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Isotretinoin

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File:Accutane.gif
Logo of Accutane® brand of isotretinoin.

Isotretinoin is a generic medication used for the treatment of severe acne and most commonly known under the brands Accutane and Roaccutane. 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 chemical structure
Isotretinoin

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
Hypersensitivity to Isotretinoin
Sensitive to parabens

Interactions:

Vitamin A
Tetracyclines

Side effects:

Severe:
Teratogenic (Severe birth defects)
Suicide

Cardiovascular:
Palpitation, Tachycardia, Stroke, Vascular Thrombotic Disease

Ear, nose, and throat:
hearing impairment, tinnitus

Endocrinal:
hypertriglyceridemia

Eye:
corneal opacities, decreased night vision, cataracts, color vision disorder, conjunctivitis, dry eyes, eyelid inflammation, keratitis, optic neuritis, photophobia, visual disturbances

Gastrointestinal:
inflammatory bowel disease, hepatitis, pancreatitis, bleeding and inflammation of the gums, colitis, esophagitis/esophageal ulceration, ileitis, nausea

Hematological:
allergic reactions, nemia, thrombocytopenia, neutropenia, agranulocytosis

Musculoskeletal:
skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure, decreases in bone mineral density, arthritis, tendonitis, rhabdomyolysis

Neurological:
pseudotumor cerebri, dizziness, drowsiness, headache, insomnia, lethargy, malaise, nervousness, paresthesias, seizures, stroke, syncope, weakness

Psychological:
suicidal ideation, suicide attempts, suicide, depression, psychosis, aggression, violent behaviors, emotional instability

Respiratory:
bronchospasms, respiratory infection, voice alteration

Skin:
acne fulminans, alopecia, bruising, cheilitis, dry mouth, drynose, dry skin, epistaxis, eruptive xanthomas, flushing, fragility of skin, hair abnormalities, hirsutism, hyperpigmentation, hypopigmentation, infections, nail dystrophy, paronychia, peeling of palms and soles, photoallergic/photosensitizing reactions, pruritus, pyogenic granuloma, rash, sunburn susceptibility increased, sweating, urticaria, vasculitis, abnormal wound healing

Urogenital and reproductive:
abnormal menses

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.

Brand names

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

Some brands of isotretinoin include:

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 0.5mg/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:

  • Alopecia (hair loss)
  • Arthralgias
  • Decreased night vision

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

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]. 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

Several studies [2][3][4] 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] Statistical evidence shows that the suicide rate among Accutane users is actually lower than average. [6]

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)

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 hours after his junior prom in May 2000.

See also

References

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