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Isotretinoin

Clinical data
Trade names	Accutane
AHFS/Drugs.com	Monograph
MedlinePlus	a681043
License data	US FDA: Isotretinoin
Pregnancy category	AU: X (High risk)
Routes of administration	Oral, topical
ATC code	D10AD04 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only) US: WARNINGRx-only
Pharmacokinetic data
Bioavailability	Variable
Protein binding	99.9%
Metabolism	Hepatic
Elimination half-life	10–20 hours
Excretion	Renal and fecal
Identifiers
IUPAC name (2Z,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenoic acid
CAS Number	4759-48-2
PubChem CID	5282379
DrugBank	DB00982
ChemSpider	4445539
UNII	EH28UP18IF
KEGG	D00348
ChEBI	CHEBI:6067
ChEMBL	ChEMBL547
CompTox Dashboard (EPA)	DTXSID4023177
ECHA InfoCard	100.022.996
Chemical and physical data
Formula	C20H28O2
Molar mass	300.44 g/mol g·mol
3D model (JSmol)	Interactive image
SMILES O=C(O)\C=C(/C=C/C=C(/C=C/C1=C(/CCCC1(C)C)C)C)C
InChI InChI=1S/C20H28O2/c1-15(8-6-9-16(2)14-19(21)22)11-12-18-17(3)10-7-13-20(18,4)5/h6,8-9,11-12,14H,7,10,13H2,1-5H3,(H,21,22)/b9-6+,12-11+,15-8+,16-14- Key:SHGAZHPCJJPHSC-XFYACQKRSA-N
(verify)

Isotretinoin, INN, /ˌaɪsoʊtrˈtɪnoʊ.n/, (also known as 13-cis retinoic acid) first marketed as Accutane by Hoffmann-La Roche, is a medication primarily used to treat cystic acne. Rarely, it is also used to prevent certain skin cancers (squamous-cell carcinoma), and can be used in the treatment of brain, pancreatic and other cancers. It is used to treat harlequin-type ichthyosis, a usually lethal skin disease, and lamellar ichthyosis. It is a retinoid, meaning it is related to vitamin A, and is found in small quantities naturally in the body.

Isotretinoin is primarily used as a treatment for severe acne. The most common adverse effects are a transient worsening of acne (lasting 2–3 weeks), dry lips (cheilitis), dry and fragile skin, and an increased susceptibility to sunburn. Uncommon and rare side effects include: muscle aches and pains (myalgias), headaches. Isotretinoin is known to cause birth defects due to in utero exposure 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 procedure is required to obtain the pharmaceutical. In most other countries a consent form is required which explains these risks. Women taking isotretinoin must not get pregnant during, and for 1 month after isotretinoin therapy. Sexual abstinence, or effective contraception is mandatory during this period. Barrier methods by themselves (such as condoms) are not considered adequate due to the unacceptable failure rates of approximately 3%. Women who fall pregnant whilst on isotretinoin therapy are generally counselled to have a termination. Isotretinoin has no effect on male reproduction.

There is little evidence in the medical literature linking isotretinoin use with depression and suicide. Despite this, there exists a popular misconception amongst the public that isotretinoin use commonly causes depression.

In 2009, Roche decided to remove Accutane from the US market after juries had awarded millions of dollars in damages to former Accutane users over inflammatory bowel disease claims. Other common brands are Roaccutane (Hoffman-La Roche, known as Accutane in the United States before July 2009), Amnesteem (Mylan), Claravis (Barr), Absorica (Ranbaxy), and Isotroin (Cipla).

Medical uses

Isotretinoin is used primarily for severe cystic acne and acne that has not responded to other treatments. Acne treatment usually begins with topical retinoids (e.g.tretinoin, adapalene), in combination with topical antibiotics (e.g. clindamycin, erythromycin) or antiseptics (e.g. benzoyl peroxide-containing preparations), followed by oral antibiotics (e.g. doxycycline or minocycline). In women a cyproterone-containing contraceptive pill can be useful if there are no contraindications.

In cases of hormonal acne, such as in women in their 20s and 30s with cyclical acne, often a course of isotretinoin can permanently improve acne obviating the need for lifelong hormonal manipulation.

Indications

The primary indication for Isotretinoin is the treatment of severe cystic acne vulgaris. 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.

It is also somewhat effective for hidradenitis suppurativa and some cases of severe acne rosacea. 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 for this indication as there are more effective treatments. Isotretinoin may represent an efficacious and safe alternative systemic form of therapy for RCA of the cervix. In most countries this therapy is currently unapproved and only used if other therapies failed.

Prescribing restrictions

In most countries, isotretinoin cannot be prescribed except by dermatologists or specialist physicians; some countries also allow limited prescription by general practitioners and family doctors. In the United Kingdom and Australia, isotretinoin may be prescribed only by or under the supervision of a consultant dermatologist. Because severe cystic acne has the potential to cause permanent scarring over a short period, restrictions on its more immediate availability have proved contentious. In New Zealand, isotretinoin can be prescribed by any doctor but subsidised only when prescribed by a vocationally-registered general practitioner, dermatologist or nurse practitioner.

In the United States, dispensing of isotretinoin is by an FDA-mandated website called iPLEDGE. iPLEDGE applied to isotretinoin prescriptions from 1 March 2006. Under it, dermatologists must register their patients on the system before prescribing isotretinoin. Pharmacists must then verify the prescription on the iPLEDGE website before dispensing isotretinoin. The website allows no more than thirty days' supply of the drug to be prescribed or dispensed; and after issuance, another prescription may not be written for at least 30 days (even in the case of lost prescriptions). Prescriptions expire from iPLEDGE if not picked up from the pharmacy seven days after issuance. Physicians and pharmacists must verify written prescriptions on the system before filling an isotretinoin prescription. Due to the teratogenic effects of isotretinoin, iPLEDGE makes additional requirements of female patients filling prescriptions for the drug: women with child-bearing potential must commit to using two forms of effective contraception simultaneously for the duration of isotretinoin therapy and for a month immediately preceding and a month immediately following therapy. Alerts continue to exist against purchasing isotretinoin online.

Most other national health services emphasise that isotretinoin is a teratogen, but do not impose the same stringent conditions on the dispensing process as the United States does. In Mexico and Brazil the use of the drug is restricted: official identification and a signature must be provided by the patient before an isotretinoin prescription will be filled by a pharmacist.

Clinical guidelines for most countries recommends or mandates that the dispensing physician monitor patients, or provide instructions to the patient's regular doctor for monitoring. As part of the monitoring, patients' blood is periodically re-tested throughout treatment for blood lipids, pregnancy, and several other factors. Women, diabetics, and patients with liver problems are particularly at risk and will be monitored especially closely.

Dosage

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, given as a single dose with food). Usually a course will last 8–10 months. A second course may be required. 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.

Nearly all patients achieve initial clearing of acne during a normal course of isotretinoin therapy. 90% of patients achieve excellent clearance of their acne after a cumulative dose of 150 mg/kg.

Lower-dosage treatments, such as 10–20 mg/day (approximately half the high dosage treatments above), can also be effective, with greatly diminished side effects. However, such lower dosage courses may be associated with higher relapse rates, requiring additional courses, especially if not taken for sufficient time.

Usually, a starting dose of 20 mg is taken with the largest meal of the day. After a few months, the dose is increased, e.g. to 40 mg/d. If side-effects permit, a higher dose such as 60 mg/d can be prescribed although daily dose rarely exceeds 60 mg. If 20 mg capsules are supplied, patients may take (for example) 20 mg one day, then 40 mg the next to provide an average daily dose of 30 mg/d. In most cases, isotretinoin achieves a complete clearing of acne during a standard-dose 12–16 week course. Some patients' acne will respond to a course before recurring, necessitating multiple courses of treatment.

Adverse effects

Increasingly higher dosages will result in higher toxicity, resembling vitamin A toxicity. The following are adverse drug reactions from Roche's UK product information for Roaccutane as of October 2010:

Research suggests vitamin E supplementation in the form of alpha-tocopherol reduces the toxicity of isotretinoin treatment in subjects with cancer and myelodysplastic syndrome. 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.

One study noted that keloid formation may be induced by isotretinoin therapy.

Possible permanent effects

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

• Advanced bone age and premature epiphyseal closure (see stunted growth below)
• Decreased night vision (see below)
• Hyperostosis
• Inflammatory bowel disease (see below)
• Keloids
• Keratoconjunctivitis sicca (dry eyes)
• Xeroderma (dry skin)

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." Several reports state that premature epiphyseal closure can occur in acne patients receiving recommended doses of Accutane, and has been seen after only 5 months of treatment with a dose of 0.5 mg/kg in a 16 year old boy. 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. These effects are seen because isotretinoin like all retinoids (including excessive vitamin a intake) negatively impairs chondrogenesis (formation of new cartilage), 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) 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. And a study in 2010 found that isotretinoin treatment decreases insulin-like growth factor-1 (IGF-1) levels. 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. 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. 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. As of January 2012, there were an additional 6,000 cases pending.

A study looking at 45,000 patients showed no association between isotretinoin and inflammatory bowel disease (Ulcerative Colitis and Crohn's Disease). The authors concluded "Because inflammatory acne in children and adolescents carries a high psychological burden, clinicians should not be discouraged from prescribing this drug owing to a putative association with IBD."

Eye changes

Extremely rarely, patients notice reduced night vision. This has been reported in cases of underlying cystic fibrosis which causes low vitamin A levels due to poor absorption of fat-soluble vitamins. It was suggested that patients with cystic fibrosis or other conditions associated with fat malabsorption should have adequate vitamin A levels prior to isotretinoin therapy. If a career in aviation or the armed forces is considered, it is recommended that patients check with their local authorities.

Skin

The most common side effects are muco-cutaneous: dry lips and skin. Regular lip balm and moisturizer is recommended. Sometimes, however, the dose needs to be decreased to reduce these side effects. The skin becomes more fragile -especially to frictional forces- and may not heal as quickly as normal. For this reason: waxing of hair, tattooing, tattoo removal, piercings, dermabrasion, exfoliation etc. are not recommended. Treatment of acne scars (e.g. with fractional laser such as "Fraxel") is generally deferred until 12 months after completion of a course of isotretinoin.

Acne usually flares up 2–3 weeks into the treatment and is usually mild and tolerable. Occasionally this flareup is severe, necessitating oral antiobiotics such as erythromycin. A short course of oral prednisolone may be required. Some dermatologists favour a few weeks pre-treatment with oral antibiotics before commencing isotretinoin to reduce the chance of a severe flare.

Teratogenicity (birth defects)

Isotretinoin is a teratogen and is highly likely to cause birth defects if taken by women during pregnancy or even a short time before conception. 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.

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.

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 by a registered pharmacy. All patients, including women not of child-bearing age and men, must register with iPLEDGE. FDA's intent with the iPLEDGE program is to tightly control the distribution and dispensing of isotretinoin and thereby prevent the potential for distribution or sharing of the drug outside of the program to women of child-bearing age. As of 2013, the FDA has yet to provide information or statistics to validate whether the iPLEDGE program has achieved its goal of reducing pregnancies among women patients of child-bearing age.

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.

Psychological effects

The association between isotretinoin use and psychopathology has been controversial. Beginning in 1983, isolated case reports emerged suggesting mood change, particularly depression, occurring during or soon after isotretinoin use. A number of studies have been conducted since then of the drug's effect on depression, psychosis, suicidal thoughts and other psychological effects. Recent reviews of the studies and reports have found that an association has not been proven, with varying opinions on the likelihood of an association.

A 2008 review found that based on clinical studies and case reports, “the link between suicides and severe depressions has not yet been clearly demonstrated.” A 2009 review found that evidence strongly suggested a link between the use of isotretinoin and psychopathology, but did not establish a causal link. It recommended that “clinicians should be on the alert for potential psychiatric side effects following treatment with isotretinoin, especially in vulnerable populations.”

The U.S. Food and Drug Administration recommends that ”all patients treated with isotretinoin should be observed closely for symptoms of depression or suicidal thoughts, such as sad mood, irritability, acting on dangerous impulses, anger, loss of pleasure or interest in social or sports activities, sleeping too much or too little, changes in weight or appetite, school or work performance going down, or trouble concentrating, or for mood disturbance, psychosis, or aggression. Patients should stop isotretinoin and they or their caregiver should contact their healthcare professional right away if the patient has any of the previously mentioned symptoms. Discontinuation of treatment may be insufficient and further evaluation may be necessary.”

The U.K. National Health Service, in its guidance on side effects of 20 mg isotretinoin tablets, includes the following as “rare” side effect (more than 1 in 10,000 users): “thoughts of committing suicide, behavioural problems or worsening of behavioural problems including: aggression, feeling anxious, mood changes, depression or psychosis or psychotic-like behaviour - you or your carer must seek medical advice if you become depressed or if your depression worsens.”

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. Cell death may be instigated in the meibomian glands, hypothalamic cells, hippocampus cells and—important for treatment of acne—in sebaceous gland cells. Isotretinoin has a low affinity for retinoic acid receptors (RAR) and retinoid X receptors (RXR), but may be converted intracellularly to metabolites that act as agonists of RAR and RXR nuclear receptors.

One study found Isotretinoin significantly changes the expression of hundreds of genes in skin after eight weeks of therapy. Isotretinoin is one of several drugs discussed in a recent study examining epigenetic side effects (for example DNA methylation) of common pharmaceuticals that leads to silencing of genes.

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. The drug decreases the size and sebum output of the sebaceous glands. Isotretinoin is the only available acne drug that affects all four major pathogenic processes in acne, which distinguishes it from alternative treatments (such as antibiotics) and accounts for its efficacy in severe, nodulocystic cases. The effect of Isotretinoin on sebum production can be temporary, or remission of the disease can be "complete and prolonged."

Isotretinoin has been speculated to down-regulate the telomerase enzyme and hTERT, inhibiting "cellular immortalization and tumorigenesis." In a 2007 study, Isotretinoin was proven to inhibit the action of the metalloprotease MMP-9 (gelatinase) in sebum without any influence in the action of TIMP1 and TIMP2 (the tissue inhibitors of metalloproteases). It is already known that metalloproteases play an important role in the pathogenesis of acne.

Pharmacokinetics

Oral Isotretinoin is best absorbed when taken with a high-fat meal, because it has a high level of lipophilicity. The efficacy of isotretinoin doubles when taken after a high-fat meal compared to when taken without food. Due to Isotretinoin's molecular relationship to Vitamin A, it should not be taken with Vitamin A supplements due to the danger of toxicity through cumulative overdosing. Accutane also negatively interacts with tetracycline, another class of acne drug, and with micro-dosed ('mini-pill') progesterone preparations, norethindrone/ethinyl estradiol ('OrthoNovum 7/7/7'), St. John's Wort, Phenytoin, and systemic corticosteroids.

Isotretinoin is primarily (99.9%) bound to plasma proteins, mostly albumin. Three metabolites of Isotretinoin are detectable in human plasma after oral administration: 4-oxo-isotretinoin, retinoid acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin). Isotretinoin also oxidizes, irreversibly, to 4-oxo-isotretinoin—which forms its geometric isomer 4-oxo-tretinoin. After an orally-administered, 80 mg dose of liquid suspension 14C-isotretinoin, 14C-activity in blood declines with a half-life of 90 hours. The metabolites of isotretinoin and its conjugates are then excreted in the subject's urine and faeces in relatively equal amounts. After a single, 80 mg oral dose of Isotretinoin to 74 healthy adult subjects under fed conditions, the mean ±SD elimination half-life (t_1/2) of isotretinoin and 4-oxo-isotretinoin were 21.0 ± 8.2 hours and 24.0 ± 5.3 hours, respectively. After both single and multiple doses, the observed accumulation ratios of isotretinoin ranged from 0.90 to 5.43 in patients with cystic acne.

History

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. 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. 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.

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.

Among others, actor James Marshall sued Roche over Accutane-related disease that resulted in removal of his colon. The jury, however, decided that James Marshall had a pre-existing bowel disease.

See also

• Hypervitaminosis A syndrome

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External links

• Drugs.com Isotretinoin Information
• Dermatology Vol 9: issue 5: Night blindness, vitamin A deficiency, and isotretinoin psychotoxicity
• DermNet treatments/isotretinoin

• Ill-formatted IPAc-en transclusions
• Retinoids
• Anti-acne preparations