014 review a group of Australian dermatologists and psychiatrists collaborated on a set of recommendations for safe prescribing of isotretinoin.[63] However, whether isotretinoin use is causally associated with mental illness remains controversial.[63]
Evidence for depression being causally associated with isotretinoin use includes 41 reports of positive challenge/dechallenge/rechallenge with isotretinoin, involving administering isotretinoin, withdrawing the drug, and then re-administering it.[54] The majority of these cases had no psychiatric history.[54] There is also a temporal relationship between the development of depression and initiation of isotretinoin treatment, with most cases developing after 1–2 months of treatment.[54] Further, higher doses of isotretinoin increase the risk of developing depression, with 25% of people showing depression on a dose of 3 mg/kg/day as compared with 3–4% at normal doses.[54] Studies have uncovered several biological processes which may credibly explain the affective changes induced by isotretinoin.[citation needed]
Psychosis
Isotretinoin has also been linked to psychosis.[31] Many of the side effects of isotretinoin mimic hypervitaminosis A, which has been associated with psychotic symptoms.[54] The dopamine hypothesis of schizophrenia and psychosis suggests that an increase in dopaminergic stimulation or sensitivity in the limbic system causes psychotic symptoms.[64]
It has been suggested that dysregulation of retinoid receptors by retinoids such as isotretinoin may cause schizophrenia.[65][66] The evidence for this is threefold: transcriptional activation of the dopamine D2 receptor – in addition to serotonin and glutamate receptors – is regulated by retinoic acid;[65] schizophrenia and the retinoid cascade have been linked to the same gene loci;[65] and retinoid dysfunction causes congenital anomalies identical to those observed in people with schizophrenia.[65] Further, the expression of dopamine receptors has indeed been shown to be regulated by retinoic acid.[67][68]
Musculoskeletal
Isotretinoin has a number of muscoloskeletal effects. Myalgia (muscular pain) and arthralgia (joint pain) are common side effects.[48] Retinoids, such as high dose etretinate, are well known to cause bone changes, the most common type of which is hyperostotic changes (excessive bone growth), especially in growing children and adolescents.[48] While excessive bone growth has been raised as a possible side effect for isotretinoin, a 2006 review found little evidence for this.[69] Other problems include premature epiphyseal closure and calcification of tendons and ligaments.[48] The bones of the spine and feet are most commonly affected. Risk factors for skeletal effects include older age, greater dosage and longer course of treatment. Most bone changes cause no symptoms and may only be noticed using X-ray imaging.[48]
Gastrointestinal
Isotretinoin may cause non-specific gastrointestinal symptoms including nausea, diarrhea and abdominal pain.[48] The drug is associated with inflammatory bowel disease (IBD)—ulcerative colitis, but not Crohn's disease.[70] There are also reports of people developing irritable bowel syndrome (IBS) and worsening of existing IBS.[71]
Eyes
Isotretinoin and other retinoids are well known to affect the eyes. Dry eyes are very common during treatment and is caused by isotretinoin's apoptotic effect on the meibomian glands. Some people develop contact lens intolerance as a result.[48] In some people, these changes are long-lasting or irreversible and represent Meibomian Gland Dysfunction (MGD).[41] Other common effects on the eyes include inflammation of the eyelid (blepharitis), red eye caused by conjunctivitis and irritation of the eye. More rare ocular side effects include blurred vision, decreased night vision (which may be permanent), colour blindness, development of corneal opacities, inflammation of the cornea (keratitis), swelling of the optic disk (papilloedema, associated with IIH), photophobia and other visual disturbances.[14]
Pharmacology
Mechanism of action
Isotretinoin's exact
One study suggests the drug amplifies production of
Isotretinoin has been speculated to down-regulate the enzyme
CNS activities
A possible biological basis for the case reports of depression involves decreased metabolism in the orbitofrontal cortex (OFC) of the frontal lobe.[54] It has also been found that decreased OFC metabolism was correlated with headaches.[54] People reporting headache as a side effect often report comorbid neuropsychiatric symptoms, especially depression; a statistically significant relationship between headache and depression has been established.[88] It is suggested that people sensitive to isotretinoin-induced CNS effects may also be susceptible to other psychiatric side effects such as depression.[54]
Studies in mice and rats have found that retinoids, including isotretinoin, bind to dopaminergic receptors in the central nervous system.[55][89][90] Isotretinoin may affect dopaminergic neurotransmission by disrupting the structure of dopamine receptors and decreasing dopaminergic activity.[56] The dopaminergic system is implicated in numerous psychological disorders, including depression. Isotretinoin is also thought to affect the serotonergic system – it increases expression of 5-HT1A receptors in the pre-synaptic neuron, which inhibit serotonin secretion.[56] Isotretinoin also directly and indirectly increases the translation of the serotonin transporter protein (SERT), leading to increased reuptake and consequently reduced synaptic availability of serotonin.[56]
Inhibition of hippocampal neurogenesis may also play a role in the development of isotretinoin-induced depression.[54] A further effect of isotretinoin on the brain involves retinoic acid function in the hypothalamus, the hormone regulatory centre of the brain and part of the hypothalamus-pituitary-adrenal axis, a key part of the body's stress response.[54] Other brain regions regulated by retinoic acid and potentially disrupted by isotretinoin include the frontal cortex and the striatum.[54]
Pharmacokinetics and pharmacodynamics
Oral isotretinoin is best absorbed when taken with a high-fat meal, because it has a high level of
Isotretinoin is primarily (99.9%) bound to plasma proteins, mostly
History
The compound 13-cis retinoic acid was first studied in the 1960s at Roche Laboratories in Switzerland by Werner Bollag as a treatment for skin cancer. Experiments completed in 1971 showed that the compound was likely to be ineffective for cancer but, surprisingly, that it could be useful to treat acne. However, they also showed that the compound was likely to cause birth defects, so in light of the events around thalidomide, Roche abandoned the product.[94] In 1979, an article was published reporting the drug's effectiveness as a treatment of cystic and conglobate acne on fourteen patients, thirteen of which experienced complete clearing of their disease.[81] In clinical trials, subjects were carefully screened to avoid including women who were or might become pregnant. Roche's New Drug Application for isotretinoin for the treatment of acne included data showing that the drug caused birth defects in rabbits.[medical citation needed] The FDA approved the application in 1982.[94]
Scientists involved in the clinical trials published articles warning of birth defects at the same time the drug was launched in the US, but nonetheless, isotretinoin was taken up quickly and widely, both among dermatologists and general practitioners. Cases of birth defects showed up in the first year, leading the FDA to begin publishing case reports and to Roche sending warning letters to doctors and placing warning stickers on drug bottles, and including stronger warnings on the label. Lawsuits against Roche started to be filed. In 1983 the FDA's advisory committee was convened and recommended stronger measures, which the FDA took and were at that time unprecedented: warning blood banks not to accept blood from people taking the drug and adding a warning to the label advising women to start taking contraceptives a month before starting the drug. However, the use of the drug continued to grow, as did the number of babies born with birth defects. In 1985 the label was updated to include a boxed warning. In early 1988 the FDA called for another advisory committee, and FDA employees prepared an internal memo estimating that around 1,000 babies had been born with birth defects due to isotretinoin, that up to around 1,000 miscarriages had been caused, and that between 5,000 and 7,000 women had had abortions due to isotretinoin. The memo was leaked to The New York Times[95] a few days before the meeting, leading to a storm of media attention. In the committee meeting, dermatologists and Roche each argued to keep the drug on the market but to increase education efforts; pediatricians and the Centers for Disease Control and Prevention (CDC) argued to withdraw the drug from the market. The committee recommended restricting physicians who could prescribe the drug and requiring a second opinion before it could be prescribed. The FDA, believing it did not have authority under the law to restrict who had the right to prescribe the drug, kept the drug on the market but took further unprecedented measures: it required Roche to make warnings yet more visible and graphic, provide doctors with informed consent forms to be used when prescribing the drug, and to conduct follow up studies to test whether the measures were reducing exposure of pregnant women to the drug. Roche implemented those measures, and offered to pay for contraception counseling and pregnancy testing for women prescribed the drug; the program was called the "Pregnancy Prevention Program".
A CDC report published in 2000,[96] showed problems with the Pregnancy Prevention Program and showed that the increase in prescriptions was from off-label use, and prompted Roche to revamp its program, renaming it the "Targeted Pregnancy Prevention Program" and adding label changes like requirements for two pregnancy tests, two kinds of contraception, and for doctors to provide pharmacists with prescriptions directly; providing additional educational materials, and providing free pregnancy tests. The FDA had another advisory meeting in late 2000 that again debated how to prevent pregnant women from being exposed to the drug; dermatologists testified about the remarkable efficacy of the drug, the psychological impact of acne, and demanded autonomy to prescribe the drug; others argued that the drug be withdrawn or much stricter measures be taken. In 2001 the FDA announced a new regulatory scheme called SMART (the System to Manage Accutane Related Teratogenicity) that required Roche to provide defined training materials to doctors, and for doctors to sign and return a letter to Roche acknowledging that they had reviewed the training materials, for Roche to then send stickers to doctors, which doctors would have to place on prescriptions they give people after they have confirmed a negative pregnancy test; prescriptions could only be written for 30 days and could not be renewed, thus requiring a new pregnancy test for each prescription.[97]
In February 2002, Roche's patents for isotretinoin expired, and there are now many other companies selling cheaper generic versions of the drug. On 29 June 2009,
Among others, actor
Several trials over inflammatory bowel disease claims have been held in the United States, with many of them resulting in multimillion-dollar judgments against the makers of isotretinoin.[102]
Society and culture
Brands
As of 2017, isotretinoin was marketed under many brand names worldwide: A-Cnotren, Absorica, Accuran, Accutane, Accutin, Acne Free, Acnecutan, Acnegen, Acnemin, Acneone, Acneral, Acnestar, Acnetane, Acnetin A, Acnetrait, Acnetrex, Acnogen, Acnotin, Acnotren, Acretin, Actaven, Acugen, Acutret, Acutrex, Ai Si Jie, Aisoskin, Aknal, Aknefug Iso, Aknenormin, Aknesil, Aknetrent, Amnesteem, Atlacne, Atretin, Axotret, Casius, Ciscutan, Claravis, Contracné, Curacne, Curacné, Curakne, Curatane, Cuticilin, Decutan, Dercutane, Effederm, Epuris, Eudyna, Farmacne, Flexresan, Flitrion, I-Ret, Inerta, Inflader, Inotrin, Isac, Isdiben, Isoacne, Isobest, Isocural, Isoderm, Isoface, IsoGalen, Isogeril, Isolve, Isoprotil, Isoriac, Isosupra, Isosupra Lidose, Isotane, Isotina, Isotinon, Isotren, Isotret, Isotretinoin, Isotretinoina, Isotretinoína, Isotretinoine, Isotretinoïne, Isotrétinoïne, Isotretinoinum, Isotrex, Isotrin, Isotroin, Izotek, Izotziaja, Lisacne, Locatret, Mayesta, Medinac, Myorisan, Neotrex, Netlook, Nimegen, Noitron, Noroseptan, Novacne, Oralne, Oraret, Oratane, Piplex, Policano, Procuta, Reducar, Retacnyl, Retin A, Roaccutan, Roaccutane, Roacnetan, Roacta, Roacutan, Rocne, Rocta, Sotret, Stiefotrex, Tai Er Si, Teweisi, Tretin, Tretinac, Tretinex, Tretiva, Tufacne, Zenatane, Zerocutan, Zonatian ME, and Zoretanin.[1]
The topical combination drug erythromycin/isotretinoin combines the antibiotic erythromycin with isotretinoin and has been marketed under the brand names Isotrex Eritromicina, Isotrexin, and Munderm.[1]
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