Isotretinoin
|
|
Isotretinoin is a medication used for the treatment of acne. It is a retinoid, meaning it is derived from Vitamin A and is found naturally in the body, produced by the liver in small quantities. Isotretinoin is sold under many brand names, including Accutane® and Roaccutane® by Roche. It is also marketed as Accure® (Alphapharm), Oratane® (Douglas Pharmaceuticals), Isohexal® (Hexal Australia), Amnesteem® (Bertek) and Claravis® (Barr).
|
Missing image | |
| 13-cis-retinoic acid | |
| CAS number 4759-48-2 | ATC code D10AD04 |
| Chemical formula | C20H28O2 |
| Molecular weight | 300.44 |
| Bioavailability | ? |
| Metabolism | Liver |
| Elimination half life | 21 hours |
| Excretion | Feces and Urine |
| Pregnancy category | X (USA) X (Aus) X (UK) |
| Legal status | Prescription |
| Delivery | ? |
| Indicated for: Severe Recalcitrant Nodular Acne |
| Contraindications: Pregnancy and/or Breast feeding |
| Interactions: |
| Side effects:
Missing image Severe: Cardiovascular: Ear, nose, and throat: Endocrinal: Eye: Gastrointestinal: Hematological: Musculoskeletal: Neurological: Psychological: Respiratory: Skin: Urogenital and reproductive: |
| Contents |
History
Prior to the development of isotretinoin, the mainstay treatment of severe 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, 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.
The development of the derivative of retinoic acid, 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 side effects. In February 2002 Roche's patents for isotretinoin expired, there are now many other companies selling cheaper generic versions of the drug.
Today isotretinoin is usually prescribed after other acne treatments have failed to produce results. The treatment of acne usually begins with topicals, moves onto oral antibiotics (or a combination) and finally isotretinoin therapy. This is because other treatments, while less effective than isotretinoin, produce far fewer side effects.
Available forms
Isotretinoin is available as Accutane® inside the USA and as Roaccutane® outside of the USA, both of these brands being produced by Hoffmann-La Roche. It is also available in other brand names around the world.
It is available as 10mg (light pink), 20mg (maroon) and 40mg (yellow) color coded capsules when sold as Accutane®, and other brands have similar systems.
Indications
Isotretinoin is indicated for treatment for a number of dermatological conditions, most commonly acne. It is generally not used as a first-line treatment due to the potential side effects. Antibiotics (such as the tetracyclines) are usually prescribed before isotretinoin.
Severe forms of acne (conglobata, fulminans and nodulocystic) as well as acne that scars can be successfully treated with isotretinoin.
Acne that has not responded to other treatment will usually respond to isotretinoin. Dysmorphobic patients may also be prescribed isotretinoin.
Pharmacodynamics
Isotretinoin noticeably reduces the production of sebum and shrinks the sebaceous glands. It stabilises keratinization and prevents comedones from forming. The exact mechanism of action is unknown, however it is known that it alters DNA transcription.
The dose of isotretinoin a patient receives is dependent on their weight and the severity of the condition. Generally it is prescribed from between .5mg/kg/day to 2mg/kg/day, for example a 70kg (155 pounds) person would take from between 35mg to 140mg per day dependant on the severity of their condition.
It should also be noted that some studies have associated remission of the condition with the total dose taken. It is generally advisable to take a dose of greater than 125mg/kg over the entire treatment period to see maximum benefit.
Pharmacokinetics
Absorption
Isotretinoin, when administered orally, is best absorped 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.
Distribution
Isotretinoin is primarily (99.9%) bound to plasma proteins, mostly albumin.
Metabolism
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.
Elimination
The metabolites of isotretinoin are excreted through both urine and feces. The mean elimination half life for isotretinoin is 21 hours, with a standard deviation from this mean of 8.2 hours.
Drug Interactions
Vitamin A, in supplement form, should be strictly avoided while undertaking therapy with isotretinoin. It increases the risk of side effects associated with use.
Tetracycline antibiotics, also prescribed for acne, should also be avoided. A significant increase in the risk of pseudotumor cerebri is associated with concurrent use of these drugs.
Side-effects
Isotretinoin has many side effects, listed in the table on the right. The more severe side effects are listed here in more detail.
It is also worth noting that the following side effects can persist, even after discontinuing therapy:
- Alocepia (Hair Loss)
- Arthralgias
- Decreased night vision
Teratogenicity
Isotretinoin is a teratogen - it is highly likely that if taken during pregnancy that it will cause birth defects. In the USA isotretinoin is in pregnancy category X. Isotretinoin must be prescribed under a policy that mandates that female patients be placed on two separate, effective forms of birth control [1] (http://www.fda.gov/cder/drug/infopage/accutane/smart.pdf). Male patients should be informed of the risk associated with use during pregnancy, emphasising that they should not share the drug, especially with females.
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. About 160 babies with birth defects were born. Doctors normally require two separate methods of birth control for sexually active women taking isotretinoin and until one month after terminating the drug.
Depression
Many studies [2] (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12629595)[3] (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14669543)[4] (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14561949) have emerged suggesting a possible link between isotretinoin and depression. It must however be acknowledged that its primary use is for the treatment of the most severe acne. The possibility that this severe acne is causing the depression is therefore not to be ruled out. Moreover, improvement of a patient's acne by successful treatment with isotretinoin can actually reduce symptoms of anxiety and depression. [5] (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=2956296) Statistical evidence shows that the suicide rate among Accutane users is actually lower than average. [6] (http://www.stats.org/record.jsp?type=news&ID=85)
After Charles Bishop, a 15-year old student pilot, flew a light aircraft into a Tampa, Florida building on January 5, 2002, his family claimed Accutane had caused severe psychosis in the boy and filed a $70 million lawsuit against Hoffman-La Roche. However, an autopsy found no traces of the drug in the boy's system.
See also
External links
- Hoffmann-La Roche (http://www.roche.com) (Makers of (Ro)accutane)
- FDA's Accutane Information Page (http://www.fda.gov/cder/drug/infopage/accutane/default.htm)
- Accutane Action Group (http://www.accutaneaction.com/) (Group of people who suffered continuing side effects from isotretinoin).
- Acne.org Message board (http://www.acne.org/messageboard/) (provides a forum on which many people keep diaries on Accutane use)
- Australian Roaccutane Survivors (http://www.roaccutanesurvivors.com) (Similar to AAG above)
- Roaccutane Action Group Forum (http://www.ragforum.com/) (A forum where people share experiences of serious long term side effects after Accutane usage)
- Drugs.com Isotretinoin Information (http://www.drugs.com/MTM/isotretinoin.html)
- Bumps in the night: The Accutane story is all scare and no science (http://reason.com/hod/mf012302.shtml) (Reason Online)
- Skin deep: Accutane didn't depress me, it helped me live again (http://reason.com/hod/mf012302.shtml) (Reason Online)