Isotretinoin

Isotretinoin, INN, is a medication used mostly for cystic acne, however, it is also employed for a number of cancers and a few severe skin conditions. It was first developed to be used as a chemotherapy medication for the treatment of brain cancer, pancreatic cancer, and other cancers. It is still used in the treatment of these cancers because of its ability to kill rapidly dividing cells. Its effects are systemic and nonselective. In some cases, it is used to treat harlequin-type ichthyosis, usually a lethal skin deformation in which sufferers develop armor plated-like skin and usually die soon after birth, and lamellar ichthyosis. It is a retinoid, meaning it derives from vitamin A, and is found in small quantities naturally in the body.

Oral isotretinoin has been marketed under various trade names, the most common ones being Roaccutane (Hoffman-La Roche, known as Accutane in the United States before July 2009), Amnesteem (Mylan), Claravis (Barr), Clarus (PremPharm), Decutan (Actavis), Isotane (Pacific Pharmaceuticals), Izotek (BlauFarma), Oratane (Genepharm Australasia),  ISOTRET  (Liva Healthcare Ltd.) or Sotret (Ranbaxy), while topical isotretinoin is most commonly marketed under the trade names Isotrex or Isotrexin (Stiefel).. Some of these are not manufactured any longer.

Isotretinoin's most well-known side effect is that it acts as a severe teratogen. This is related to the molecule's close resemblance to retinoic acid, a natural vitamin A derivative which controls normal embryonic development. Isotretinoin's potential to cause birth defects has resulted in a set of government-regulatory and pharmaceutical-maker restrictions that make isotretinoin one of the most difficult pharmaceuticals to obtain in the United States.

Medical uses
Except in the most severe cases, isotretinoin is used only after other acne treatments fail to produce results. Treatment of acne usually begins with topical medications (e.g., benzoyl peroxide or adapalene), followed by oral antibiotics (or a combination) and finally isotretinoin therapy, because other treatments, while less effective than isotretinoin, are thought to be associated with fewer adverse effects and lower cost.

Indications
Isotretinoin's main indication is for 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.

Prescribing restrictions
In the United Kingdom, this drug 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. 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). 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.

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

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, 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. 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. Each additional course, however, has a higher probability of cure.

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. However, such lower dosage courses may be associated with higher relapse rates, requiring additional courses, especially if not taken for sufficient time.

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).

Adverse effects
Increasingly higher dosages will result in higher toxicity, resembling vitamin A toxicity.

Adverse drug reactions associated with isotretinoin therapy include:


 * Common: Extreme severe acne flare, dryness of skin, lips and mucous membranes, infection of the cuticles, cheilitis, itch, rosacea, skin fragility, skin peeling, rash, flushing, nose bleeds, dry eyes, diffuse alopecia areata, eye irritation, conjunctivitis, reduced tolerance to contact lenses, hyperlipidaemia, raised liver enzymes, permanent thin skin, headaches, temporary or permanent hair thinning (this could start or continue after treatment), myalgia and/or arthralgia, back pain and hyperhidrosis


 * Infrequent: mild acne flare, raised blood glucose level, decreased libido or erectile dysfunction, increased erythrocyte sedimentation rate, and fatigue


 * Rare: impaired night vision, cataracts, optic neuritis, menstrual disturbances, inflammatory bowel disease, pancreatitis, hepatitis, corneal opacities, papilloedema, idiopathic intracranial hypertension, skeletal hyperostosis, extraosseous calcification, psychosis, and depression

During a prospective study in Mexico that evaluated the efficacy and safety of isotretinoin in acne, six male patients reported clinical symptoms of depression along with difficulties in maintaining adequate penile erection, suggesting a potential link between isotretinoin and risk of erectile dysfunction.

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.

Its 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.

Permanent side effects
The following adverse effects have been reported to persist, even after discontinuing therapy: alopecia (hair loss), arthralgias (joint pain), decreased night vision, inflammatory bowel disease,   degenerative disc disease, keloids, osteopenia, hyperlipidemia, erectile dysfunction, psychiatric disturbances, dry eyes, and "dry skin". High dosages of isotretinoin have been reported to cause rosacea (a disease of severe facial skin redness and irritation). It is not known how these side effects can be permanent, but several studies have shown it induces apoptosis (cell death) in various cells. Isotretinoin is one of the drugs discussed in a recent study examining epigenetic side effects (for example, DNA methylation) of common pharmaceuticals.

Stunted growth in height
The FDA's medication guide for Accutane states the drug "may stop long bone growth in teenagers who are still growing." Several reports state spontaneous premature epiphyseal closure can occur in acne patients receiving recommended doses of Accutane. Since the age until complete ossification of bones 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 deaccelerating, there is a risk for a gray zone with people being affected without knowledge about it. The effect of multiple courses of Accutane on epiphyseal closure is unknown.

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.

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. The iPLEDGE program also applies to males, even though there has been no evidence of isotretinoin excretion through seminal fluids.

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.

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. However, there have also been studies arguing that there is no evidence of such a link. 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.

Several recent studies have shown a link between isotretinoin and clinical depression. Psychiatrist Dr. Doug Bremner found decreased orbifrontal 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 isotretinion 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.

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.

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. Chee Hong describes isotretinoin-related depression as "an idiosyncratic side-effect", claiming, often anxiety can bring on acne and depression, creating more anxiety. 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.

Spontaneous suicides, or suicides where the victim exhibited no signs of clinical depression, of Accutane users have been reported. These reports signal Accutane may be able to cause users to make extremely irrational decisions, and could explain why the FDA and pharmaceutical companies have failed to establish a causal relationship between Accutane and depression, as Accutane could be causing the brain to experience something different from clinical depression. The fact that some suicides are "spontaneous" means Chee Hong's aforementioned "idiosyncratic" theory is false in many cases of Accutane- related suicide.

Former U.S. Representative Bart Stupak believes unadvertised psychological side effects from the drug drove his teenage son to commit suicide in 2000.

Crohn's disease and ulcerative colitis
Several scientific studies have posited isotretinoin is a possible cause of Crohn's disease and ulcerative colitis in some individuals. Six trials have been held in the United States thus far, with all six resulting in multimillion dollar judgments against the makers of isotretinoin; there are an additional 4,000 cases pending.

Mechanism of action
Isotretinoin's exact mechanism of action is unknown. Recent research 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'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.

The effect on sebum production is temporary. However, 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."

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). 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.

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 America.

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.