Isotretinoin

Isotretinoin (INN) ( or ) is a medication used for the treatment of severe acne. It is sometimes used in prevention and treatment of certain skin cancers. 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.

Presently, 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 higher dosages used. Taking a toxic level of any substance requires medical supervision. 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.

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 is 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.

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. It can also be used to help treat harlequin ichthyosis, and is used in xeroderma pigmentosum cases to relieve keratoses. Although extremely rare, isotretinoin has been used as a treatment for Fibrodysplasia Ossificans Progressiva.

Prescribing restrictions
In the United Kingdom, this drug may only be prescribed by, or under the supervision of, a consultant dermatologist. 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 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. Doctors 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 30-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 wait 30 days without any medication. 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. 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: 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: The following adverse effects have been reported to persist, even after discontinuing therapy: alopecia (hair loss), arthralgias, decreased night vision, 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).
 * Common: mild acne flare, dryness of skin, lips and mucous membranes, infection of the cuticles, cheilitis, itch, skin fragility, skin peeling, rash, flushing, photosensitivity, nose bleeds, dry eyes, eye irritation, conjunctivitis, reduced tolerance to contact lenses, hyperlipidaemia, raised liver enzymes, headaches, hair thinning, myalgia and/or arthralgia.
 * Infrequent: severe acne flare, raised blood glucose level, increased erythrocyte sedimentation rate, fatigue.
 * Rare: impaired night vision, cataracts, optic neuritis, menstrual disturbances, inflammatory bowel disease, pancreatitis, hepatitis, corneal opacities, papilloedema, idiopathic intracranial hypertension, skeletal hyperostosis, extraosseous calcification, and it is believed that severe depression can occur, although there is no conclusive evidence for this.

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.

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.

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.

Teratogenicity (Birth Defects)
Isotretinoin is a teratogen and is highly likely to cause birth defects if taken during pregnancy. Isotretinoin is classified as FDA Pregnancy Category X and ADEC Category X, and use is contraindicated in pregnancy.

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.

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.

Drug interactions
The concurrent use of isotretinoin with tetracycline antibiotics or vitamin A supplementation is not 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.