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In the United Kingdom, this drug may only be prescribed by, or under the supervision of, a consultant [[dermatologist]].<ref name="BNF47">Joint Formulary Committee. [[British National Formulary]]. 47th ed. London: British Medical Association and Royal Pharmaceutical Society of Great Britain. ISBN 0-85369-584-9</ref> A similar situation exists in most [[Australia]]n states – in [[New South Wales]], for instance, the prescriber must be a [[Fellow]] of the Australasian College of Dermatologists (FACD).<ref>Pharmaceutical Services Branch. Guide to poisons and therapeutic goods legislation for medical practitioners and dentists. Sydney: NSW Department of Health; 2006.</ref>
In the United Kingdom, this drug may only be prescribed by, or under the supervision of, a consultant [[dermatologist]].<ref name="BNF47">Joint Formulary Committee. [[British National Formulary]]. 47th ed. London: British Medical Association and Royal Pharmaceutical Society of Great Britain. ISBN 0-85369-584-9</ref> A similar situation exists in most [[Australia]]n states – in [[New South Wales]], for instance, the prescriber must be a [[Fellow]] of the Australasian College of Dermatologists (FACD).<ref>Pharmaceutical Services Branch. Guide to poisons and therapeutic goods legislation for medical practitioners and dentists. Sydney: NSW Department of Health; 2006.</ref>


Since [[1 March]] [[2006]], the dispensing of isotretinoin in the United States has been controlled by a [[Food and Drug Administration|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 and pharmacists 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.
Since [[1 March]] [[2006]], the dispensing of isotretinoin in the United States has been controlled by a [[Food and Drug Administration|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. 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. 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 and pharmacists must also verify written prescriptions in an online system before patients may fill the prescription.


===Dosage===
===Dosage===

Revision as of 01:55, 15 June 2007

Isotretinoin
Clinical data
License data
Pregnancy
category
  • AU: X (High risk)
Routes of
administration		Oral, topical
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: WARNING[1]Rx-only
Pharmacokinetic data
BioavailabilityVariable
Protein binding99.9%
MetabolismHepatic
Elimination half-life10–20 hours
ExcretionRenal and fecal
Identifiers
  • (2Z,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-
    cyclohexenyl)nona-2,4,6,8-tetraenoic acid
CAS Number
PubChem CID
DrugBank
CompTox Dashboard (EPA)
ECHA InfoCard100.022.996 Edit this at Wikidata
Chemical and physical data
FormulaC20H28O2
Molar mass300.44 g/mol g·mol−1

Isotretinoin (INN) (IPA: [ˌaɪsoʊˈtrɛtənoʊɪn]) is a medication used for the treatment of severe acne. It is sometimes used in prevention of certain skin cancers. 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 (Roche), Amnesteem (Mylan), Claravis (Barr), Sotret (Ranbaxy), 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.

For reasons unknown, high dosages of the drug became mainstream in treatment. Lower dosages were found to be effective in treatment by independent tests, but Roche's dosage recommendations were used instead. Because of the use of higher dosages, the teratogenic potential was more pronounced, and pregnancies with the drug were strongly discouraged. When they occurred, they were found to have approximately 30% rates of congenital malformation, versus a 3-5% baseline risk.[2] This led to scrutiny of pregnancy testing beginning in 1998. Before this fewer than half of prescribers were testing for pregnancy, usually relying on less sensitive urine tests.[3] Thus, on the grounds that pregnancies by women taking the drug had been underreported by the manufacturer between 1982 and 2000, and that once generic manufacturers entered the market risk management was no longer centralized, the FDA instituted restrictions on prescribing and dispensing the drug, first with the "System to Manage Accutane Related Teratogenicity" (SMART) in 2000, and subsequently the iPLEDGE program in 2006. A retrospective cohort study recently found that pregnancy rates were quite high during the period (1 per 30 women per year), but 84% of pregnancies were ended by induced abortion.[4]

Isotretinoin used to be prescribed after other acne treatments failed to produce results. Treatment of acne usually began with topical medications (e.g. benzoyl peroxide, adapalene, etc), was followed by oral antibiotics (or a combination) and finally isotretinoin therapy. This is because other treatments, while less effective than isotretinoin, used to be associated with far fewer adverse effects and lower cost. The higher cost was due to the higher dosages used. Not only did it multiply the cost of the medicine by 4 to 8 times, but it also required medical supervision while taking a substancially toxic dosage.

In countries that do not restrict distribution of isotretinoin, pharmacists recommend 5mg to 10mg per day, since at lower dosages many of the adverse effects are diminished or non-existent. Women should consult a doctor about taking 5mg a day if there is a possibility of pregnancy (for safety, the "upper limit" of Vitamin A may be used instead).

Isotretinoin is available over the internet from countries where it can be dispensed without a prescription. It is an ongoing problem for governments where a prescription is required, as it is mailed illegally across borders.

Pharmacodynamics

Isotretinoin noticeably reduces the production of sebum and shrinks the sebaceous glands. It stabilizes keratinization and prevents comedones from forming. The exact mechanism of action is unknown, however it is known that like other retinoids, Isotretinoin works by altering DNA transcription.[5] This effect decreases the size and output of sebaceous glands, makes the cells that are sloughed off into the sebaceous glands less sticky, and therefore less able to form comedones.

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.[6][7] It is also effective for hidradenitis suppurativa and some cases of severe acne rosacea.[7] It can also be used to help treat harlequin ichthyosis, and is used in xeroderma pigmentosum cases to relieve keratoses.

Prescribing restrictions

In the United Kingdom, this drug may only be prescribed by, or under the supervision of, a consultant dermatologist.[8] 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).[9]

Since 1 March 2006, the dispensing of isotretinoin in the United States has been controlled by a 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. 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. 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 and pharmacists must also verify written prescriptions in an online system before patients may fill the prescription.

Dosage

10 mg capsule

The dose of isotretinoin a patient receives is dependent on their weight and the severity of the condition. High dose treatments are administered between 0.5 mg/kg/day to 2 mg/kg/day (usually at 0.5 to 1 mg/kg/day[10], divided into two doses), for a total treatment of 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.[6][7] High dose treatment should only be used as a last resort due to adverse side effects. Other studies show that a lower dosage treatment may be just as effective.[11][12] In these experiments, subjects used 20mg/day, which is 0.25 mg/kg/day for an 80 kg (176 pounds) person.

Preparations

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

Isotretinoin is marketed under many brand names by various manufacturers. It is typically available as 5 mg, 10 mg, 20 mg, 30mg 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 (with erythromycin).

Adverse effects

Increasingly higher dosages will result in higher toxicity, resembling vitamin A toxicity. Adverse drug reactions associated with isotretinoin therapy include:[6]

The following adverse effects have been reported to persist, even after discontinuing therapy: alopecia (hair loss), arthralgias, decreased night vision, degenerative disc disease, keloids, bone disease. High dosages of isotretinoin have been reported to cause rosacea (a disease of severe facial skin redness and irritation).

While vitamin E supplements have been advocated by some to reduce the toxicity of high-dose retinoids without reducing drug efficacy, test results have proven this to be false.[13]

Patients receiving isotretinoin therapy are not permitted to donate blood during and for at least one month after discontinuation of isotretinoin therapy due to reported birth defects to unborn children.

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.[7]

The manufacturer recommends that pregnancy be 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.[14]

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 or miscarriage. 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.[15][16] 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.[17] While analyses have suggested an association between isotretinoin therapy and depression, no causal relationship has been established and further studies are required.[18][19]

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.[20][21] Isotretinoin related depression, as Chee Hong describes, is "an idiosyncratic side-effect." Often anxiety can bring on acne and depression, creating more anxiety.[22] Correspondingly, treatment of severe acne with isotretinoin has been shown to reduce anxiety and depression, for the acne seems to be a main depressant in most patients' lives.[23][24]

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.[25]

U.S. Representative Bart Stupak (D-MI) is known for his distrust of Accutane. He believes unadvertised psychological side effects from the drug drove his teenage son, Bartholomew Thomas "B.J" Stupak Jr., to commit suicide in 2000.

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.[7]

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.[6]

Concurrent use of isotretinoin with marijuana may increase the symptoms of depression.[citation needed]

See also

References

  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
  2. ^ PMID
  3. ^ PMID
  4. ^ PMID
  5. ^ DrugBank database - Isotretinoin (APRD00140), 12 November 2006, University of Alberta, accessed January 2007
  6. ^ a b c d Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
  7. ^ a b c d e Klasco RK, editor. Drugdex system, vol. 128. Greenwood Village (CO): Thomson Micromedex; 2006.
  8. ^ Joint Formulary Committee. British National Formulary. 47th ed. London: British Medical Association and Royal Pharmaceutical Society of Great Britain. ISBN 0-85369-584-9
  9. ^ Pharmaceutical Services Branch. Guide to poisons and therapeutic goods legislation for medical practitioners and dentists. Sydney: NSW Department of Health; 2006.
  10. ^ United States Pharmacopeia Staff. Consumer Reports Complete Drug Reference. Yonkers, NY: Consumer Reports Books, 1995. Pg 998.
  11. ^ Amichai B, Shemer A, Grunwald M (2006). "Low-dose isotretinoin in the treatment of acne vulgaris". J Am Acad Dermatol. 54 (4): 644–6. PMID 16546586.{{cite journal}}: CS1 maint: multiple names: authors list (link) Summary of study results
  12. ^ Seukeran D, Cunliffe W (1998). "Acne vulgaris in the elderly: the response to low-dose isotretinoin". Br J Dermatol. 139 (1): 99–101. PMID 9764156.
  13. ^ 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
  14. ^ Roche Products Pty Ltd. Roaccutane (Australian Approved Product Information). Dee Why (NSW): Roche; 2005.
  15. ^ 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 12629595
  16. ^ Bremner JD. Does isotretinoin cause depression and suicide? Psychopharmacol Bull 2003;37(1):64-78. PMID 14561949
  17. ^ 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
  18. ^ Ng CH, Schweitzer I. The association between depression and isotretinoin use in acne. Aust N Z J Psychiatry 2003;37(1):78-84. PMID 12534661
  19. ^ Hull 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
  20. ^ 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 9892952
  21. ^ Niemeier 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
  22. ^ Chee Hong Ng, Isaac Schweitzer (2003)The association between depression and isotretinoin use in acne Australian and New Zealand Journal of Psychiatry 37 (1), 78–84. doi:10.1046/j.1440-1614.2003.01111.x
  23. ^ 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 2956296
  24. ^ Chia 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
  25. ^ 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

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