Isotretinoin is a generic medication used for the treatment of severe acne and most commonly known under the brands Accutane, Roaccutane, Amnesteem, Claravis, Isotane, Sotret and Oratane. 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.

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, and 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 to oral antibiotics (or a combination) and finally isotretinoin therapy. This is because other treatments, while less effective than isotretinoin, produce far fewer side effects.

Effective March 1, 2006, the dispensing of isotretinoin in the United States is contolled by a cumbersome FDA-mandated website called iPLEDGE. Dermatologists must register their patients, and pharmacists then check the website before prescribing the drug.

Brand names

Isotretinoin is produced under many brand names by many manufacturers. It is available typically as 5 mg, 10 mg, 20 mg and (in the USA) 40 mg capsules.

Some brands of isotretinoin include:

• Accure® by Alphapharm
• Accutane® and Roaccutane® by Roche
• Aknenormin® by Hermal
• Amnesteem® by Mylan
• Ciscutan® by Pelpharma
• Claravis® by Barr
• Isohexal® by Hexal Australia
• Isotroin® by Cipla
• Oratane® by Douglas Pharmaceuticals
• Sotret® by Ranbaxy

Indications

Isotretinoin is indicated for treatment of cystic acne vulgaris in men and in women who will not get pregnant while on the drug. It is also effective for hidradenitis suppurativa and some cases of severe acne rosacea.

It is generally not used as a first-line treatment in moderate cases due to the potential side effects. In these patients, oral antibiotics (such as the tetracyclines)and topical medications like tretinoin ("Retin A") and benzoyl peroxide are usually prescribed before isotretinoin. But in severe cystic acne, isotretinoin is used immediately.

Acne that has not responded to other treatment is another indication for isotretinoin therapy.

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 0.5 mg/kg/day to 2 mg/kg/day, for example a 70 kg (155 pounds) person would take from between 35 mg to 140 mg per day dependent on the severity of their condition.

Some studies have associated remission of the condition with the total dose taken. It is generally advisable to take a dose of greater than 125 mg/kg over the entire treatment period to see maximum benefit.

Pharmacokinetics

Absorption

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.

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.

According to some studies, vitamin E reduces the toxicity of high-dose retinoids without reducing drug efficacy. [1] However, another study found that vitamin E does not reduce the side-effects of isotretinoin. [2]

Side effects

The most feared complication of isotretinoin is its teratogenicity, i.e., the ability to cause birth defects. Isotretinoin has many side effects, listed in the table on the right. The more severe side effects are listed here in more detail.

The following side effects can persist, even after discontinuing therapy:

• Alopecia (hair loss)
• Arthralgias
• Decreased night vision
• Degenerative disc disease
• Cartilage degeneration
• Bone disease
• Depression (in some cases)
• High dosages of isotretinoin have been reported to cause rosacea

It should also be mentioned that isotretinoin users are not allowed to give blood for at least a month after discontinuing isotretinoin use.

Treatment of Side Effects

Acne fulminans- Linked pustules that result in severe scarring (predominantly keloid scarring.) Treatment carried out by a dermatologist would involve first removal of isotretinoin pills completely and any oral steroids (gradually remove), which are often prescribed when initial symptoms start. Medication generally is of a combination of clindamycin and dapsone combined with isotrexin gel (isotretinoin in a topical form.) Any pyrogenic granulomas (granulated pretruding weeping tissue) that does not heal may be cauterised with silver nitrate so the skin may grow correctly again. Once the wound has fully healed so no weeping (months) any keloid scars are injected with steroids to flatten the scar and reduce inflammation. Further scarring may be treated by non-ablative laser called N-lite to promote collagen formation and healing.

Teratogenicity

Isotretinoin is a teratogen - it is highly likely that it will cause birth defects if taken during pregnancy. 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 [3]. 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. The FDA approved a strengthened risk management plan for Accutane and generic Isotretinoin on August 12, 2005, to make sure females do not become pregnant while taking this medicine. This new plan is called iPLEDGE. By March 1, 2006, only prescribers registered and activated in iPLEDGE will be able to prescribe Isotretinoin and only patients registered and qualified in iPLEDGE will be able to be dispensed Isotretinoin.

Depression

Several studies [4][5][6] 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. [7] Statistical evidence shows that the suicide rate among Accutane users is actually lower than average. [8] In summary, there is no scientific data linking isotretinoin to depression. In fact, studies indicate that acne sufferers treated with isotretinoin are less depressed than a control group. They are seeing a dermatologist, have rapport with their physician, and are successfully treating their acne.

Emory University conducted a study of isotretinoin and depression. The study subjects were given psychological tests beforehand that showed no correlation between the severity of their acne and feelings of depression. A baseline PET scan of all the subjects was done. A second PET scan showed that individuals who had used the drug for four months showed decreased activity in the orbitofrontal cortex, a section of the brain thought to control mood and social interaction. Individuals in the control group who had not used the drug showed no change. (Bremner et al. 2005)

The Journal of the American Medical Association (JAMA) Archives of Dermatology published a study [9] in May of 2005 which appears to refute claims that Accutane can cause depression. In their conclusion the authors state, "The use of isotretinoin (Accutane) in the treatment of moderate-severe acne in adolescents did not increase symptoms of depression. On the contrary, treatment of acne either with conservative therapy or with isotretinoin was associated with a decrease in depressive symptoms."

Alleged cases of isotretinoin linked suicide

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.

Bart Stupak, a Michigan congressman, has alleged this connection ever since his son, B.J., an Accutane user, committed suicide with his father's loaded and unlocked handgun hours after his junior prom in May 2000.

See also

• Acne
• Retinoids
• Vitamin A
• iPLEDGE

References

• Bremner JD, Fani N, Ashraf A, Votaw JR, Brummer ME, Cummins T, Vaccarino V, Goodman MM, Reed L, Siddiq S, Nemeroff CB (2005). "Functional brain imaging alterations in acne patients treated with isotretinoin". American Journal of Psychiatry 162 (5): 983-91. PMID 15863802.

External links

• Hoffmann-La Roche (Makers of (Ro)accutane)
• FDA's Accutane Information Page
• Accutane Action Group (Group of people who suffered continuing side effects from isotretinoin).
• Acne.org Message board (provides a forum on which many people keep diaries on Accutane use)
• Australian Roaccutane Survivors (Similar to AAG above)
• Accutane/Roaccutane Action Group Forum (A forum where people share experiences of serious long term side effects after Accutane usage)
• Drugs.com Isotretinoin Information
• Bumps in the night: The Accutane story is all scare and no science (Reason Online)
• Skin deep: Accutane didn't depress me, it helped me live again (Reason Online)
• Dermatology Vol 9: issue 5: Night blindness, vitamin A deficiency, and isotretinoin psychotoxicity
• DermNet NZ - Isotretinoin