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. In its pure form, isotretinoin is an orange powder.
The most common adverse effects are dry lips (cheilitis), dry and fragile skin (xeroderma), dry eyes and an increased susceptibility to sunburn. Uncommon and rare side effects include muscle aches and pains (myalgias), headaches, and depression in some users. 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, and 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 (RCA) 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 (or be) 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,Specifically, doctors who are fellows of the Australasian College of Dermatologists (FACD); cf. Pharmaceutical Services Branch, Guide to poisons and therapeutic goods legislation for medical practitioners and dentists, Sydney: NSW Department of Health; 2006. 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:
According to information leafletsAccording to studies Type of disordersVery common (≥ 1/10) Common (≥ 1/100, < 1/10) Rare (≥ 1/,< 1/1000) Very rare (≤ 1/)Unknown FrequencyFrequency Infections Gram-positive (mucocutaneous) bacterial infection Blood and lymphatic system Anemia Increased red blood cell sedimentation rate Thrombocytopenia Thrombocytosis Neutropenia Lymphadenopathy Immune system Allergic skin reaction Anaphylactic reactions Hypersensitivity Metabolism Diabetes mellitus Hyperuricaemia Psychiatric Depression Aggravated depression Aggressive tendencies Anxiety Mood alterations Abnormal behaviour Psychotic disorder Suicidal ideation Suicide attempt SuicidePsychiatric: 25.15% Nervous system Headache Idiopathic intracranial hypertension Convulsions Drowsiness Dizziness Eye Blepharitis Conjunctivitis Dry eyes Eye irritation Blurred vision Cataract Colour blindness Contact lens intolerance Corneal opacity Decreased night vision Keratitis Papilloedema Photophobia Visual disturbances Ear Impaired hearing Vascular Vasculitis (i.e. Granulomatosis with polyangiitis, allergic vasculitis) Respiratory, thoracic and mediastinal Epistaxis Nasal dryness Nasopharyngitis Bronchospasm (particularly in people with asthma) Hoarseness Gastrointestinal Colitis Ileitis Dry throat Gastrointestinal haemorrhage Haemorrhagic diarrhoea Inflammatory bowel disease Nausea Pancreatitis Hepatobiliary Increased transaminase Hepatitis Skin and subcutaneous tissues Cheilitis Dermatitis Dry skin Localised exfoliation Pruritus Rash erythematous Skin fragility (with a risk of frictional trauma) Paronychia Alopecia- hair shedding from telogen effluvium Acne fulminans Aggravated acne (acne flare) Erythema (facial) Exanthema Hair disorders Hirsutism Nail dystrophy Paronychia Photosensitivity reaction Pili torti Pyogenic granuloma Skin hyperpigmentation Increased sweating Erythema multiforme Stevens-Johnson Syndrome Toxic epidermal necrolysis.100% Musculo-skeletal and connective tissue Arthralgia Myalgia Back pain Arthritis Calcinosis (calcification of ligaments and tendons) Premature epiphyseal fusion Exostosis Hyperostosis Osteopenia Tendonitis Rhabdomyolysis Kidney and urinary Glomerulonephritis Dark or cola-coloured urineReproductive system and breast disorders Sexual dysfunction, including erectile dysfunction and decreased libido General Increased formation of granulation tissue Malaise Investigation Increased triglycerides Decreased HDL Increased blood cholesterol Increased blood glucose Haematuria Proteinuria Increased creatine phosphokinase
Possible permanent effects The adverse effects of isotretinoin may be permanent. This has been proposed to be due to induction of apoptosis (programmed cell death) 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. See FDA Index page for NDA 018662 for updates 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 (dry eye). 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 (cheilitis), redness of the skin (erythema), rashes, peeling, eczema (dermatitis), itching (pruritus) and nose bleeds (epistaxis). Absence of dryness of the lips is considered an indication of non-compliance with treatment (not taking the drug as advised), 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 (oral) 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.Roche Products Pty Ltd. Roaccutane (Australian Approved Product Information). Dee Why (NSW): Roche; 2005.