Everything about Accutane totally explained
Isotretinoin (
INN) (or /ˌaɪsoʊtrɨˈtɪnoʊɨn/) is a
medication used for the treatment of severe
acne. It is sometimes used as a chemotherapy medication for prevention and treatment of certain skin cancers. In some cases, it's used to treat
Harlequin type ichthyosis. It is a
retinoid, meaning it derives from
vitamin A and is found in small quantities naturally in the body. Oral isotretinoin is marketed under various trade names, most commonly
Accutane (
Roche),
Amnesteem (
Mylan),
Claravis (
Barr),
Decutan (
Actavis),
Isotane (
Pacific Pharmaceuticals),
Sotret (
Ranbaxy),
Oratane (Genepharm Australasia) or
Roaccutane (
Roche); while topical isotretinoin is most commonly marketed under the trade names
Isotrex or
Isotrexin (
Stiefel).
History
Prior to the development of isotretinoin, the mainstay treatment of moderate to severe or persistent acne was oral
antibiotics such as the
tetracyclines and
erythromycin. While these drugs have proven efficacy, they worked against only one contributing factor of acne – the
Propionibacterium acnes bacteria. The antibiotics gradually became less effective over time as more resistant strains of the bacterium became prominent.
An early, effective treatment of acne was high doses of the fat-soluble vitamin A. At these dose levels (sometimes 500,000
IU per day) effects such as reduced production of
sebum and dry hair could be noticed . However the vitamin also had many other prominent side effects which inhibited its widespread use .
Increasingly higher dosages of isotretinoin will result in higher toxicity, resembling vitamin A toxicity (the higher the dosage, the more pronounced the side effects will be). The "upper limit" for Vitamin A (Retinol) is 3 milligrams (10,000 IU). This is the dosage at which the scientific community agrees there are no side effects for Vitamin A. Isotretinoin is available in 2.5mg capsules (as well as 5mg, 10mg, 20mg, 40mg). However, isotretinoin is more teratogenic (causes birth defects) than vitamin A at the same dosage .
The development of the
retinoic acid derivative isotretinoin (13-
cis-retinoic acid), and its release in
1982 by
Hoffmann-La Roche, was a great step forward in the treatment of acne. The synthetic compound provided better therapeutic benefit than vitamin A, while also producing fewer
adverse effects. In February 2002, Roche's patents for isotretinoin expired and there are now many other companies selling cheaper generic versions of the drug.
Because of a 1984 study funded by Roche, high dosages of the drug became mainstream in treatment. Lower dosages were found to be effective in treatment by independent research (see dosage section of this article), but Roche's dosage recommendations still continue to be used.
Currently, isotretinoin continues to be used only after other acne treatments fail to produce results. Treatment of acne begins with topical medications (for example
benzoyl peroxide,
adapalene, etc), followed by oral antibiotics (or a combination) and finally isotretinoin therapy. This is because other treatments, while less effective than isotretinoin, are thought to be associated with fewer adverse effects and lower cost. The higher cost is due to the higher dosages used. The cost of the medicine is also a factor (example: taking 5, 10, or even 20mg daily is far less expensive than taking 80mg daily).
From the time of its introduction the drug was known to have
teratogenic potential, and pregnancies with the drug were strongly discouraged. When they occurred, they were found to have approximately 30% rates of congenital malformation, versus a 3-5% baseline risk. Beginning in 1998, prescriptions of the drug came under scrutiny, as fewer than half of prescribers were testing for pregnancy, usually relying on less sensitive urine tests. On the grounds that pregnancies by women taking the drug had been underreported by the manufacturer between 1982 and 2000, and that once generic manufacturers entered the market risk management was no longer centralized, the FDA instituted restrictions on prescribing and dispensing the drug, first with the "System to Manage Accutane Related Teratogenicity" (SMART) in 2000, and subsequently the
iPLEDGE program in 2006. A retrospective cohort study recently found that pregnancy rates were quite high during the period (1 per 30 women per year), but 84% of pregnancies were ended by induced
abortion.
In countries that don't restrict distribution of isotretinoin, pharmacists recommend 5mg or 10mg daily, since at lower dosages the adverse side effects are diminished. Isotretinoin in topical form is also prescribed.
Isotretinoin is available over the internet from countries where it can be dispensed without a prescription. It is an ongoing problem for governments where a prescription is required, as it's mailed illegally across borders.
Pharmacodynamics
Isotretinoin noticeably reduces the production of
sebum and shrinks the
sebaceous glands. It stabilizes
keratinization and prevents
comedones from forming. The exact
mechanism of action is unknown, however it's known that like other
retinoids, Isotretinoin works by altering
DNA transcription. This effect decreases the size and output of sebaceous glands, makes the cells that are sloughed off into the sebaceous glands less sticky, and therefore less able to form comedones.
Pharmacokinetics
Isotretinoin, when administered orally, is best absorbed when taken after a high fat meal, as it has a high level of
lipophilicity. In a crossover study, it was found that the peak plasma concentration more than doubled when taken after a high fat meal versus a fasted condition. Isotretinoin is primarily (99.9%) bound to plasma proteins, mostly albumin. At least three metabolites have been detected in human plasma after oral administration of isotretinoin. These are 4-oxo-isotretinoin, retinoic acid and 4-oxo-retinoic acid. Isotretinoin also oxidises, irreversibly, to 4-oxo-isotretinoin. The metabolites of isotretinoin are excreted through both
urine and
feces. The mean
elimination half-life is 21 hours, with a standard deviation from this mean of 8.2 hours.
Clinical use
Indications
Isotretinoin is indicated for the treatment of severe cystic
acne vulgaris. It is also effective for
hidradenitis suppurativa and some cases of severe
acne rosacea. A similar situation exists in most
Australian states – in
New South Wales and
Victoria, for instance, the prescriber must be a
Fellow of the Australasian College of Dermatologists (FACD). In
New Zealand, isotretinoin can be prescribed by any doctor but is subsidised only if prescribed by a skin specialist/
dermatologist. As New Zealand General Practitioner visits are subsidised it's usually cheaper for the patient to buy their isotretinoin with a GP prescription than to pay to see a dermatologist.
Since
1 March 2006, the dispensing of isotretinoin
in the United States has been controlled by a
FDA-mandated website called
iPLEDGE – dermatologists are required to register their patients before prescribing and pharmacists are required to check the website before dispensing the drug. The patient must visit the iPLEDGE website or call the hotline number in order to log in with his or her ID code to answer the iPLEDGE questionaire. The prescription may not be dispensed until all three parties have complied. A physician may not prescribe more than a 30-day supply. A new prescription may not be written for at least 30 days. Pharmacies are also under similar restriction. There is also a 7-day window in which the medication must be picked up at the pharmacy. If the original prescription is lost, or pick-up window is missed, the patient must re-qualify to have another prescription written. Doctors and pharmacists must also verify written prescriptions in an online system before patients may fill the prescription.
In Mexico, this drug is of restricted use, and an official identification and patient signature is required by the pharmacies.
Dosage
The dose of isotretinoin a patient receives is dependent on their weight and the severity of the condition. High dose treatments are administered between 0.5 mg/kg/day to 2 mg/kg/day (usually at 0.5 to 1 mg/kg/day, divided into two doses), for a total treatment of 4–6 months. A second course may be used two months following the cessation of the initial course if severe acne recurs. Efficacy appears to be related to the cumulative dose of isotretinoin taken, with a total cumulative dose of 120–150 mg/kg used as a guideline.
In these experiments, subjects used 20mg/day, which is 0.25 mg/kg/day for an 80 kg (176 pounds) person.
More experiments and studies showing the success of low dosage treatments with diminished or non-existent side effects:
http://www.uspharmacist.com/oldformat.asp?url=newlook/files/Feat/apr00iso.cfm&pub_id=8&article_id=508
http://archderm.ama-assn.org/cgi/content/abstract/130/3/319
http://www.blackwell-synergy.com/doi/abs/10.1111/j.1365-4362.1994.tb01500.x
http://www.blackwell-synergy.com/doi/abs/10.1111/j.1468-3083.1998.tb00763.x
http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowFulltext&ProduktNr=223854&Ausgabe=227284&ArtikelNr=45270
Preparations
Isotretinoin is marketed under many brand names by various manufacturers. It is typically available as 5 mg, 10 mg, 20 mg, 30mg and (in the USA) 40 mg capsules. Some brands of oral isotretinoin include:
Accure (
Alphapharm),
Accutane and
Roaccutane (
Roche),
Aknenormin (
Hermal),
Amnesteem (
Mylan),
Ciscutan (
Pelpharma),
Claravis (
Barr),
Clarus (
Prepharm),
Isohexal (
Hexal Australia),
Isotane (
Pacific Pharmaceuticals),
Isotroin (
Cipla),
Oratane (
Douglas Pharmaceuticals), and
Sotret (
Ranbaxy).
It is also available as a 0.05%
topical preparation, marketed by
Stiefel under the trade name
Isotrex or
Isotrexin (with
erythromycin)..
Adverse effects
Increasingly higher dosages will result in higher toxicity, resembling vitamin A toxicity.
Adverse drug reactions associated with isotretinoin therapy include: Despite this, sexual dysfunction isn't acknowledged as a side-effect in the official literature accompanying the medication.
While
vitamin E supplements have been advocated by some to reduce the toxicity of high-dose retinoids without reducing drug efficacy, test results have proven this to be false (though no indication of what form of vitamin E was used).
Patients receiving isotretinoin therapy are not permitted to donate blood during and for at least one month after discontinuation of isotretinoin therapy due to reported birth defects to unborn children.
Patients that get a
tattoo while on this medication might get scarring on the tattoed area, and also rejection of the ink .
Teratogenicity (Birth Defects)
Isotretinoin is a
teratogen and is highly likely to cause birth defects if taken during pregnancy. A few of the more common birth defects that this drug can cause are hearing and visual impairment, missing earlobes, facial dysmorphism, and mental retardation. Isotretinoin is classified as
FDA Pregnancy Category X and
ADEC Category X, and use is contraindicated in pregnancy.
In the
U.S. more than 2,000 women have become pregnant while taking the drug between 1982 and 2003, with most pregnancies ending in
abortion or
miscarriage. About 160 babies with birth defects were born. Consequently, the
iPLEDGE program was introduced by the U.S.
Food and Drug Administration on
12 August 2005 in an attempt to ensure that female patients receiving isotretinoin don't become pregnant – as of
1 March 2006, only prescribers registered and activated in iPLEDGE are able to prescribe isotretinoin, and only patients registered and qualified in iPLEDGE will be able to have isotretinoin dispensed.
Depression
Several studies have suggested a possible link between isotretinoin and
clinical depression. However, no conclusive evidence has been produced. Despite this, the argument that isotretinoin caused depression and suicide has won a few lawsuits, and is partially responsible for the strict control of the drug, especially in the United States. Various case reports of depression, suicidal ideation, suicide attempt, and suicide in patients treated with isotretinoin have been reported to the U.S. FDA Adverse Events Reporting System, with 431 cases reported between 1982 and May 2001 – of these 37 patients had committed suicide. While analyses have suggested an association between isotretinoin therapy and depression, no causal relationship has been established and further studies are required.
Studies have shown that patients with acne, the population group eligible to receive isotretinoin therapy, have an increased risk of clinical depression compared with the general population. Chee Hong describes Isotretinoin-related depression as "an
idiosyncratic side-effect", claiming, often anxiety can bring on acne and depression, creating more anxiety. Correspondingly, treatment of severe acne with isotretinoin has been shown to reduce anxiety and depression, for tests have shown acne to be a main depressant in most tested patients' lives.
One study utilising
positron emission tomography (PET) showed functional brain imaging changes in patients treated with isotretinoin, however the clinical relevance of this finding is unclear.
U.S. Representative
Bart Stupak (D-MI) is known for his distrust of Accutane. He believes unadvertised psychological side effects from the drug drove his teenage son, Bartholomew Thomas "B.J" Stupak Jr., to commit suicide in
2000.
Psychological effects
In addition to possible anxiety, several studies have shown that male patients taking isotretinoin show increased sensitivity to testosterone, and related psychological effects such as unusual irritability, over-inflated self-confidence and increased sexual desire. It should be noted that none of these symptoms have been known to last more than one month after the end of the treatment.
Am J Psychiatry 2007;122(5):996-67. PMID 16363402
Crohn's Disease and Ulcerative colitis
Accutane use has also been linked to
Crohn's Disease and
Ulcerative colitis. Several cases in the United States have resulted in multi-million dollar judgements against the makers of isotretinoin.
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Drug interactions
The concurrent use of isotretinoin with
tetracycline antibiotics or
vitamin A supplementation isn't recommended. Concurrent use of isotretinoin with tetracyclines significantly increases the risk of
idiopathic intracranial hypertension. Concurrent intake of
Vitamin A supplementation increases the risk of vitamin A toxicity.
Concurrent use of isotretinoin with
methotrexate increases the risk of
hepatotoxicity and may increase methotrexate levels. The combination is used with caution and close monitoring of adverse effects and
liver function tests.
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