Isotretinoin

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Isotretinoin
Systematic (IUPAC) name
(13cis)-retinoic acid
Clinical data
Trade namesAccutane
AHFS/Drugs.commonograph
MedlinePlusa681043
Licence dataUS FDA:link
Pregnancy cat.X (AU) X (US)
Legal statusPrescription Only (S4) (AU) POM (UK) -only (US)
RoutesOral, topical
Pharmacokinetic data
BioavailabilityVariable
Protein binding99.9%
MetabolismHepatic
Half-life10–20 hours
ExcretionRenal and fecal
Identifiers
CAS number4759-48-2 YesY
ATC codeD10AD04
PubChemCID 5282379
DrugBankDB00982
ChemSpider4445539 YesY
UNIIEH28UP18IF YesY
KEGGD00348 YesY
ChEBICHEBI:6067 YesY
ChEMBLCHEMBL547 YesY
Chemical data
FormulaC20H28O2 
Mol. mass300.44 g/mol
 YesY (what is this?)  (verify)
 
  (Redirected from Accutane)
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Isotretinoin
Systematic (IUPAC) name
(13cis)-retinoic acid
Clinical data
Trade namesAccutane
AHFS/Drugs.commonograph
MedlinePlusa681043
Licence dataUS FDA:link
Pregnancy cat.X (AU) X (US)
Legal statusPrescription Only (S4) (AU) POM (UK) -only (US)
RoutesOral, topical
Pharmacokinetic data
BioavailabilityVariable
Protein binding99.9%
MetabolismHepatic
Half-life10–20 hours
ExcretionRenal and fecal
Identifiers
CAS number4759-48-2 YesY
ATC codeD10AD04
PubChemCID 5282379
DrugBankDB00982
ChemSpider4445539 YesY
UNIIEH28UP18IF YesY
KEGGD00348 YesY
ChEBICHEBI:6067 YesY
ChEMBLCHEMBL547 YesY
Chemical data
FormulaC20H28O2 
Mol. mass300.44 g/mol
 YesY (what is this?)  (verify)

Isotretinoin, INN, (play /ˌstrɨˈtɪn.ɨn/)[1] is a medication used mostly for cystic acne. It is also a chemotherapy treatment used in brain, pancreatic and other cancers. It is used to treat harlequin-type ichthyosis, a usually lethal skin disease, and lamellar ichthyosis. Its effects are systemic and nonselective. It is a retinoid, meaning it is related to vitamin A, and is found in small quantities naturally in the body.

Isotretinoin's best-known and most dangerous side effect is birth defects. This is because of the molecule's close resemblance to retinoic acid, a natural vitamin A derivative which controls normal embryonic development. In the United States a special prodecure is required to obtain the pharmaceutical (see below).

In 2009, Roche decided to pull Accutane off the US market after juries had awarded millions of dollars in damages to former Accutane users over inflammatory bowel disease claims. Among others, actor James Marshall sued Roche over Accutane-related disease that resulted in removal of his colon.[2]

The most common brands are Roaccutane (Hoffman-La Roche, known as Accutane in the United States before July 2009), Amnesteem (Mylan), Claravis (Barr), Isotroin (Cipla) or Sotret (Ranbaxy).[citation needed]

Contents

Medical uses

Due to side-effects and high cost, isotretinoin is used primarily for severe cystic acne and acne that has not responded to other treatments. Acne treatment usually begins with topical medications (e.g., benzoyl peroxide and adapalene), followed by oral antibiotics and isotretinoin as a last resort.

Indications

Isotretinoin's main indication is for the treatment of severe cystic acne vulgaris.[3][4] Many dermatologists also support its use for treatment of lesser degrees of acne that prove resistant to other treatments, or that produce physical or psychological scarring.[5]

It is also somewhat effective for hidradenitis suppurativa and some cases of severe acne rosacea.[4] It can also be used to help treat harlequin ichthyosis, lamellar ichthyosis and is used in xeroderma pigmentosum cases to relieve keratoses. Isotretinoin has been used to treat the extremely rare condition fibrodysplasia ossificans progressiva. It is also used for treatment of neuroblastoma, a form of nerve cancer.

Isotretinoin therapy has furthermore proven effective against genital warts in experimental use, but is rarely used due to potentially severe side effects. In a small-scale study, low dose oral isotretinoin showed considerable efficacy; Isotretinoin may represent an efficacious and safe alternative systemic form of therapy for RCA of the cervix. Not many studies have been conducted to further confirm its effectiveness. In most countries this therapy is currently unapproved and only used if other therapies failed.[6][7]

Prescribing restrictions

In the United Kingdom, this drug may be prescribed only by or under the supervision of a consultant dermatologist.[8] Because severe cystic acne has the potential to cause permanent scarring over a short period, restrictions on its more immediate availability have proved contentious.[9] Similar restrictions are common in most Australian states – in New South Wales and Victoria, for instance, the prescriber must be a Fellow of the Australasian College of Dermatologists (FACD).[10] In New Zealand, isotretinoin can be prescribed by any doctor, but is subsidised only if prescribed by a vocationally registered general practitioner or dermatologist.

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. The prescription may not be dispensed until both parties have complied. A physician 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 seven-day window between the time the prescription is written and the time the medication must be picked up at the pharmacy. If the original prescription is lost, or pick-up window is missed, the patient must requalify to have another prescription written. Doctors and pharmacists must also verify written prescriptions in an online system before patients may fill the prescription. Due to its teratogenic effects, women with the potential to bear children must commit to the use of two forms of contraception simultaneously for the duration of isotretinoin therapy, as well as for the month immediately preceding and the month immediately following therapy.[11]

In Mexico, Colombia and Brazil use of the drug is restricted and an official identification and patient signature is required by the pharmacies.

Dosage

10 mg capsule

The dose of isotretinoin patients receive 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,[12] divided into two doses), for a total treatment of four to six months. In some rare cases where the patient's acne is severe or unresponsive, the initial course may last up to nine months. A second course may be used at least eight weeks 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 over each course of 120–150 mg/kg used as a guideline.[3][4] Shorter, higher dose treatments or uninterrupted double courses should be used only as a last resort, due to adverse side effects.

Nearly all patients achieve initial clearing of acne during high-dose isotretinoin therapy. Furthermore, about 40% observe complete and long-term remission of the disease following one course of isotretinoin, while another 40% eventually develop less severe recurrent acne, which is treatable with less invasive medications. The remaining 20% relapse significantly enough to warrant an additional course of isotretinoin.[13] Each additional course, however, has a higher probability of cure.[citation needed]

Lower-dosage treatments, such as 10–20 mg/day (approximately half the high dosage treatments above), are also highly effective, with greatly diminished side effects.[14][15][16][17][18][19][20] However, such lower dosage courses may be associated with higher relapse rates, requiring additional courses, especially if not taken for sufficient time.[13][21][22][23][24]

Preparations

Isotretinoin is marketed under many brand names by various manufacturers. Some brands of oral isotretinoin include: Accure (Alphapharm), Accutane and Roaccutane (Roche), Aknenormin (Hermal), Amnesteem (Mylan), Ciscutan (Pelpharma), Claravis (Barr), Clarus (Prepharm), Isohexal (Hexal Australia), Istretinoin-A (Pharmathen), Isosupra (SMB Laboratories), Isotane (Pacific Pharmaceuticals), Isotroin (Cipla), Oratane (Douglas Pharmaceuticals), Atretin (Lafrancol), Nimegen (Medica Korea), Acnotin (Mega Lifesciences), Ruatine (United Pharmaceutical)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), Sotret Gel from Ranbaxy and Isotroin Gel from Cipla. In Russia Ретиноевая мазь 0.05% and 0.1%.

Adverse effects

Increasingly higher dosages will result in higher toxicity, resembling vitamin A toxicity. Following are adverse drug reactions from Roches UK product information for Roaccutane as of October 2010.[25]

Type of disordersVery common (≥ 1/10)Common (≥ 1/100, < 1/10)Rare (≥ 1/10 000,< 1/1000)Very rare (≤ 1/10 000)
Infections
  • Gram positive (mucocutaneous)
    bacterial infection
Blood and lymphatic system
  • Lymphadenopathy
Immune system
  • Allergic skin reaction
  • Anaphylactic reactions
  • Hypersensitivity
Metabolism
Psychiatric
  • Abnormal behaviour
  • Psychotic disorder
  • Suicidal ideation
  • Suicide attempt
  • Suicide
Nervous system
  • Headache
Eye
Ear
  • Impaired hearing
Vascular
Respiratory, thoracic and
mediastinal
Gastrointestinal
Hepatobiliary
Skin and
subcutaneous tissues
Musculo-skeletal and
connective tissue
Renal and urinary
General
Investigation

The most common side effects are mucocutaneous and ocular in nature (i.e., cheilitis, ocular sicca, and decreased dark adaptation). It can also cause xerosis. Patients should be made aware of these side effects before taking isotretinoin and also that use of moisturizers and eye drops can help to mitigate them. Sometimes, however, the dose needs to be decreased to reduce the induction of side effects.[26]

In a study from 2011, twenty male patients all developed heart hypertrophy and hypovolemia after 10 weeks of isotretinoin treatment with 0.5 mg/kg/day.[27]

During a prospective study in Mexico that evaluated the efficacy and safety of isotretinoin in acne, six male patients reported difficulties in maintaining adequate penile erection, in addition to depression, suggesting a potential link between isotretinoin and risk of erectile dysfunction.[28]

Research suggests vitamin E supplementation in the form of alpha-tocopherol reduces the toxicity of isotretinoin treatment in subjects with cancer[29] and myelodysplastic syndrome.[30] In contrast, a randomized study in 82 subjects taking isotretinoin (1 mg/kg/day) for acne vulgaris found no difference in the incidence or severity of side effects in the group taking an additional 800 IU/day of vitamin E in the form of d-l-alphatocopherol.[31]

Permanent side effects

The following adverse effects have been reported to persist in some patients even after discontinuing therapy:

Stunted growth

The U.S. Food and Drug Administration's (FDA) medication guide for Accutane states the drug "may stop long bone growth in teenagers who are still growing."[43] Several reports state that premature epiphyseal closure can occur in acne patients receiving recommended doses of Accutane,[44][45][46][47][48][49][50][51][52][53] and has been seen after only 5 months of treatment with a dose of 0.5 mg/kg in a 16 year old boy.[54] In a retrospective cohort done in 2011, advanced bone age was observed in 29% of children who had received isotretinoin with an accumulative dose of 13440 mg/m² body surface area for treatment of neuroblastoma as compared to none in the group treated without isotretinoin.[55] These effects are seen because isotretinoin like all retinoids (including excessive vitamin a intake) negatively impairs chondrogenesis (formation of new cartilage),[56] with diminishing cartilage in the epiphyseal plate to ossify, growth slows down and subsequently stops when all remaining cartilage has been ossified. Since the age until complete ossification of bones normally varies between individuals (17–20 years for upper limbs, 18–23 years for lower limbs)[57] and since many are prescribed Accutane in their late teens when growth still occurs, but has begun decelerating, there is a risk that deceleration of growth from use of isotretinoin is mistakenly seen as the normal deceleration of growth. It is also worth noting that stunted growth of long bones and other bones with epiphyseal plates that are not affecting an individuals height, for example the clavicles, scapula and sternum is almost impossible to detect since no measurements of these bones are done. The effect of multiple courses of Accutane on epiphyseal closure is unknown.

One study in 2007 also found a significant decrease of growth hormone (GH) levels from 0.9 mU/L to 0.3 mU/L after three months of isotretinoin treatment.[58] And a study in 2010 found that isotretinoin treatment decreases insulin-like growth factor-1 (IGF-1) levels.[59][60] IGF-1 is produced in the liver as response to growth hormone and is the primary mediator of GH.

Inflammatory bowel disease

Several scientific studies have posited isotretinoin as a possible cause of Crohn's disease and ulcerative colitis in some individuals.[61][62][63][64][65] Several trials over inflammatory bowel disease claims have been held in the United States thus far, with many of them resulting in multimillion dollar judgments against the makers of isotretinoin.[66][67] And in 2009 Roche decided to pull Accutane off the market, claiming at the time that the move was to stem the tide of Accutane lawsuits.[68] As of January 2012, there were an additional 6,000 cases pending.[69]

Teratogenicity (birth defects)

Isotretinoin is a teratogen and is highly likely to cause birth defects if taken during pregnancy. A few of the more common birth defects this drug can cause are hearing and visual impairment, missing or malformed earlobes, facial dysmorphism, and mental retardation. Isotretinoin is classified as FDA Pregnancy Category X and ADEC Category X, and use is contraindicated in pregnancy.[4]

The manufacturer recommends pregnancy be excluded in female patients two weeks prior to commencement of isotretinoin, and they should use two simultaneous forms of effective contraception at least one month prior to commencement, during, and for at least one month following isotretinoin therapy.[70]

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. As a consequence, the iPLEDGE program was introduced by the U.S. FDA on 12 August 2005 in an attempt to ensure 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. This excludes women not of child-bearing age and men.

Patients receiving isotretinoin therapy are not permitted to donate blood during and for at least one month after discontinuation of therapy due to its teratogenicity.[71]

Depression

Since the 1980s, scientific research has suggested a relationship between isotretinoin administration and the onset of psychological symptoms including depression, suicidal ideation, and psychosis.[72] And several recent studies have shown a link between isotretinoin and clinical depression.[73][74]

In a study in 2006, it was demonstrated for the first time that isotretinoin administration enhances depression-related behaviors in mice. The mechanism by which this occurs was not elucidated, although altered neuronal gene regulation and changes in hippocampal neurogenesis were thought to be involved.[72]

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.[75]

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.[76][77] Chee Hong describes isotretinoin-related depression as "an idiosyncratic side-effect", claiming, often anxiety can bring on acne and depression, creating more anxiety.[78] Correspondingly, treatment of severe acne with isotretinoin has been shown to reduce anxiety and depression, for tests have shown acne to be a main depressant in most tested patients' lives.[79][80]

Studies showing changes in brain

In 2004, two studies showed that Accutane in mice significantly reduces cell proliferation in the hippocampus and the subventricular zone, suppresses hippocampal neurogenesis, and severely disrupts the capacity of the mice to learn a spatial radial maze task.[81][82]

In 2005, psychiatrist Dr. Doug Bremner found decreased orbitofrontal cortex function on brain imaging in patients treated with Accutane (isotretinoin). Bremner's study, which used positron emission tomography (PET), found that patients treated with isotretinoin experienced an average 21% decrease in orbifrontal-lobe brain activity. However, there were no changes in the depressive state of the patients that could be measured with the Hamilton depression scale. Bremner's findings have prompted members of the scientific community to call for more studies regarding isotretinion's links to depression and suicidal behavior.[83]

In 2007, one in vitro study demonstrated that isotretinoin reduced available serotonin in synapses by increasing 5-HT1A receptors and serotonin transporter protein levels.[84]

In 2008, a study showed that isotretinoin alters the morphology of serotonergic neurons in rats, which are thought to be associated with depressive symptoms.[85]

In 2009, it was shown that isotretinoin given to mice alters metabolism in raphe nuclei and disrupts functional connectivity between the raphe nuclei and the hippocampal formation, which the researchers thought may contribute to the observed increase in depression-related behaviors.[86]

in 2010, one in vitro study showed that isotretinoin lead to a decrease of hypothalamic cells and that it may contribute to the increased depression-related behaviors observed in mice given isotretinoin.[87]

Mechanism of action

Isotretinoin's exact mechanism of action is unknown but several studies have shown that isotretinoin induces apoptosis (cell death) in various cells in the body such as cells in meibomian glands,[39][40] hypothalamic cells,[87] hippocampus cells[81][82] and important for treatment of acne, in sebaceous gland cells.[41][42]

One study found that isotretinoin significantly changed the expression of hundreds of genes in skin after 8 weeks of therapy.[88]

Isotretinoin is also one of several drugs discussed in a recent study[89] examining epigenetic side effects (for example DNA methylation) of common pharmaceuticals that leads to silencing of genes.[citation needed]

One study suggests the drug amplifies production of neutrophil-gelatinase-associated lipocalin (NGAL) in the skin, which has been shown to reduce sebum production by inducing apoptosis in sebaceous gland cells, while exhibiting an antimicrobial effect on Propionibacterium acnes.[90][91][92] The drug decreases the size and sebum output of the sebaceous glands.[93] Isotretinoin's combined impact on several of acne's contributory factors distinguishes it from alternative remedies, such as antibiotics, and accounts for its greater efficacy in severe, nodulocystic cases.[citation needed]

The effect on sebum production can be temporary[94] and remission of the disease can be "complete and prolonged."[93][95][96]

Isotretinoin has been speculated to down-regulate the telomerase enzyme and hTERT, inhibiting "cellular immortalization and tumorigenesis."[97]

Isotretinoin has also been proved, according to a 2007 study, to inhibit the action of the metalloprotease MMP-9 (gelatinase) in sebum, without any influence in the action of TIMP1 and TIMP2 (tissue inhibitors of metalloproteases).[98] It is already known that metalloprotases play an important role in the pathogenesis of acne,[99] thus the inhibition of their action by isotretinoin is an additional mechanism of action that contributes to the efficacy of Isotretinoin.

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, the peak plasma concentration was found to be 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: 4-oxo-isotretinoin, retinoic acid, and 4-oxo-retinoic acid. Isotretinoin also oxidizes, 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.

History

An early treatment of acne first used during the 1930s was high doses of the fat-soluble vitamin A (retinoic acid).[citation needed] At these dosage levels (sometimes 500,000 IU per day), sebum production is notably reduced, thwarting acne, but overly dry hair is a negative side effect, and such high doses can lead to vitamin A toxicity. Use of animal-based vitamin A at nutritive levels (where the upper limit dosage is 10,000 IU daily), taken over the course of a year, has also been shown to reduce acne.[citation needed]

Building on the discovery that vitamin A can inhibit sebum production at toxic dosages, the retinoic acid derivative isotretinoin (13-cis-retinoic acid) was developed in 1982 by Hoffmann-La Roche. Dr. Gary Peck is credited with discovering its use for the treatment of cystic acne, as well as disorders of keratinization, such as lamellar ichthyosis, Darier's disease, and pityriasis rubra pilaris. In addition, he demonstrated its chemopreventive properties in patients with basal cell nevus syndrome, also known as nevoid basal cell carcinoma syndrome and Gorlin's syndrome. In fact, within one year of attaining the U.S. patent for discovering the use of isotretinoin in the treatment of acne, he received the Inventor's Award from the US Department of Commerce and a Meritorious Service Medal from the US Public Health Services in 1983. In 2003, he was honored with The Discovery Award by the Dermatology Foundation in "recognition of extraordinary scientific accomplishments that have had a profound influence on the specialty of dermatology and have gained the respect and admiration of the world scientific community".

Dosage requirements of isotretinoin have been disputed. After a 1984 study funded by Roche, relatively high dosages of isotretinoin became mainstream in treatment in the United States. Lower dosages were found to be effective in treatment by independent research (see dosage section).

From the time of its introduction, the drug was known to have teratogenic potential, 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.[100] Beginning in 1998, prescriptions of the drug came under scrutiny, as fewer than half of prescribers were testing for pregnancy, usually relying on less-sensitive urine tests.[101] 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 (one per 30 women per year), and 84% of pregnancies were ended by induced abortion.[100]

In February 2002, Roche's patents for isotretinoin expired, and there are now many other companies selling cheaper generic versions of the drug. On June 29, 2009, Roche Pharmaceuticals, the original creator and distributor of isotretinoin, officially discontinued both the manufacture and distribution of their Accutane brand in the United States due to what the company described as business reasons related to low market share (below 5%), coupled with the high cost of defending personal-injury lawsuits brought by some patients prescribed the drug. Generic isotretinoin will remain available in the United States through various manufacturers. Roche USA continues to defend Accutane and claims to have treated over 13 million patients since its introduction in 1982. F. Hoffmann-La Roche Ltd. apparently will continue to manufacture and distribute Roaccutane outside of the United States.[102]

Isotretinoin is available over the internet from countries where it can be dispensed without a prescription. This presents a dilemma for acne sufferers residing in countries with highly regulated medical and pharmaceutical industries (FD&C Act), as private importation might violate existing statutes.

See also

References

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