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 is 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), Izotek (BlauFarma); while topical isotretinoin is most commonly marketed under the trade names Isotrex or Isotrexin (Stiefel).
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 (e.g. 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 medical supervision required in taking a toxic dosage. 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 do not 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 is mailed illegally across borders.
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 is 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, Colombia and probably other Latin American countries, this drug is of restricted use, and an official identification and patient signature is required by the pharmacies.
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. High dose treatments should only be used as a last resort due to adverse side effects.
Other studies show that lower dosage treatments are just as effective. 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:
The following adverse effects have been reported to persist, even after discontinuing therapy: alopecia (hair loss), arthralgias, decreased night vision, inflammatory bowel disease, degenerative disc disease, keloids, bone disease. High dosages of isotretinoin have been reported to cause rosacea (a disease of severe facial skin redness and irritation).
Erectile dysfunction in the form of difficulty in maintaining erection was reported in several patients in a clinical study. The impotence may have been caused by the psychiatric side effects of isotretinoin. Despite this, sexual dysfunction is not 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 .
The manufacturer recommends that pregnancy be excluded in female patients two weeks prior to commencement of isotretinoin, and that they should use effective contraception (sometimes two simultaneous forms are recommended) at least one month prior to commencement, during, and for at least one month following isotretinoin therapy.
In the U.S. more than 2,000 women have become pregnant while taking the drug between 1982 and 2003, with most pregnancies ending in abortion or miscarriage. About 160 babies with birth defects were born. 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 do not become pregnant – as of 1 March 2006, only prescribers registered and activated in iPLEDGE are able to prescribe isotretinoin, and only patients registered and qualified in iPLEDGE will be able to have isotretinoin dispensed.
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.
Several scientific studies have posited that isotretinoin is a probable cause of Crohn's Disease and Ulcerative colitis in some individuals. Three cases in the United States have gone to trial thus far, with all three resulting in multi-million dollar judgments against the makers of isotretinoin; there are an additional 425 cases pending.
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.
Please add the following significant reference to Wikipedia's Isotretinoin (section). It announces—more emphatically than creator Roche has stressed—that isotretinoin (brand name Accutane)is a potential TRIGGER of Crohn's disease and ulcerative colitis:
Prokop LP. Isotretinoin: Possible Component Cause of Inflammatory Bowel Disease. Amer J Gastroenterol. 1999; 94(9):2568.
This reference has now been cited nearly twenty times internationally, in both medical journals and textbooks.