Acne Treatment With Out Benzoyl Peroxide
Isotretinoin (INN) (pronounced /ˌaɪsoʊtrɨˈtɪnɵʊɨn/) is a medication used for the treatment of moderate to severe acne. It was first developed to be used as a chemotherapy medication for the treatment of brain cancer, pancreatic cancer and more. It is still used in the treatment of these cancers to this day because of its ability to kill cells off that divide too quickly. The effects of the medication are non-selective and highly widespread. In some cases, it is used to treat Harlequin type ichthyosis, a usually lethal skin deformation in which sufferers develop armor plated-like skin and usually die soon after birth. 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), Clarus (PREMPHARM), 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).
On June 29, 2009, Roche Pharmaceuticals discontinued the manufacture and distribution of Accutane brand isotretinoin in the United States for what the company described as business reasons related to low market share (below 5 percent) coupled with the high cost defending personal-injury lawsuits brought forth by some patients prescibed the drug. Isotretinoin will remain available in the United States under various generic brands. Roche continues to defend Accutane and claims to have treated 13 million patients since its introduction in 1982. Roaccutane will continue to be used outside of America.
History
An early, effective treatment of acne first used during the 1930s 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.
Building on this discovery, the retinoic acid derivative isotretinoin (13-cis-retinoic acid) was developed and released in 1982 by Hoffmann-La Roche. Advantages of the synthetic compound included fewer side effects when compared to vitamin A, and overall better success at treating acne. 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.
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 5 mg or 10 mg 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. This presents a dilemma for acne sufferers residing in countries with highly regulated medical and pharmaceutical industries (FD&C Act), as private importation might violate existing statutes.
Pharmacodynamics
Isotretinoin's exact mechanism of action is unknown. However it is known that, like other retinoids, the drug alters DNA transcription. The drug decreases the size and sebum output of the sebaceous glands. It also stabilizes keratinization, makes the cells that are sloughed off into the sebaceous glands less sticky, and therefore inhibits the formation of comedones. Isotretinoin's combined impact on several of acne's contributory factors distinguishes isotretinoin from alternative remedies such as antibiotics and accounts for its greater efficacy in severe, nodulocystic cases.
The effect on sebum production is temporary. However, remission of the disease can be "complete and prolonged."
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
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 20 mg daily is far less expensive than taking 80 mg daily).
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. Isotretinoin has been used to treat the extremely rare condition Fibrodysplasia Ossificans Progressiva.
Prescribing restrictions
In the United Kingdom, this drug may only be prescribed 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 isotretinoin's more immediate availability have proved contentious. Similar restrictions are common 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, there have been significant changes in the regulations regarding the prescribing of oral Isotretinoin as of 1 March, 2009. Under the new provisions, a vocationally registered General Practitioner is permitted to prescribe oral Isotretinoin under a group of requirements as detailed on the Pharmac Special Authority form available from the link :
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 at least Mexico and Colombia, 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. Hi
