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 – 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.

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.

Today isotretinoin is usually prescribed after other acne treatments have failed to produce results. The treatment of acne usually begins with topical medications (eg. 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 associated with far fewer adverse effects and lower cost.

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.

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

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 is generally not used as a first-line treatment in moderate cases due to the potential adverse effects.

Prescribing restrictions

In the United Kingdom, isotretinoin 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, for instance, the prescriber must be a Fellow of the Australasian College of Dermatologists (FACD). Since 1 March 2006, the dispensing of isotretinoin in the United States has been controlled by an 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.

For many patients, the iPLEDGE programme has caused delays in receiving isotretinoin. 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. No more than a 30 day supply may be filled. 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 wait 30 days without any medication. Doctors must also verify written prescriptions in an online system before patients may fill the prescription. This sequence of requirements can make it very difficult for patients to receive and take isotretinoin on the prescribed schedule. Many patients are forced to wait several days without medication.

Dosage

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 (and perhaps most often at 0.5 to 1 mg/kg/day) for 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.

Preparations

Isotretinoin is marketed under many brand names by various manufacturers. It is typically available as 5 mg, 10 mg, 20 mg 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), Isohexal (Hexal Australia), 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.

Adverse effects

Most adverse effects resemble vitamin A toxicity. Adverse drug reactions associated with isotretinoin therapy include:

   * Common (≥1% of patients): mild acne flare, dryness of skin, lips and mucous membranes, 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 (0.1–1% of patients): severe acne flare, raised blood glucose level, increased erythrocyte sedimentation rate, fatigue and/or mood changes.
   * Rare (<0.1% of patients): impaired night vision, cataracts, optic neuritis, menstrual disturbances, inflammatory bowel disease, pancreatitis, hepatitis, corneal opacities, papilloedema, idiopathic intracranial hypertension, skeletal hyperostosis and extraosseous calcification.

The following adverse effects have been reported to persist, even after discontinuing therapy: alopecia (hair loss), arthralgias, decreased night vision, degenerative disc disease, keloids (cartilage degeneration), bone disease, depression (in some cases). High dosages of isotretinoin have been reported to cause rosacea.

While vitamin E supplements have been advocated by some to reduce the toxicity of high-dose retinoids without reducing drug efficacy, it does not appear to be effective.

Patients receiving isotretinoin therapy are not permitted to donate blood during and for at least one month after discontinuation of isotretinoin therapy.

Teratogenicity

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 is 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. About 160 babies with birth defects were born. Consequently, the iPLEDGE programme 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 US. 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. Correspondingly, treatment of severe acne with isotretinoin has been shown to reduce anxiety and depression.

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.

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.