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Isotretinoin
 

Isotretinoin (INN) (IPA: ) is a medication used for the treatment of severe acne. It is a retinoid, meaning it is derived from vitamin A and is found in small quantities naturally in the body. Oral isotretinoin is marketed under various trade names, most commonly Accutane or Roaccutane (Roche); while topical isotretinoin is most commonly marketed under the trade names Isotrex or Isotrexin (Stiefel).

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. A generic drug is identical in chemical makeup to the brand-name version of the drug. Accutane in generic form is sold as Amnesteem or Claravis, and there may be additional generic versions of this drug in the future.

Today isotretinoin is usually prescribed after other acne treatments have failed to produce results. The treatment of acne usually 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 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.Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3 Klasco RK, editor. Drugdex system, vol. 128. Greenwood Village (CO): Thomson Micromedex; 2006. 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 for adverse effects.

Prescribing restrictions

In the United Kingdom, isotretinoin may only be prescribed by, or under the supervision of, a consultant dermatologist.Joint Formulary Committee. British National Formulary. 47th ed. London: British Medical Association and Royal Pharmaceutical Society of Great Britain. ISBN 0-85369-584-9 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).Pharmaceutical Services Branch. Guide to poisons and therapeutic goods legislation for medical practitioners and dentists. Sydney: NSW Department of Health; 2006. 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 program 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. In turn, pharmacies must order the correct dosage, but not before the patient physically presents the prescription along with an iPLEDGE ID card. Prescriptions cannot legally be phoned-in, or ordered by pharmacies ahead-of-time. 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 1–1.25 mg/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 100–150 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:

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.Kus S, Gün D, Demirçay Z, Sur H. Vitamin E does not reduce the side-effects of isotretinoin in the treatment of acne vulgaris. Int J Dermatol 2005;44(3):248-51. PMID 15807739

Patients receiving isotretinoin therapy are not permitted to donate blood 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.Roche Products Pty Ltd. Roaccutane (Australian Approved Product Information). Dee Why (NSW): Roche; 2005.

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 program 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.O'Donnell J. Overview of existing research and information linking isotretinoin (accutane), depression, psychosis, and suicide. Am J Ther 2003;10(2):148-59. PMID 12629595Bremner JD. Does isotretinoin cause depression and suicide? Psychopharmacol Bull 2003;37(1):64-78. PMID 14561949 Various case reports of depression, suicidal ideation, suicide attempt, and suicide in patients treated with isotretinoin have been reported ot the U.S. FDA Adverse Events Reporting System, with 431 cases reported between 1982 and May 2001 – of these 37 patients had committed suicide.Wysowski DK, Pitts M, Beitz J. An analysis of reports of depression and suicide in patients treated with isotretinoin. J Am Acad Dermatol 2001;45(4):515-9. PMID 11568740 While analyses have suggested an association between isotretinoin therapy and depression, no causal relationship has been established and further studies are required. Ng CH, Schweitzer I. The association between depression and isotretinoin use in acne. Aust N Z J Psychiatry 2003;37(1):78-84. PMID 12534661Hull PR, D'Arcy C. Isotretinoin use and subsequent depression and suicide: presenting the evidence. Am J Clin Dermatol 2003;4(7):493-505. PMID 12814338

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.Gupta MA, Gupta AK. Depression and suicidal ideation in dermatology patients with acne, alopecia areata, atopic dermatitis and psoriasis. Br J Dermatol. 1998;139(5):846-50. PMID 9892952Niemeier V, Kupfer J, Demmelbauer-Ebner M, Stangier U, Effendy I, Gieler U. Coping with acne vulgaris. Evaluation of the chronic skin disorder questionnaire in patients with acne. Dermatology 1998;196(1):108-15. PMID 9557243 Correspondingly, treatment of severe acne with isotretinoin has been shown to reduce anxiety and depression.Rubinow DR, Peck GL, Squillace KM, Gantt GG. Reduced anxiety and depression in cystic acne patients after successful treatment with oral isotretinoin. J Am Acad Dermatol 1987;17(1):25-32. PMID 2956296Chia CY, Lane W, Chibnall J, Allen A, Siegfried E. Isotretinoin therapy and mood changes in adolescents with moderate to severe acne: a cohort study. Arch Dermatol 2005;141(5):557-60. PMID 15897376

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.Bremner JD, Fani N, Ashraf A, Votaw JR, Brummer ME, Cummins T, et al.Functional brain imaging alterations in acne patients treated with isotretinoin. Am J Psychiatry 2005;162(5):983-91. PMID 15863802

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.

See also

References

External links

Pharmacologic agents | Teratogens

Isotretinoin | ایزوترتینوین | Isotrétinoïne | רואקוטן

 

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