Isotretinoin , also known as 13- cis -retinoic acid (and colloquially referred to by its former brand name Accutane or Roaccutane ), is a drug especially used to treat severe acne. Rarely, it is also used to prevent certain skin cancers (squamous cell carcinoma), and in the treatment of other cancers. It is used to treat harlequin-type ichthyosis, usually lethal skin diseases, and lamellar ichthyosis. It is a retinoid, which means it is related to vitamin A, and is found in small amounts naturally in the body. The isomer, tretinoin, is also a cure for acne.
Isotretinoin is primarily used as a treatment for severe acne. The most common side effects are acne that worsens temporarily (lasts 1-4 months), dry lips (cheilitis), dry and brittle skin, and increased susceptibility to sunburn. Rare and rare side effects include muscle aches and pains (myalgia), and headaches. Isotretinoin is known to cause birth defects due to in-utero exposure because of the resemblance of molecules similar to retinoic acid, a natural vitamin A derivative that controls the development of normal embryos. It is also associated with psychiatric side effects, most commonly depression but also, less frequently, psychosis and unusual behavior. Other rare side effects including hyperostosis, and premature epiphyseal closure, have been reported persistently.
In the United States, special procedures are required to obtain pharmaceuticals. In most other countries, an approval form that explains this risk is required. Women taking isotretinoin should not become pregnant during and for 1 month after discontinuation of isotretinoin therapy. Sexual abstinence or effective contraception is mandatory during this period. Self-blocking methods (eg, condoms) are not considered adequate because of an unacceptable failure rate of about 3%. Women who become pregnant while using isotretinoin therapy are generally counseled to experience discontinuation.
Isotretinoin was first marketed as Accutane by Hoffmann-La Roche. It sold well for many years, but in 2009, Roche decided to remove Accutane from the US market after a jury had given millions of dollars in damages to former Accutane users for claims of inflammatory bowel disease. The American College of Gastroenterologists has released a position paper stating that people with inflammatory bowel disease should not be blocked from having their acne treated with isotretinoin. Then it becomes generic and in 2017 is marketed under many brand names worldwide.
Video Isotretinoin
Medical use
Isotretinoin is used primarily for severe cystic acne and acne that has not responded to other treatments. Many dermatologists also support their use for treatment of lower acne levels that are shown to be resistant to other treatments, or that produce physical or psychological scarring. Isotretinoin is not indicated for the treatment of prepubertal acne and is not recommended in children younger than 12 years.
It is also somewhat effective for suppenaliva hydradenitis and some severe cases of acne rosacea. It can also be used to help treat ichthyosis harlequin, lamellar ichthyosis and is used in cases of xeroderma pigmentosum to relieve keratosis. Isotretinoin has been used to treat very rare conditions of fibrodysplasia ossificans progressiva. It is also used for the treatment of neuroblastoma, a form of nerve cancer.
Isotretinoin therapy has been shown to be effective against genital warts in experimental use, but is rarely used for this indication because there is more effective treatment. Isotretinoin may represent a potent and safe form of systemic therapy for recombinant condylomata acuminata (RCA) of the cervix. In most countries, this therapy is currently not approved and is only used if other therapies fail.
Prescribe restrictions
Isotretinoin is a teratogen; there is about 20-35% risk of congenital defects in infants exposed to the drug in the uterus, and about 30-60% of children exposed to isotretinoin before birth have been reported to exhibit neurocognitive impairment. Because of this, there is strict control on prescription isotretinoin for women who may become pregnant and women who become pregnant while taking isotretinoin are strongly advised to stop their pregnancy.
In most countries, isotretinoin can only be prescribed by a dermatologist or a specialist; some countries also permit limited recipes by general practitioners and family doctors. In the UK 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 in a short time, its faster availability restriction has proven to be controversial. In New Zealand, isotretinoin may be prescribed by any physician but subsidized only when prescribed by a registered general practitioner, dermatologist, or nursing practitioner in the vocational field.
In the United States, since March 2006 isotretinoin spending is run through a website called iPLEDGE. The FDA requires companies to market drugs in the US, which at the time iPLEDGE was launched is Roche, Mylan, Barr, and Ranbaxy, to place the site as a risk evaluation and mitigation strategy. These companies formed a group called the Isotretinoin Products Manufacturing Group, and the company hired Covance to run the website. Receptors, pharmacists, and everyone prescribed should register on the site and record the information into it. Women with childbearing potential should commit to using two effective forms of contraception simultaneously during isotretinoin therapy and for a month immediately before and one month immediately after therapy. In addition they should have two negative pregnancy tests for 30 days and have a negative pregnancy test before each prescription is written.
Maps Isotretinoin
Adverse effects
The higher the dose will result in higher toxicity, resembling vitamin A toxicity. Adverse effects include:
Possible permanent effects
Isotretinoin can stop long bone growth in young people who are still growing. Premature epiphyseal closure can occur in people with acne who receive the recommended dose of Accutane.
Isotretinoin is known to cause dysfunction of the meibom gland which causes keratoconjunctivitis sicca (dry eyes). Problems with the meibom and salivary glands are likely to be caused by non selective apoptosis from the exocrine gene cells. The decreased night vision has been reported to persist in some people following the isotretinoin therapy termination.
Skin and mucosal tissue
The most common side effect is mucocutane: dry lips, skin and nose. Other common mucocutaneous side effects include inflammation and chapping of the lips (cheilitis), redness of the skin (erythema), rash, flaking, eczema (dermatitis), pruritus and nose bleeding (epistaxis). Absence of dryness of the lips is considered an indication of non-adherence to treatment (not taking the drug as recommended), as it occurs in almost everyone who drinks it.
Regular use of lip balm and moisturizer is recommended during treatment to reduce this problem. Dosage may need to be reduced to reduce the severity of these side effects. The skin becomes more fragile - especially for the frictional style - and may not heal as quickly as normal. For this reason hair waxing, tattoos, tattoo removal, piercings, dermabrasion, flaking, etc. are not recommended. Acne scar treatment is generally delayed up to 12 months after completing the isotretinoin course.
Acne usually lit 2-3 weeks into the treatment and is usually mild and tolerable. Occasionally, these flare-ups are severe, requiring oral antibiotics such as erythromycin. Short oral prednisolone is required. Some dermatologists support several weeks of pre-treatment with oral antibiotics before starting isotretinoin to reduce the likelihood of a severe flare. The "stepping" course can also be used to reduce the possibility of this initial flare, with which the initial dose is low (eg 0.5 mg/kg) and then increases throughout the course.
Use of Isotretinoin can rarely lead to more severe forms of acne, acne fulminans.
Teratogenicity
< Isotretinoin is a teratogen that is very likely to cause birth defects if taken by women during pregnancy or even short time before conception. Some of the more common birth defects caused by this medication are hearing and vision loss, missing or defective ears, facial dysmorphism, and brain dysfunction. Isotretinoin is classified as FDA Pregnancy Category X and ADEC Category X, and its use is contraindicated in pregnancy.
Manufacturers recommend that pregnancy should be released two weeks before the onset of isotretinoin, and women should use two simultaneous forms of effective contraception at least one month before commencement, during, and at least one month after isotretinoin therapy.
In the US, about 2,000 women became pregnant while taking medication between 1982 and 2000, with most pregnancies ending in abortion or miscarriage. About 160 babies born birth defects. After the FDA placed a more stringent iPLEDGE program in place for drug-marketing companies in the US, 155 pregnancies occurred among 129,544 potentially pregnant women using isotrentinoin (0.12%).
People taking isotretinoin are not allowed to donate blood for and at least one month after discontinuation of therapy due to teratogenicity.
Psychological effects
Rare psychological side effects may include depression, worsening pre-existing depression, aggressive tendencies, irritability and anxiety. Very rare effects include abnormal behavior, psychosis, suicidal ideation, suicide attempts and suicide. In a total of 5577 adverse reactions reported to MHRA UK until March 31, 2017, the majority (1207, or 22%) of psychiatric effects were concerned. There are 85 reports of suicidal ideals, 56 of complete suicides and 43 suicide attempts.
The relationship between isotretinoin use and psychopathology has become controversial. Beginning in 1983, isolated case reports appear to indicate mood swings, especially depression, occurring during or shortly after the use of isotretinoin. A number of studies have been conducted since then on the effects of drugs on depression, psychosis, suicidal thoughts and other psychological effects.
Depression and suicide
Isotretinoin is the only non-psychiatric drug in the list of the top 10 FDA drugs associated with depression and is also included in the top 10 for suicide attempts. The black box warning for suicide, depression and psychosis has been present on isotretinoin packaging in the United States since 2005.
In 2012, a systematic review covering all the articles in literature relating to isotretinoin, depression and suicide, as well as articles relating to class effects, dose responses, and biological sense found that the reviewed literature consistent with isotretinoin administration associations and depression. and by 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 series of recommendations for safe isotretinoin administration. However, whether the use of isotretinoin is causally associated with mental illness is controversial.
The evidence for depression that is causally related to the use of isotretinoin includes 41 reports of positive/challenge/rechallenge challenges with isotretinoin, which involves administration of isotretinoin, withdrawing the drug and then re-administering it. The majority of these cases have no psychiatric history. There is also a temporal relationship between the development of depression and the initiation of isotretinoin treatment, with most cases developing after 1-2 months of treatment. Furthermore, higher doses of isotretinoin increase the risk of developing depression, with 25% of people showing depression at a dose of 3 mg/kg/day compared with 3-4% at normal doses. Research has found some biological processes that can credibly explain the affective changes caused by isotretinoin.
Psychosis
Isotretinoin has also been associated with psychosis. Many side effects of isotretinoin mimic hypervitaminosis A, which has been associated with psychotic symptoms. The hypothesis of schizophrenia dopamine and psychosis suggests that increased dopaminergic stimulation or sensitivity in the limbic system causes psychotic symptoms.
It has been argued that retinoid-retarded dysregulation by retinoids such as isotretinoin may cause schizophrenia. The evidence for this is threefold. - Activation of Dopamine D2 receptor transcription, in addition to serotonin receptors and glutamate, regulated by retinoic acid, schizophrenia and retinoid cascade have been associated with the same gene locus and retinoid dysfunction causing congenital anomalies identical to those observed in people with schizophrenia. Furthermore, the expression of dopamine receptors has indeed been shown to be regulated by retinoic acid.
Musculoskeletal
Isotretinoin has a number of muskoloskeletal effects. Myalgia (muscle aches) and arthralgia (joint pain) are rare side effects. Retinoids, such as high-dose etretinate, are notorious for causing bone changes, the most common type being hyperostotic changes (excessive bone growth), especially in growing children and adolescents. Other problems include early epiphyseal closure and tendon and ligament calcification. The bones of the spine and legs are most commonly affected. Risk factors for skeletal effects include older age, larger doses and longer treatment. Most bone changes do not cause symptoms and can only be seen using X-ray imaging.
Gastrointestinal
Isotretinoin may cause non-specific gastrointestinal symptoms including nausea, diarrhea and abdominal pain. This drug is associated with inflammatory bowel disease (IBD) - ulcerative colitis, but not Crohn's disease. There are also reports of people developing irritable bowel syndrome (IBS) and worsening of existing IBS.
Okular
Isotretinoin and other retinoids are known to affect the eyes. Dry eye is very common during treatment and is caused by the effects of isotretinoin apoptosis on the meibom glands. Some people develop contact lens intolerance as a result. In some people, this change is long-lasting or irreversible and is a Meibomian Mammary Dysfunction (MGD). Other common effects on the eye include inflammation of the eyelids (blepharitis), red eyes caused by conjunctivitis and eye irritation. Less common ocular side effects include blurred vision, diminished (perhaps permanent) night vision, color blindness, corneal turbidity development, corneal inflammation (keratitis), optical disc swelling (papilloedema, associated IIH), photophobia and other visual disorders.
Sexual
Isotretinoin is also associated with sexual side effects, namely erectile dysfunction and decreased libido. In October 2017, the UK MHRA issued a Drug Safety Update to the physician in response to a report on the issue. This is a response to an EU review, published in August 2017, which states that a reasonable physiological explanation of these side effects "may be a reduction in testosterone plasma". The review also states that "product information should be updated to include 'sexual dysfunction including erectile dysfunction and decreased libido' as an undesirable effect with unknown frequency". There are also reports of spermatogenesis disorders, such as oligospermia. 27 cases of sexual dysfunction reports either negative dechallenges or positive challenges.
Pharmacology
Action mechanism
The mechanism of action of Isotretinoin is unknown, but several studies have shown that isotretinoin induces apoptosis (programmed cell death) in various cells in the body. Cell death can be triggered in the meibom glands, hypothalamus cells, hippocampal cells and - essential for the treatment of acne - in cells of the sebaceous glands. Isotretinoin has a low affinity for retinoic acid receptors (RAR) and X retinoid receptors (RXR), but can be converted intracellularly into metabolites that act as RAR and RXR nuclear receptor agonists.
One study showed that the drug strengthens the production of gelatinase associated with gelatinase (NGAL) in the skin, which has been shown to reduce sebum production by inducing apoptosis in sebaceous gland cells, while exhibiting the antimicrobial effect on Propionibacterium acnes . >. Drugs reduce the size and sebaceous sebaceous glands output. Isotretinoin is the only available acne medication that affects all four major pathogenic processes in acne, distinguishing it from alternative treatments (such as antibiotics) and explaining its efficacy in severe nodulocystic cases. The effect of Isotretinoin on sebum production can be temporary, or the remission of the disease can be "complete and prolonged."
Isotretinoin has been speculated to regulate the telomerase and hTERT enzymes, inhibiting "cellular immortalization and tumorigenesis." In a 2007 study, Isotretinoin proved to inhibit the action of MMP-9 (gelatinase) metalloproteases in the sebum without any effect in the actions of TIMP1 and TIMP2 (inhibitors of metalloprotease tissue). It is well known that metalloproteases play an important role in the pathogenesis of acne.
CNS Activity
The possible biological basis for depression case reports involves decreased metabolism in the orbitofrontal cortex (OFC) of the frontal lobes. It has also been found that the reduction of OFC metabolism correlates with headaches. People who report headache as a side effect often report symptoms of comorbid neuropsychiatry, especially depression; a statistically significant relationship between headache and depression has been established. It is suggested that people who are sensitive to CNS effects of isotretinoin may also be susceptible to other psychiatric side effects such as depression.
Studies in rats and mice 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 reducing dopaminergic activity. The dopaminergic system is involved in a variety of psychological disorders, including depression. Isotretinoin is also thought to affect the serotonergic system - it increases the expression of 5-HT receptor 1A in pre-synaptic neurons, which inhibits serotonin secretion. Isotretinoin also directly and indirectly improves the translation of the serotonin transporter protein (SERT), which leads to increased reuptake and consequently reduces the availability of synaptic serotonin.
Inhibition of hippocampal neurogenesis may also play a role in the development of isotretinoin-induced depression. The further effects of isotretinoin on the brain involve the function of retinoic acid in the hypothalamus, the central regulation of the brain hormone and part of the hypothalamic-pituitary-adrenal axis, an important part of the body's stress response. Other brain regions are governed by retinoic acid and potentially disturbed by isotretinoin including the frontal cortex and striatum.
Pharmacokinetic and pharmacodynamic
Oral Isotretinoin is best absorbed when taken with a high-fat diet, because it has a high lipophilicity rate. The efficacy of double isotretinoin when taken after a high-fat meal than when taken without food. Because of the molecular relationship of Isotretinoin with Vitamin A, it should not be taken with Vitamin A supplements because of the danger of toxicity through cumulative overdoses. Accutane also interacts negatively with tetracycline, another class of acne medications, and with the preparation of progesterone micro-dose ('mini pill'), norethisterone/ethinylestradiol ('OrthoNovum 7/7/7'), St. John's Wort, phenytoin, and systemic corticosteroids.
Isotretinoin is mainly (99.9%) bound to plasma proteins, most of albumin. Three Isotretinoin metabolites detected in human plasma after oral administration: 4- oxo -exexinoin, retinoid acid (tretinoin), and 4- oxo -retinoic acid (4- oxo -tretinoin). Isotretinoin also oxidizes, irreversibly, into 4- oxo -sotretacinin - which forms its geometric isomer 4- oxo -tretinoin. After oral administration, 80 mg dose of <14> C/isotretinoin c-isotretinoin suspension C-activity in the blood decreases with a half-life of 90 hours. The metabolites of isotretinoin and conjugate are then excreted in the urine and faeces of the subject in relatively equal amounts. After one dose, 80 mg oral Isotretinoin for 74 healthy adult subjects under feeding conditions, mean ± ± elimination half-life (t 1/2 ) of isotretinoin and 4- okso -exotretinoin is 21.0 Ã, Â ± 8.2 hours and 24.0 Ã, Â ± 5.3 hours, respectively. After a single dose and a double, the accumulated isotretinoin ratio observed ranged from 0.90 to 5.43 in people with cystic acne.
History
The 13-cis retinoic acid compound was first studied in the 1960s at Roche Laboratories in Switzerland by Werner Bollag as a treatment for skin cancer. The experiment completed in 1971 showed that the compound was probably not effective for cancer and, surprisingly, it could be useful for treating acne. However, they also show that the compound is likely to cause birth defects, so given the events around thalidomide, Roche abandoned the product. In 1975, Gary Peck and Frank Yoder independently rediscovered drug use as a cystic acne treatment while studying it as a treatment for lamellar ichthyosis, and published the work. Roche went back to work on the medicine. In clinical trials, subjects are carefully examined to avoid including women who are or may be pregnant. Roche's new drug application for isotretinoin for acne treatment includes data showing that the drug causes birth defects in rabbits. The FDA approved this application in 1982.
Scientists involved in clinical trials published articles of birth defects at the same time the drug was launched in the US, but even so isotretinoin was taken quickly and widely, both among dermatologists and general practitioners. The case of birth defects emerged in the first year, leading the FDA to start issuing case reports and to Roche sending a warning letter to the doctor and placing a warning sticker on the medicine bottle, and included stronger warnings on the label. Lawsuits against Roche began to be filed. In 1983 the FDA advisory committee was held and recommended more robust measures, taken by the FDA and at that time unprecedented: blood bank warnings not to receive blood from people taking the drug, and added a warning to the label advising women to start use contraception. months before starting the drug. But drug use continues to grow, as do the number of babies born with birth defects. In 1985, the label was updated to include a box warning. In early 1988, the FDA requested another advisory committee, and FDA employees prepared an internal memo estimating about 1,000 babies born with birth defects due to isotretinoin, up to about 1,000 miscarriages had occurred, and that between 5,000 and 7,000 women had an abortion because of isotretinoin. The memo leaked to the New York Times a few days before the meeting, which caused a storm of media attention. In committee meetings, dermatologists and Roche each intend to store drugs on the market but to improve educational efforts; pediatricians and CDC argued to withdraw drugs from the market. The committee recommends to limit physicians who can prescribe drugs and require a second opinion before it can be prescribed. The FDA believes it has no authority under the law to limit who is eligible to prescribe drugs, store drugs on the market but take unprecedented steps: it is necessary for Roche to make warnings yet more visible and graphic, giving doctors with forms informed consent for use when prescribing medications, and to conduct further research to test whether the action reduces the exposure of pregnant women to the drug. Roche applies these steps, and offers to pay contraceptive counseling and pregnancy tests to women prescribing the drug - the program is called "Pregnancy Prevention Program".
A CDC report published in 2000 pointed out a problem with the Pregnancy Prevention Program and showed that prescription enhancement stems from outside use of labels, and encourages Roche to change its program, change its name to "Targeted Pregnancy Prevention Program" and add label changes such as requirements for two pregnancy tests, two types of contraceptives, and for the physician to give the pharmacist a prescription directly; provide additional educational materials, and provide free pregnancy tests. The FDA had another advisory meeting in late 2000 that once again debated how to prevent pregnant women from exposure to drugs; dermatologists testify about the remarkable efficacy of the drug, the psychological impact of acne, and demands autonomy for prescribing drugs; others argue that the drug is withdrawn or a much more restrictive action is taken. In 2001 the FDA announced a new regulatory scheme called SMART (System for Managing Accutane Associated Teratogenicity) which requires Roche to provide training materials specified to the doctor, and for doctors to sign and return a letter to Roche who admits that they have reviewed the training materials, in order for Roche to send stickers to doctors, which doctors should give on prescriptions given to people after they confirm a negative pregnancy test; recipes can only be written for 30 days and can not be updated, thus requiring a new pregnancy test for each recipe.
In February 2002, Roche's patent for isotretinoin came to an end, 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 the manufacture and distribution of their Accutane brand in the United States because of what the company describes as business reasons related to low market share (under 5%), coupled with the high cost of defending private lawsuits brought by several people taking 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 more than 13 million people since its introduction in 1982. F. Hoffmann-La Roche Ltd. apparently will continue to produce and distribute Roaccutane outside of the United States.
Among other things, actor James Marshall sued Roche on suspicion of Accutane-related illness that resulted in the removal of his colon. However, the jury decided that James Marshall had a pre-existing bowel disease.
Several experiments on claims of inflammatory bowel disease have been held in the United States so far, with many of them generating millions of dollars worth of judgments on isotretinoin-makers.
Society and culture
Brand
Pada 2017 isotretinoin dipasarkan di bawah banyak nama merek di seluruh dunia: A-Cnotren, Absorica, Accurane, Accutane, Accutine, Acne, Acnecutan, Acnegen, Acne, Acne, Acne, Acne, , Acnotin, Acnotren, Acutret, Acutrex, Acyrex, Akin, Aknefug Iso, Aknenormin, Aknesil, Aknetrent, Amnesteem, Atlacine, Atretin, Axotret, Casius, Ciscutan, Claravis, Curacin, Curacin, Cuticilin, Decutan, Dercutane, Effederm, Epuris, Eudyna, Pharmacne, Flexresan, Flitrion, I- Ret, Inert, Inflader, Inotrin, Isac, Isobor, Isoface, IsoGalen, Isogeril, Isolve, Isoprotil, Isoriac, Isosupra, Isosupra Lido Isotane, isotin, Isotinon, Isotren, Isotret, isotretinoin, isotretinoin, IsotretinoÃÆ'na, isotretinoin, IsotretinoÃÆ'¯ne, IsotrÃÆ' Â © tinoÃÆ'¯ne, Isotretinoinum, Isotrex, Isotrin, Isotroin, Izotek, Izotziaja, Lisa Locatet, Mayesta, Myorisan, Neotrex, Netose, Nimegen, Noitron, Noroseptan, Novacne, Oralne, Oraret, Oratane, Piplex, Policano, Procuta, Reducar, Retin A, Roaccutan, Roaccutane, Roacnetan, Roacutan, Rocne, Rocta Sotret, Stiefotrex, Tai Er Si, Teweisi, Tretin, Tretinac, Tretinex, Tretvita, Tufacne, Zenatane, Zerocutan, Zonatian ME, dan Zoretanin.
In 2017 it is marketed as a topical combination drug with erythromycin under the brand name Isotrex Eritromicina, Isotrexin, and Munderm.
Research
While excessive bone growth has caused possible side effects, a 2006 review found little evidence for this.
See also
- Retinoid
- Etretinate
- Hypervitaminosis Syndrome
References
External links
- Isotretinoin Drugs.com Information
- DermNet care/isotretinoin
Source of the article : Wikipedia
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