Pharmacodynamics

Isotretinoin's exact mechanism of action is unknown. Recent research suggests that the drug may amplify production of the antimicrobial protein neutrophil-gelatinase associated lipocalin in the skin, thereby reducing sebum production.  Generally, it is thought that similar to other retinoids, the drug alters DNA transcription.  The drug decreases the size and sebum output of the sebaceous glands. It also stabilizes keratinization, makes the cells that are sloughed off into the sebaceous glands less sticky, and therefore inhibits the formation of comedones.[citation needed] Isotretinoin's combined impact on several of acne's contributory factors distinguishes isotretinoin from alternative remedies such as antibiotics and accounts for its greater efficacy in severe, nodulocystic cases.

New studies have linked retinoids and other similar chemotherapy agents to telomere shortening, causing many to believe that telomere shortening is accutane's mechanism of action.Telomere shortening leads to an increase in the rate of cell death within the body, which could possibly explain why accutane causes side-effects such as pre-epiphyseal closure, depression, and others.

The effect on sebum production is temporary. However, remission of the disease can be "complete and prolonged."

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 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.

Clinical use

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, adapalene, etc), followed by oral antibiotics (or a combination) and finally isotretinoin therapy. This is because other treatments, while less effective than isotretinoin, are thought to be associated with fewer adverse effects and lower cost. The higher cost is due to the medical supervision required in taking a toxic dosage. The cost of the medicine is also a factor (example: taking 5, 10, or even 20 mg daily is far less expensive than taking 80 mg daily).

Indications

Isotretinoin is indicated 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 effective for hidradenitis suppurativa and some cases of severe acne rosacea.  It can also be used to help treat harlequin 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 brain cancer.

Prescribing restrictions

In the United Kingdom, this drug may only be prescribed 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 isotretinoin's 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 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. 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 7 day window from the time the prescription is written 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 re-qualify to have another prescription written. Doctors and pharmacists must also verify written prescriptions in an online system before patients may fill the prescription.

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

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 , 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.  High dose treatments should only be used 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.

Lower dosage treatments, such as 10-20mg/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 of isotretinoin.
Preparations

Isotretinoin is marketed under many brand names by various manufacturers. It is typically available as 5 mg, 10 mg, 20 mg, 30 mg and 40 mg capsules. 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) 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: Mild 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/permanent hair thinning (this could start or continue after treatment), myalgia and/or arthralgia, back pain.
Infrequent: severe acne flare, raised blood glucose level, decreased libido/erectile dysfunction, increased erythrocyte sedimentation rate, 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; depression

There are spontaneous reports of premature epiphyseal closure in acne patients receiving recommended doses of Accutane. The effect of multiple courses of Accutane on epiphyseal closure is unknown.

The following adverse effects have been reported to persist, even after discontinuing therapy: alopecia (hair loss), arthralgias, decreased night vision, inflammatory bowel disease, 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).

Erectile dysfunction in the form of difficulty in maintaining erection was reported in several patients in a clinical study.

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 (though no indication of what form of vitamin E was used).

Patients with degenerative conditions, such as muscular dystrophy, should not take isotretinoin as it may exacerbate and/or accelerate the underlying condition. This may be due to a suspected effect similar to accelerated aging on the skin and tissues of the body, including muscle fibers.[citation needed]

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

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 that 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 that pregnancy be excluded in female patients two weeks prior to commencement of isotretinoin, and that 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. 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. The iPLEDGE program also applies to males, even though there has been no evidence of isotretinoin excretion through seminal fluids.

Depression

Several studies have suggested a possible link between isotretinoin and clinical depression.[38][39] Psychiatrist Dr. Doug Bremner found decreased frontal lobe function on brain imaging in patients treated with Accutane (isotretinoin).
The first scientific evidence of a link between a drug for severe acne and depression was unveiled by Bath University in September 2006, following years of denials by Hoffmann–La Roche that the prescription medicine could be in any way responsible for suicides.The research showed that the drug, which had been given to British teenagers for more than two decades, causes depression in mice. Biochemist Dr Sarah Bailey looked at how healthy mice were affected by a six-week course of Roaccutane, which has a similar structure to vitamin A. She found that when given levels of Roaccutane equivalent to those used to treat teenagers, the creatures developed symptoms of depression, stress or despair.

One study utilising positron emission tomography (PET) found that patients treated with isotretinion experienced an average twenty-one percent decrease in frontal-lobe brain activity but showed no changes in depressive state in the patients that could be measured with the Hamilton depression scale. This finding has 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.  This suicide rate is in line with national rates and does not exceed the national average.

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.

U.S. Representative Bart Stupak (D-MI) believes unadvertised psychological side effects from the drug drove his teenage son, Bartholomew Thomas Stupak Jr., to commit suicide in 2000.

Crohn's Disease and Ulcerative Colitis

Several scientific studies have posted that isotretinoin is a possible cause of Crohn's Disease and Ulcerative colitis in some individuals. Three cases in the United States have gone to trial thus far, with all three resulting in multi-million dollar judgments against the makers of isotretinoin; there are an additional 425 cases pending.