13-cis-retinoic acid
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Isotretinoin, also known as 13-''cis''-retinoic acid and sold under the brand name Accutane among others, is a medication primarily used to treat severe acne. It is also used to prevent certain skin cancers (
squamous-cell carcinoma Squamous-cell carcinomas (SCCs), also known as epidermoid carcinomas, comprise a number of different types of cancer that begin in squamous cells. These cells form on the surface of the skin, on the lining of hollow organs in the body, and on the ...
), and in the treatment of other cancers. It is used to treat harlequin-type ichthyosis, a usually lethal skin disease, and lamellar ichthyosis. It is a
retinoid The retinoids are a class of chemical compounds that are vitamers of vitamin A or are chemically related to it. Retinoids have found use in medicine where they regulate epithelial cell growth. Retinoids have many important functions throughout t ...
, meaning it is related to vitamin A, and is found in small quantities naturally in the body. Its
isomer In chemistry, isomers are molecules or polyatomic ions with identical molecular formulae – that is, same number of atoms of each element – but distinct arrangements of atoms in space. Isomerism is existence or possibility of isomers. Iso ...
, tretinoin, is also an acne drug. The most common adverse effects are dry lips (
cheilitis Cheilitis is a medical condition characterized by inflammation of the lips. The inflammation may include the perioral skin (the skin around the mouth), the vermilion border, or the labial mucosa. The skin and the vermilion border are more common ...
), dry and fragile skin, and an increased susceptibility to sunburn. Uncommon and rare side effects include muscle aches and pains (
myalgia Myalgia (also called muscle pain and muscle ache in layman's terms) is the medical term for muscle pain. Myalgia is a symptom of many diseases. The most common cause of acute myalgia is the overuse of a muscle or group of muscles; another likel ...
s), and headaches. Isotretinoin is known to cause birth defects due to in-utero exposure because of the molecule's close resemblance to retinoic acid, a natural vitamin A derivative that controls normal embryonic development. It is also associated with psychiatric side effects, most commonly depression but also, more rarely, psychosis and unusual behaviours. Other rare side effects include hyperostosis and premature
epiphyseal closure The epiphyseal plate (or epiphysial plate, physis, or growth plate) is a hyaline cartilage plate in the metaphysis at each end of a long bone. It is the part of a long bone where new bone growth takes place; that is, the whole bone is alive, with ...
, which have been reported to be persistent. Isotretinoin was patented in 1969 and approved for medical use in 1982. In 2020, it was the 264th most commonly prescribed medication in the United States, with more than 1million prescriptions.


Medical uses

Isotretinoin is used primarily for severe cystic acne and acne that has not responded to other treatments. 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. Isotretinoin is not indicated for treatment of prepubertal acne and is not recommended in children less than 12 years of age. It is also somewhat effective for
hidradenitis suppurativa Hidradenitis suppurativa (HS), sometimes known as acne inversa or Verneuil's disease, is a long-term dermatological condition characterized by the occurrence of inflamed and swollen lumps. These are typically painful and break open, releasing ...
and some cases of severe rosacea.Klasco RK, editor. Drugdex system, vol. 128. Greenwood Village (CO): Thomson Micromedex; 2006. It can also be used to help treat
harlequin ichthyosis Harlequin (; it, Arlecchino ; lmo, Arlechin, Bergamasque pronunciation ) is the best-known of the ''zanni'' or comic servant characters from the Italian ''commedia dell'arte'', associated with the city of Bergamo. The role is traditionally be ...
, 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 the treatment of neuroblastoma, a form of nerve cancer. Isotretinoin therapy has furthermore proven effective against genital warts in experimental use, but is rarely used for this indication as there are more effective treatments. Isotretinoin may represent an efficacious and safe alternative systemic form of therapy for
recalcitrant condylomata acuminata Genital warts are a sexually transmitted infection caused by certain types of human papillomavirus (HPV). They are generally pink in color and project out from the surface of the skin. Usually they cause few symptoms, but can occasionally be pai ...
(RCA) of the cervix. In most countries this therapy is currently unapproved and only used if other therapies failed.


Prescribing restrictions

Isotretinoin is a teratogen; there is about a 20–35% risk for congenital defects in infants exposed to the drug ''in utero'', and about 30–60% of children exposed to isotretinoin prenatally have been reported to show neurocognitive impairment. Because of this, there are strict controls on prescribing isotretinoin to women who may become pregnant and women who become pregnant while taking isotretinoin are strongly advised to terminate their pregnancies. 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 and Australia, isotretinoin 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. In New Zealand, isotretinoin can be prescribed by any doctor but subsidised only when prescribed by a vocationally-registered general practitioner, dermatologist or nurse practitioner. In the United States, since March 2006, the dispensing of isotretinoin is run through a website called
iPLEDGE The iPLEDGE program is a program by the Food and Drug Administration (United States), U.S. Food and Drug Administration (FDA) for managing the risk of isotretinoin (also known as Accutane), a prescription medication used for the treatment of acn ...
. The US Food and Drug Administration (FDA) requires the companies marketing the drug to put this website in place as a
risk evaluation and mitigation strategy Risk Evaluation and Mitigation Strategies (REMS) is a program of the US Food and Drug Administration for the monitoring of medications with a high potential for serious adverse effects. REMS applies only to specific prescription drugs, but can apply ...
. These companies formed a group called the Isotretinoin Products Manufacturing Group, and it hired Covance to run the website. Prescribers, pharmacists, and all people to whom the drug is prescribed need to register on the site and log information into it. Women with child-bearing potential must commit to using two forms of effective contraception simultaneously for the duration of isotretinoin therapy and for a month immediately preceding and a month immediately following therapy. Additionally, they must have two negative pregnancy tests 30 days apart and have negative pregnancy tests before each prescription is written.


Adverse effects

Increasingly higher dosages will result in higher toxicity, resembling
vitamin A toxicity Hypervitaminosis A refers to the toxic effects of ingesting too much preformed vitamin A (retinyl esters, retinol, and retinal). Symptoms arise as a result of altered bone metabolism and altered metabolism of other fat-soluble vitamins. Hypervit ...
. Adverse effects include:


Possible permanent effects

Isotretinoin may stop
long bone The long bones are those that are longer than they are wide. They are one of five types of bones: long, Short bone, short, Flat bone, flat, Irregular bone, irregular and Sesamoid bone, sesamoid. Long bones, especially the femur and tibia, are subj ...
growth in young people who are still growing. Se
FDA Index page for NDA 018662
for updates
Premature
epiphyseal The epiphysis () is the rounded end of a long bone, at its joint with adjacent bone(s). Between the epiphysis and diaphysis (the long midsection of the long bone) lies the metaphysis, including the epiphyseal plate (growth plate). At the joi ...
closure can occur in people with acne receiving recommended doses of Accutane. Generally, though, premature epiphyseal closure seems to be primarily related to: * high doses of isotretinoin beyond the recommended dose of 1 mg/kg/day * long-duration beyond the usual course of what is required for an acne patient for treatment (usually 5–7 months) * early onset of treatment (young teenage age 12–14 or younger) Isotretinoin is known to cause
meibomian gland Meibomian glands (also called tarsal glands, palpebral glands, and tarsoconjunctival glands) are sebaceous glands along the rims of the eyelid inside the tarsal plate. They produce meibum, an oily substance that prevents evaporation of the eye' ...
dysfunction which causes persistent keratoconjunctivitis sicca (dry eye). Problems with the meibomian and salivary glands are likely due to the
non-selective In biochemistry and pharmacology, a ligand is a Chemical substance, substance that forms a Complex (chemistry), complex with a biomolecule to serve a biological purpose. The etymology stems from ''ligare'', which means 'to bind'. In protein-lig ...
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
of the cells of the exocrine glands. Decreased
night vision Night vision is the ability to see in low-light conditions, either naturally with scotopic vision or through a night-vision device. Night vision requires both sufficient spectral range and sufficient intensity range. Humans have poor night vi ...
has been reported to persist in some people after discontinuation of isotretinoin therapy.


Sexual

Isotretinoin is also associated with sexual side effects, namely
erectile dysfunction Erectile dysfunction (ED), also called impotence, is the type of sexual dysfunction in which the penis fails to become or stay erect during sexual activity. It is the most common sexual problem in men.Cunningham GR, Rosen RC. Overview of male ...
and reduced libido. In October 2017, the UK
MHRA MHRA may refer to: Organisations * Medicines and Healthcare products Regulatory Agency, UK * Michigan Hot Rod Association, US * Modern Humanities Research Association, UK ** ''MHRA Style Guide'', an academic style guide Other uses * Men's human r ...
issued a Drug Safety Update to physicians in response to reports of these problems. 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". 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". There have also been reports of
spermatogenesis Spermatogenesis is the process by which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testis. This process starts with the mitotic division of the stem cells located close to the basement membrane of the tubule ...
disorders, such as oligospermia. 27 cases of sexual dysfunction report either negative dechallenge or positive dechallenge.


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 Cheilitis is a medical condition characterized by inflammation of the lips. The inflammation may include the perioral skin (the skin around the mouth), the vermilion border, or the labial mucosa. The skin and the vermilion border are more common ...
), redness of the skin ( erythema), rashes, peeling, eczema ( dermatitis), itching ( pruritus) and nose bleeds ( epistaxis). 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. 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. 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 teratogen highly likely to cause birth defects if taken by women during pregnancy or even a short time before conception. A few of the more common birth defects this drug can cause are hearing and visual impairment, missing or malformed earlobes, facial dysmorphism, and abnormalities in brain function. Isotretinoin is classified as
FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...
Pregnancy Category X and ADEC Category X, and use is contraindicated in pregnancy. In the EU, isotretinoin (oral) is contraindicated in pregnancy and must not be taken by women able to have children unless the conditions of a pregnancy prevention programme are met. 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.Roche Products Pty Ltd. Roaccutane (Australian Approved Product Information). Dee Why (NSW): Roche; 2005. In the US, around 2000 women became pregnant while taking the drug between 1982 and 2000, with most pregnancies ending in abortion or
miscarriage Miscarriage, also known in medical terms as a spontaneous abortion and pregnancy loss, is the death of an embryo or fetus before it is able to survive independently. Miscarriage before 6 weeks of gestation is defined by ESHRE as biochemical lo ...
. 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 among 129,544 women of childbearing potential taking isotrentinoin (0.12%). People taking isotretinoin are not permitted to donate blood during and for at least one month after discontinuation of therapy due to its teratogenicity.


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 Suicide is the act of intentionally causing one's own death. Mental disorders (including depression, bipolar disorder, schizophrenia, personality disorders, anxiety disorders), physical disorders (such as chronic fatigue syndrome), and s ...
. In a total of 5577 adverse reactions reported to the UK's
MHRA MHRA may refer to: Organisations * Medicines and Healthcare products Regulatory Agency, UK * Michigan Hot Rod Association, US * Modern Humanities Research Association, UK ** ''MHRA Style Guide'', an academic style guide Other uses * Men's human r ...
up to 31 March 2017, the plurality (1207, or 22%) concerned psychiatric effects. There were 85 reports of suicidal ideation, 56 of suicide and 43 of suicide attempts. 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. A number of studies have been conducted since then of the drug's effect on depression, psychosis, suicidal thoughts and other psychological effects.


Depression and suicidality

Isotretinoin is the only non-psychiatric drug on the
FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...
's top 10 list of drugs associated with depression and is also within the top 10 for suicide attempts. A black box warning for suicide, depression and psychosis has been present on isotretinoin's packaging in the United States since 2005. In March 2018,
European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...
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. 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. 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. However, whether isotretinoin use is causally associated with mental illness remains controversial. 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. The majority of these cases had no psychiatric history. 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. 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. Studies have uncovered several biological processes which may credibly explain the affective changes induced by isotretinoin.


Psychosis

Isotretinoin has also been linked to psychosis. Many of the side effects of isotretinoin mimic hypervitaminosis A, which has been associated with psychotic symptoms. The dopamine hypothesis of schizophrenia and psychosis suggests that an increase in dopaminergic stimulation or sensitivity in the limbic system causes psychotic symptoms. It has been suggested that dysregulation of retinoid receptors by retinoids such as isotretinoin may cause schizophrenia. 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; schizophrenia and the retinoid
cascade Cascade, Cascades or Cascading may refer to: Science and technology Science *Cascade waterfalls, or series of waterfalls * Cascade, the CRISPR-associated complex for antiviral defense (a protein complex) * Cascade (grape), a type of fruit * Bioc ...
have been linked to the same gene loci; and retinoid dysfunction causes congenital anomalies identical to those observed in people with schizophrenia. Further, the expression of dopamine receptors has indeed been shown to be regulated by retinoic acid.


Musculoskeletal

Isotretinoin has a number of muscoloskeletal effects.
Myalgia Myalgia (also called muscle pain and muscle ache in layman's terms) is the medical term for muscle pain. Myalgia is a symptom of many diseases. The most common cause of acute myalgia is the overuse of a muscle or group of muscles; another likel ...
(muscular pain) and arthralgia (joint pain) are rare side effects.
Retinoid The retinoids are a class of chemical compounds that are vitamers of vitamin A or are chemically related to it. Retinoids have found use in medicine where they regulate epithelial cell growth. Retinoids have many important functions throughout t ...
s, 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. Other problems include premature
epiphyseal closure The epiphyseal plate (or epiphysial plate, physis, or growth plate) is a hyaline cartilage plate in the metaphysis at each end of a long bone. It is the part of a long bone where new bone growth takes place; that is, the whole bone is alive, with ...
and calcification of tendons and ligaments. 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.


Gastrointestinal

Isotretinoin may cause non-specific gastrointestinal symptoms including nausea, diarrhea and abdominal pain. The drug is associated with
inflammatory bowel disease Inflammatory bowel disease (IBD) is a group of inflammation, inflammatory conditions of the colon (anatomy), colon and small intestine, Crohn's disease and ulcerative colitis being the principal types. Crohn's disease affects the small intestine a ...
(IBD)— ulcerative colitis, but not Crohn's disease. There are also reports of people developing irritable bowel syndrome (IBS) and worsening of existing IBS.


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 gland Meibomian glands (also called tarsal glands, palpebral glands, and tarsoconjunctival glands) are sebaceous glands along the rims of the eyelid inside the tarsal plate. They produce meibum, an oily substance that prevents evaporation of the eye' ...
s. Some people develop contact lens intolerance as a result. In some people, these changes are long-lasting or irreversible and represent Meibomian Gland Dysfunction (MGD). Other common effects on the eyes include inflammation of the eyelid (
blepharitis Blepharitis is one of the most common ocular conditions characterized by inflammation, scaling, reddening, and crusting of the eyelid. This condition may also cause swelling, burning, itching, or a grainy sensation when introducing foreign objects ...
), 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 Color blindness or color vision deficiency (CVD) is the decreased ability to see color or differences in color. It can impair tasks such as selecting ripe fruit, choosing clothing, and reading traffic lights. Color blindness may make some aca ...
, development of corneal opacities, inflammation of the cornea ( keratitis), swelling of the optic disk (
papilloedema Papilledema or papilloedema is optic disc swelling that is caused by increased intracranial pressure due to any cause. The swelling is usually bilateral and can occur over a period of hours to weeks. Unilateral presentation is extremely rare. I ...
, associated with IIH), photophobia and other visual disturbances.


Pharmacology


Mechanism of action

Isotretinoin's exact mechanism of action is unknown, but several studies have shown that isotretinoin induces
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
(programmatic cell death) in various cells in the body. Cell death may be instigated in the
meibomian gland Meibomian glands (also called tarsal glands, palpebral glands, and tarsoconjunctival glands) are sebaceous glands along the rims of the eyelid inside the tarsal plate. They produce meibum, an oily substance that prevents evaporation of the eye' ...
s,
hypothalamic The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamus i ...
cells, hippocampus cells and—important for treatment of acne—in sebaceous gland cells. Isotretinoin has a low affinity for retinoic acid receptors (RAR) and retinoid X receptors (RXR), but may be converted intracellularly to metabolites that act as
agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
s of RAR and RXR
nuclear receptor In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of speci ...
s. 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 Cutibacterium acnes. The drug decreases the size and sebum output of the sebaceous glands. Isotretinoin is the only available acne drug that affects all four major pathogenic processes in acne, which distinguishes it from alternative treatments (such as antibiotics) and accounts for its efficacy in severe, nodulocystic cases. The effect of isotretinoin on sebum production can be temporary, or remission of the disease can be "complete and prolonged." Isotretinoin has been speculated to down-regulate the enzyme telomerase and
hTERT Telomerase reverse transcriptase (abbreviated to TERT, or hTERT in humans) is a catalytic subunit of the enzyme telomerase, which, together with the telomerase RNA component (TERC), comprises the most important unit of the telomerase complex. T ...
, inhibiting " cellular immortalization and tumorigenesis." In a 2007 study, isotretinoin was proven to inhibit the action of the metalloprotease MMP-9 ( gelatinase) in sebum without any influence in the action of
TIMP1 TIMP metallopeptidase inhibitor 1, also known as TIMP1, a tissue inhibitor of metalloproteinases, is a glycoprotein with a molecular weight of 28 kDa. TIMP1 is expressed from several tissues of organisms. This protein is a member of the TIMP fami ...
and TIMP2 (the tissue inhibitors of metalloproteases). It is already known that metalloproteases play an important role in the pathogenesis of acne.


CNS activities

A possible biological basis for the case reports of depression involves decreased metabolism in the orbitofrontal cortex (OFC) of the frontal lobe. It has also been found that decreased OFC metabolism was correlated with headaches. 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. It is suggested that people sensitive to isotretinoin-induced CNS effects may also be susceptible to other psychiatric side effects such as depression. Studies in mice and rats have found that retinoids, including isotretinoin, bind to dopaminergic receptors in the central nervous system. Isotretinoin may affect dopaminergic neurotransmission by disrupting the structure of dopamine receptors and decreasing dopaminergic activity. 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. 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. Inhibition of hippocampal
neurogenesis Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). It occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NECs) ...
may also play a role in the development of isotretinoin-induced depression. 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. Other brain regions regulated by retinoic acid and potentially disrupted by isotretinoin include the
frontal cortex The frontal lobe is the largest of the four major lobes of the brain in mammals, and is located at the front of each cerebral hemisphere (in front of the parietal lobe and the temporal lobe). It is parted from the parietal lobe by a groove betwe ...
and the
striatum The striatum, or corpus striatum (also called the striate nucleus), is a nucleus (a cluster of neurons) in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutamate ...
.


Pharmacokinetics and pharmacodynamics

Oral isotretinoin is best absorbed when taken with a high-fat meal, because it has a high level of lipophilicity. The efficacy of isotretinoin doubles when taken after a high-fat meal compared to when taken without food. Due to isotretinoin's molecular relationship to vitamin A, it should not be taken with vitamin A supplements due to the danger of toxicity through cumulative overdosing. Accutane also negatively interacts with tetracycline, another class of acne drug, and with micro-dosed ('mini-pill')
progesterone Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the m ...
preparations,
norethisterone Norethisterone, also known as norethindrone and sold under many brand names, is a progestin medication used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication is available in both ...
/ ethinylestradiol ('OrthoNovum 7/7/7'), St. John's Wort, phenytoin, and systemic
corticosteroid Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involv ...
s. Isotretinoin is primarily (99.9%) bound to plasma proteins, mostly albumin. Three metabolites of isotretinoin are detectable in human plasma after oral administration: 4-''oxo''-isotretinoin, retinoid acid (tretinoin), and 4-''oxo''-retinoic acid (4-''oxo''-tretinoin). Isotretinoin also oxidizes, irreversibly, to 4-''oxo''-isotretinoin—which forms its geometric isomer 4-''oxo''-tretinoin. After an orally-administered, 80 mg dose of liquid suspension 14C-isotretinoin, 14C-activity in blood declines with a half-life of 90 hours. The metabolites of isotretinoin and its conjugates are then excreted in the subject's urine and faeces in relatively equal amounts. After a single, 80 mg oral dose of Isotretinoin to 74 healthy adult subjects under fed conditions, the mean ±SD elimination half-life (t1/2) of isotretinoin and 4-''oxo''-isotretinoin were 21.0 ± 8.2 hours and 24.0 ± 5.3 hours, respectively. After both single and multiple doses, the observed accumulation ratios of isotretinoin ranged from 0.90 to 5.43 in people with cystic acne.


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. 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. 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. The FDA approved the application in 1982. 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 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 the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears on the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administration specifies that it ...
. 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'' 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 Informed consent is a principle in medical ethics and medical law, that a patient must have sufficient information and understanding before making decisions about their medical care. Pertinent information may include risks and benefits of treatme ...
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, 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. 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, 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 people who took the drug. Roche USA continues to defend Accutane and claims to have treated over 13million people since its introduction in 1982. F. Hoffmann-La Roche Ltd. apparently will continue to manufacture and distribute Roaccutane outside of the United States. Among others, actor James Marshall sued Roche over allegedly Accutane-related disease that resulted in removal of his colon. The jury, however, decided that James Marshall had a pre-existing bowel disease. 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.


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, 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. As of 2017, it was marketed as a topical combination drug with
erythromycin Erythromycin is an antibiotic used for the treatment of a number of bacterial infections. This includes respiratory tract infections, skin infections, chlamydia infections, pelvic inflammatory disease, and syphilis. It may also be used duri ...
under the brand names Isotrex Eritromicina, Isotrexin, and Munderm.


Research

While excessive bone growth has been raised as a possible side effect, a 2006 review found little evidence for this.


References


External links

* {{Portal bar , Medicine Cyclohexenes Hoffmann-La Roche brands Polyenes Enones Isotretinoin