Isotretinoin


Isotretinoin, also known as 13-cis-retinoic acid and sold under the brand name Accutane among others, is a medication used to treat skin diseases like harlequin-type ichthyosis, lamellar ichthyosis, and severe cystic acne or moderate acne that is unresponsive to antibiotics. Isotretinoin is used off-label to treat basal cell carcinoma and squamous cell carcinoma, although clinical evidence suggests it is not effective in this setting. It is a retinoid, meaning it is related to vitamin A, and is found in small quantities naturally in the body. Its isomer, tretinoin, is also an acne drug.
The most common adverse effects are dry lips, dry and fragile skin, dry eyes and an increased susceptibility to sunburn. Uncommon and rare side effects include muscle aches and pains, and headaches. Some of those side effects can persist long after the discontinuation of the use of the drug. Isotretinoin may cause liver failure, therefore the patient's blood levels should be regularly tested. It 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 that controls normal embryonic development. It is associated with psychiatric side effects, most commonly depression but also, more rarely, psychosis and unusual behaviors. Other rare side effects include hyperostosis and premature epiphyseal closure, which have been reported to be persistent.
Isotretinoin was patented in 1969 and approved for medical use in 1982. In 2021, it was the 264th most commonly prescribed medication in the United States, with more than 1million prescriptions.

Medical uses

Isotretinoin is used primarily for persistent cystic acne. Many dermatologists also support its use for treatment of lesser degrees of acne that prove resistant to other treatments, or that produce scarring or psychological distress. Isotretinoin is not indicated for the treatment of prepubertal acne and is not recommended in children less than 12 years of age.
It is also somewhat effective for hidradenitis suppurativa and some cases of severe 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 the treatment of pediatric neuroblastoma in Japan, but data for its efficacy is not conclusive and it has not been approved in other countries.
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 recalcitrant condylomata acuminata of the cervix. In most countries, this therapy is currently unapproved and only used if other therapies fail.

Prescribing restrictions

Isotretinoin is a teratogen; there is about a 20–35% risk for congenital defects in infants exposed to the drug in utero, and about 30–60% of children exposed to isotretinoin prenatally have been reported to show neurocognitive impairment. Because of this risk, there are strict controls prescribing isotretinoin to women who have potential to become pregnant while taking isotretinoin and many are strongly advised to terminate their pregnancies because of the 20-60% risk. Isotretinoin is also not recommended for use by breastfeeding women.
In the United States, since March 2006, the dispensing of isotretinoin is run through the iPLEDGE program, under the direction of the Food and Drug Administration. Prescribers, pharmacists, and all people to whom the drug is prescribed need to register on the site and log information into it. 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. Additionally, they must have two negative pregnancy tests 30 days apart and have negative pregnancy tests before each prescription is written.
In most countries, isotretinoin can only be prescribed by dermatologists or specialist physicians; some countries also allow limited prescriptions 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 subsidized only when prescribed by a vocationally-registered general practitioner, dermatologist or nurse practitioner.

Adverse effects

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

Possible permanent effects

The effects of isotretinoin may be permanent. This has been proposed to be due to induction of apoptosis in sebaceous glands, meibomian glands, neuroblastoma cells, hypothalamic cells, hippocampus cells, Dalton's lymphoma ascites cells, B16F-10 melanoma cells, neuronal crest cells, stem cells and others, that it changes epigenetics and shortens telomeres.
Isotretinoin may stop long bone growth in young people who are still growing. Premature epiphyseal closure can occur in people receiving recommended doses of Accutane.
Isotretinoin is known to cause meibomian gland dysfunction which causes persistent keratoconjunctivitis sicca. Problems with the meibomian and salivary glands are likely due to the non-selective apoptosis of the cells of the exocrine glands. Decreased night vision has been reported to persist in some people after discontinuation of isotretinoin therapy, although most cases of decreased night vision appear to resolve after discontinuing the medication.

Sexual

Isotretinoin is also associated with permanent sexual side effects, namely erectile dysfunction and reduced libido. In October 2017, the UK MHRA issued a Drug Safety Update to physicians in response to reports of these problems. This was in response to an EU review, published in August 2017, which states that a plausible physiological explanation of these side effects "may be a reduction in plasma testosterone". The review also stated that "the product information should be updated to include 'sexual dysfunction including erectile dysfunction and decreased libido' as an undesirable effect with an unknown frequency". There have also been reports of spermatogenesis disorders, such as oligospermia. 27 cases of sexual dysfunction report either negative dechallenge or positive dechallenge.

Skin

The most common side effects are mucocutaneous: dry lips, skin, and nose. Other common mucocutaneous side effects are inflammation and chapping of the lips, redness of the skin, rashes, peeling, eczema, itching and nose bleeds. Absence of dryness of the lips is considered an indication of non-compliance with treatment, as it occurs in almost all people who take it.
Regular use of lip balm and moisturizer is recommended throughout treatment to reduce these problems. The dose may need to be decreased to reduce the severity of these side effects. The skin becomes more fragile—especially to frictional forces—and may not heal as quickly as normal. Wound healing is delayed. For this reason, elective surgery, waxing of hair, tattooing, tattoo removal, piercings, dermabrasion, exfoliation, etc., are not recommended during treatment. Treatment of acne scars is generally deferred until 12 months after completion of a course of isotretinoin.

Teratogenicity

Isotretinoin is a teratogen 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 abnormalities in brain function. Isotretinoin is classified as FDA Pregnancy Category X and ADEC Category X, and use is contraindicated in pregnancy. In the EU, isotretinoin is contraindicated in pregnancy and must not be taken by women able to have children unless the conditions of a pregnancy prevention program are met.
The manufacturer recommends pregnancy be ruled out two weeks before commencement of isotretinoin, and women should use two simultaneous forms of effective contraception at least one month before commencement, during, and for at least one month following isotretinoin therapy.
In the US, around 2000 women became pregnant while taking the drug between 1982 and 2000, with most pregnancies ending in abortion or miscarriage. About 160 babies with birth defects were born. After the FDA put the more strict iPLEDGE program in place for the companies marketing the drug in the US, in 2011, 155 pregnancies occurred among 129,544 women of childbearing potential taking isotretinoin.
People taking isotretinoin are advised against donating blood during and for at least one month after treatment due to its teratogenicity.

Psychological effects

Rare psychological side effects may include depression, worsening of pre-existing depression, aggressive tendencies, irritable mood, and anxiety. Very rare effects include abnormal behaviour, psychosis, suicidal ideation, suicide attempts, and suicide. In a total of 5577 adverse reactions reported to the UK's MHRA up to 31 March 2017, the plurality concerned psychiatric effects. There were 85 reports of suicidal ideation, 56 of suicide and 43 of suicide attempts.
A 2005 study initially found that isotretinoin decreases the brain metabolism in the orbitofrontal cortex by an average of 21%, a brain area known to mediate symptoms of depression. However, a subsequent re-analysis that examined whole‑brain metabolism before and after treatment did not find a statistically significant difference.
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. Several studies have been conducted since then of the drug's effect on depression, psychosis, suicidal thoughts and other psychological effects.