Isotretinoin
Isotretinoin structure.svg
Isotretinoin3d.svg
Clinical data
Pronunciation See note at tretinoin
Trade names Various
AHFS/Drugs.com Monograph
MedlinePlus a681043
License data
Pregnancy
category
  • AU: X (High risk)
  • US: X (Contraindicated)
Routes of
administration
By mouth, topical
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • CA: ℞-only
  • UK: POM (Prescription only)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability Variable
Protein binding 99.9%
Metabolism Hepatic
Biological half-life 10–20 hours
Excretion Renal and fecal
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.022.996
Chemical and physical data
Formula C20H28O2
Molar mass 300.44 g/mol
3D model (Jmol)
  (verify)

Isotretinoin (INN),[1] also known as 13-cis-retinoic acid, is an oral pharmaceutical drug primarily used to treat severe nodular acne. Rarely, it is also used to prevent certain skin cancers (squamous-cell carcinoma), and in the treatment of 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. Its isomer, tretinoin, is also an acne drug.

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), and 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 (e.g., 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.[2]

Isotretinoin was first marketed as Accutane by Hoffmann-La Roche. It sold well for many years, but 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),[D 1] Amnesteem (Mylan),[D 2] Claravis (Teva),[D 3] Absorica (Ranbaxy),[D 4] Isotroin (Cipla), and Epuris (Cipher).[3]

Contents

Medical usesEdit

Isotretinoin is used primarily for severe cystic acne and acne that has not responded to other treatments.[4][5] 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 acetate-containing contraceptive pill can be useful if there are no contraindications.

IndicationsEdit

The primary indication for isotretinoin is the treatment of severe cystic acne vulgaris.[6][7] 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.[8]

It is also somewhat effective for hidradenitis suppurativa and some cases of severe acne rosacea.[7] 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.[9][10]

Prescribing restrictionsEdit

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.[11] Because of this, there are strict controls on prescribing isotretinoin to women who may become pregnant and women who become pregnant while taking isotretinoin are strongly advised to terminate their pregnancies.[11]

Using this medicine while you are pregnant can cause very serious birth defects. Use two forms of effective birth control to keep from getting pregnant one month before beginning treatment, while you are using this medicine (even if the medicine is temporarily stopped), and for at least 1 month after you stop taking the medicine. The most effective forms of birth control are hormone birth control pills, patches, shots, vaginal rings, or implants, an IUD, or a vasectomy (for men). One of these forms of birth control should be combined with a condom, a diaphragm, or a cervical cap.[12] The only exception to this is if one's doctor allows them to choose abstinence as a form of birth control. If that is chosen, that is the only birth control needed. Should a pregnancy occur while on the course of Isotretinoin, it is strongly advised that it be terminated to the adverse side effect of the teratogen.

In most countries, isotretinoin can only be prescribed by dermatologists or specialist physicians; some countries also allow limited prescription by general practitioners and family doctors. In the United Kingdom[13] and Australia,[14][15] 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.[16] 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.[17]

In the United States, dispensing of isotretinoin is by an FDA-mandated website called iPLEDGE. iPLEDGE has applied to isotretinoin prescriptions since 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.[18] Alerts continue to exist against purchasing isotretinoin online.[19]

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.

DosageEdit

 
Roaccutane 10 mg capsule

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,[20] 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.[6][7]

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.[21][22][23][24][25][26][27] However, such lower dosage courses may be associated with higher relapse rates, requiring additional courses, especially if not taken for enough time.[28][29][30][31][32]

Adverse effectsEdit

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:[33]

Type of disorders

Very common (≥ 1/10)

Common (≥ 1/100, < 1/10)

Rare (≥ 1/10 000,< 1/1000)

Very rare (≤ 1/10 000)

Infections
  • Gram positive (mucocutaneous)

bacterial infection

Blood and lymphatic system
  • Lymphadenopathy
Immune system
  • Allergic skin reaction
  • Anaphylactic reactions
  • Hypersensitivity
Metabolism
Psychiatric
  • Abnormal behaviour
  • Psychotic disorder
  • Suicidal ideation
  • Suicide attempt
  • Suicide
Nervous system
  • Headache
Eye
Ear
  • Impaired hearing
Vascular

allergic vasculitis)

Respiratory, thoracic and

mediastinal

with asthma)

Gastrointestinal
Hepatobiliary
Skin and

subcutaneous tissues

Musculo-skeletal and

connective tissue

and tendons)

Kidney and urinary
General
Investigation

Possible permanent effectsEdit

An Accutane medication guide approved by the U.S. FDA in 2010 states that the drug "may stop long bone growth in teenagers who are still growing."[34][D 5] Several reports state that premature epiphyseal closure can occur in acne patients receiving recommended doses of Accutane.[35][36][37][38]

Isotretinoin is known to cause meibomian gland dysfunction which causes persistent keratoconjunctivitis sicca (dry eye).[39] It has also been found to cause salivary gland dysfunction in some people, causing xerostomia (dry mouth).[40][41][42][43] Problems with the meibomian and salivary glands are likely due to the non-selective apoptosis of the cells of the exocrine glands.[44] Decreased night vision has been reported to persist in some patients after discontinuation of isotretinoin therapy.[45][46]

Hyperostosis has been reported in patients receiving treatment with isotretinoin.[47][48]

SkinEdit

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.[49] 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 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 flare-up 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.

TeratogenicityEdit

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.[7]

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.[50]

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. In 2011, 155 pregnancies occurred among 129,544 women of childbearing potential taking isotrentinoin (0.12%)[51]

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.[52]

Psychological effectsEdit

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.[53] A number of studies have been conducted since then of the drug's effect on depression, psychosis, suicidal thoughts and other psychological effects.[53]

In 2012, a systematic review covering all articles in the literature related to isotretinoin, depression and suicide, as well as articles related to class effect, dose response, and biologic plausibility found that the literature reviewed was consistent with an association of isotretinoin administration and depression and with suicide in a subgroup of vulnerable individuals.[54] Following this systematic review, in a 2014 review a group of Australian dermatologists and psychiatrists collaborated on a set of recommendations for safe prescribing of isotretinoin.[55] However, whether isotretinoin use is causally associated with mental illness remains controversial.[55]

A possible biological basis for the case reports of depression involves decreased metabolism in the orbitofrontal cortex (OFC) of the frontal lobe.[56] A 2005 study found that isotretinoin, but not oral antibiotic treatment, was associated with decreased glucose metabolism in the OFC, with an average decrease of 21% for isotretinoin compared with 2% for the oral antibiotic as seen on functional PET scans.[56] The OFC has previously been implicated in depression and other psychological disorders. For instance, it has been found that artificial induction of depression through tryptophan depletion leads to reduced OFC metabolism.[57]

Rarely, irritable mood and aggression have been reported during isotretinoin use.[58][59][60][61] More severe OFC dysfunction (such as organic atrophy in frontotemporal dementia) is known to cause disinhibited behaviour.[62]

MusculoskeletalEdit

Isotretinoin has a number of muscoloskeletal effects. Myalgia (muscular pain) and arthralgia (join pain) are very common side effects.[63] Retinoids, including isotretinoin, are well-know to cause bone changes, the most common type of which is hyperostotic changes (excessive bone growth), especially in growing children and adolescents[63] Other problems include premature epiphyseal closure and calcification of tendons and ligaments.[63] The bones of the spine and feet are most commonly affected. Risk factors for skeletal effects include older age, greater dosage and longer course of treatment. Most bone changes cause no symptoms and may only be noticed using X-ray imaging.[63]

Mechanism of actionEdit

Isotretinoin's exact mechanism of action is unknown, but several studies have shown that isotretinoin induces apoptosis (programmatic cell death) in various cells in the body. Cell death may be instigated in the meibomian glands,[44][64] hypothalamic cells,[65] hippocampus cells[66][67] and—important for treatment of acne—in sebaceous gland cells.[68][69] 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.[5]

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.[70][71][72] The drug decreases the size and sebum output of the sebaceous glands.[73] 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.[74] The effect of Isotretinoin on sebum production can be temporary,[75] or remission of the disease can be "complete and prolonged."[73][76][77]

Isotretinoin has been speculated to down-regulate the telomerase enzyme and hTERT, inhibiting "cellular immortalization and tumorigenesis."[78] 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).[79] It is already known that metalloproteases play an important role in the pathogenesis of acne.[80]

PharmacokineticsEdit

Oral Isotretinoin is best absorbed when taken with a high-fat meal, because it has a high level of lipophilicity.[81] The efficacy of isotretinoin doubles when taken after a high-fat meal compared to when taken without food.[82] 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.[83] Accutane also negatively interacts with tetracycline, another class of acne drug, and with micro-dosed ('mini-pill') progesterone preparations, norethisterone/ethinylestradiol ('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.[81] The metabolites of isotretinoin and its conjugates are then excreted in the subject's urine and faeces in relatively equal amounts.[81] After a single, 80 mg oral dose of Isotretinoin to 74 healthy adult subjects under fed conditions, the mean ±SD elimination half-life (t1/2) of isotretinoin and 4-oxo-isotretinoin were 21.0 ± 8.2 hours and 24.0 ± 5.3 hours, respectively.[81] After both single and multiple doses, the observed accumulation ratios of isotretinoin ranged from 0.90 to 5.43 in patients with cystic acne.[81]

HistoryEdit

The compound 13-cis retinoic acid was first studied in the 1960s at Roche Laboratories in Switzerland by Werner Bollag as a treatment for skin cancer. Experiments completed in 1971 showed that the compound was likely to be ineffective for cancer and, surprisingly, that it could be useful to treat acne. However, they also showed that the compound was likely to cause birth defects, so in light of the events around thalidomide, Roche abandoned the product. In 1975, Gary Peck and Frank Yoder independently rediscovered the drug's use as a treatment of cystic acne while studying it as a treatment for lamellar ichthyosis, and published that work. Roche resumed work on the drug, In clinical trials, subjects were carefully screened to avoid including women who were or might become pregnant. Roche's New Drug Application for isotretinoin for the treatment of acne included data showing that the drug caused birth defects in rabbits. The FDA approved the application in 1982.

Scientists involved in the clinical trials published articles warning of birth defects at the same time the drug was launched in the US, but nonetheless isotretinoin was taken up quickly and widely, both among dermatologists and general practitioners. Cases of birth defects showed up in the first year, leading the FDA to begin publishing case reports and to Roche sending warning letters to doctors and placing warning stickers on drug bottles, and including stronger warnings on the label. Lawsuits against Roche started to be filed. In 1983 the FDA's advisory committee was convened and recommended stronger measures, which the FDA took and were that time unprecedented: warning blood banks not to accept blood from people taking the drug, and adding a warning to the label advising women to start taking contraceptives a month before starting the drug. However use of the drug continued to grow, as did the number of babies born with birth defects. In 1985 the label was updated to include a boxed warning. In early 1988 the FDA called for another advisory committee, and FDA employees prepared an internal memo estimating that around 1,000 babies had been born with birth defects due isotretinoin, that up to around 1,000 miscarriages had been caused, and that between 5,000 and 7,000 women had had abortions due to isotretinoin. The memo was leaked to the New York Times[84] a few days before the meeting, leading to a storm of media attention. In the committee meeting, dermatologists and Roche each argued to keep the drug on the market but to increase education efforts; pediatricians and the CDC argued to withdraw the drug from the market. The committee recommended to restrict physicians who could prescribe the drug and to require a second opinion before it could be prescribed. The FDA, believing it did not have authority under the law to restrict who had the right to prescribe the drug, kept the drug on the market but took further unprecedented measures: it required to Roche to make warnings yet more visible and graphic, provide doctors with informed consent forms to be used when prescribing the drug, and to conduct follow up studies to test whether the measures were reducing exposure of pregnant women to the drug. Roche implemented those measures, and offered to pay for contraception counseling and pregnancy testing for women prescribed the drug - the program was called the "Pregnancy Prevention Program".

A CDC report published in 2000[85] showed problems with the Pregnancy Prevention Program and showed that the increase in prescriptions was from off-label use, and prompted Roche to revamp its program, renaming it the "Targeted Pregnancy Prevention Program" and adding label changes like requirements for two pregnancy tests, two kinds of contraception, and for doctors to provide pharmacists with prescriptions directly; providing additional educational materials, and providing free pregnancy tests. The FDA had another advisory meeting in late 2000 that again debated how to prevent pregnant women from being exposed to the drug; dermatologists testified about the remarkable efficacy of the drug, the psychological impact of acne, and demanded autonomy to prescribe the drug; others argued that the drug be withdrawn or much stricter measures be taken. In 2001 the FDA announced a new regulatory scheme called SMART (the System to Manage Accutane Related Teratogenicity) that required Roche to provide defined training materials to doctors, and for doctors to sign and return a letter to Roche acknowledging that they had reviewed the training materials, for Roche to then send stickers to doctors, which doctors would have to place on prescriptions they give patients after they have confirmed a negative pregnancy test; prescriptions could only be written for 30 days and could not be renewed, thus requiring a new pregnancy test for each prescription.[citation needed]

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.[86] 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.[87]

Among others, actor James Marshall sued Roche over allegedly Accutane-related disease that resulted in removal of his colon.[88] The jury, however, decided that James Marshall had a pre-existing bowel disease.[89]

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.[90]

See alsoEdit

ReferencesEdit

  1. ^ "International Nonproprietary Names for Pharmaceutical Substances. Recommended International Nonproprietary Names (Rec. INN): List 19" (PDF). World Health Organization. 1979. Retrieved 9 November 2016. 
  2. ^ Millsop JW, Heller MM, Eliason MJ, Murase JE (2013). "Dermatological medication effects on male fertility". Dermatol Ther. 26 (4): 337–46. doi:10.1111/dth.12069. PMID 23914891. 
  3. ^ Epuris by Cipher Pharmaceuticals
  4. ^ Merritt B, Burkhart CN, Morrell DS (June 2009). "Use of isotretinoin for acne vulgaris". Pediatr Ann. 38 (6): 311–20. doi:10.3928/00904481-20090512-01. PMID 19588674. 
  5. ^ a b Layton A (May 2009). "The use of isotretinoin in acne". Dermatoendocrinol. 1 (3): 162–9. doi:10.4161/derm.1.3.9364. PMC 2835909 . PMID 20436884. 
  6. ^ a b Rossi S (2006). Australian medicines handbook 2006. Adelaide, S. Aust: Australian Medicines Handbook Pty Ltd. ISBN 0-9757919-2-3. [page needed]
  7. ^ a b c d Klasco RK, editor. Drugdex system, vol. 128. Greenwood Village (CO): Thomson Micromedex; 2006.[page needed]
  8. ^ Strauss JS, Krowchuk DP, Leyden JJ, Lucky AW, Shalita AR, Siegfried EC, Thiboutot DM, Van Voorhees AS, Beutner KA, Sieck CK, Bhushan R (April 2007). "Guidelines of care for acne vulgaris management". J. Am. Acad. Dermatol. 56 (4): 651–63. doi:10.1016/j.jaad.2006.08.048. PMID 17276540. 
  9. ^ Georgala S, Katoulis AC, Georgala C, Bozi E, Mortakis A (June 2004). "Oral isotretinoin in the treatment of recalcitrant condylomata acuminata of the cervix: a randomised placebo controlled trial". Sex Transm Infect. 80 (3): 216–8. doi:10.1136/sti.2003.006841. PMC 1744851 . PMID 15170007. 
  10. ^ Sehgal VN, Srivastava G, Sardana K (June 2006). "Isotretinoin--unapproved indications/uses and dosage: a physician's reference". Int. J. Dermatol. 45 (6): 772–7. doi:10.1111/j.1365-4632.2006.02830.x. PMID 16796650. 
  11. ^ a b Choi JS, Koren G, Nulman I. Pregnancy and isotretinoin therapy. CMAJ. 2013 Mar 19;185(5):411-3. doi: 10.1503/cmaj.120729. PMID 23296582. PMC 3602257
  12. ^ "What Is Myorisan?". Good Rx. Good Rx. Retrieved April 11, 2017. 
  13. ^ Joint Formulary Committee. British National Formulary. 47th ed. London: British Medical Association and Royal Pharmaceutical Society of Great Britain. ISBN 0-85369-584-9[page needed]
  14. ^ "Fresh call for GPs to prescribe Roaccutane". AustralianDoctor. 19 June 2012. 
  15. ^ 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.[page needed]
  16. ^ James M (June 1996). "Isotretinoin for severe acne". Lancet. 347 (9017): 1749–50. doi:10.1016/S0140-6736(96)90814-4. PMID 8656912. 
  17. ^ "Acne, Isotretinoin, and Depression". MEDSAFE (New Zealand Ministry of Health). June 2013 [June 2005]. Retrieved 7 February 2014. 
  18. ^ "iPledge (About iPledge)". 
  19. ^ "Isotretinoin (marketed as Accutane) Capsule Information". U.S. Food and Drug Administration (FDA). 
  20. ^ United States Pharmacopeia Staff. Consumer Reports Complete Drug Reference. Yonkers, NY: Consumer Reports Books, 1995. Pg 998.
  21. ^ Amichai B, Shemer A, Grunwald MH (April 2006). "Low-dose isotretinoin in the treatment of acne vulgaris". J. Am. Acad. Dermatol. 54 (4): 644–6. doi:10.1016/j.jaad.2005.11.1061. PMID 16546586. 
  22. ^ Seukeran DC, Cunliffe WJ (July 1998). "Acne vulgaris in the elderly: the response to low-dose isotretinoin". Br. J. Dermatol. 139 (1): 99–101. doi:10.1046/j.1365-2133.1998.02321.x. PMID 9764156. 
  23. ^ Shahidullah M, Tham SN, Goh CL (January 1994). "Isotretinoin therapy in acne vulgaris: a 10-year retrospective study in Singapore". Int. J. Dermatol. 33 (1): 60–3. doi:10.1111/j.1365-4362.1994.tb01500.x. PMID 8112947. 
  24. ^ Hermes B, Praetel C, Henz BM (September 1998). "Medium dose isotretinoin for the treatment of acne". J Eur Acad Dermatol Venereol. 11 (2): 117–21. doi:10.1111/j.1468-3083.1998.tb00763.x. PMID 9784036. 
  25. ^ Lin J, Shih I, Yu C (February 1999). "Hemodialysis-related nodulocystic acne treated with isotretinoin". Nephron. 81 (2): 146–50. doi:10.1159/000045270. PMID 9933749. 
  26. ^ Ertl GA, Levine N, Kligman AM (March 1994). "A comparison of the efficacy of topical tretinoin and low-dose oral isotretinoin in rosacea". Arch Dermatol. 130 (3): 319–24. doi:10.1001/archderm.130.3.319. PMID 8129410. 
  27. ^ Connie L. Barnes; Angie L. Osborne. "Isotretinoin Uses and Effects". U.S. Pharmacist. Archived from the original on 2007-12-25. 
  28. ^ James WD (April 2005). "Clinical practice. Acne". N. Engl. J. Med. 352 (14): 1463–72. doi:10.1056/NEJMcp033487. PMID 15814882. 
  29. ^ Zouboulis CC (2006). "The truth behind this undeniable efficacy--recurrence rates and relapse risk factors of acne treatment with oral isotretinoin". Dermatology (Basel). 212 (2): 99–100. doi:10.1159/000090646. PMID 16484812. 
  30. ^ Haryati I, Jacinto SS (December 2005). "Profile of acne patients in the Philippines requiring a second course of oral isotretinoin". Int. J. Dermatol. 44 (12): 999–1001. doi:10.1111/j.1365-4632.2005.02284.x. PMID 16409263. 
  31. ^ Azoulay L, Oraichi D, Bérard A (December 2007). "Isotretinoin therapy and the incidence of acne relapse: a nested case-control study". Br. J. Dermatol. 157 (6): 1240–8. doi:10.1111/j.1365-2133.2007.08250.x. PMID 17970803. 
  32. ^ Layton AM, Dréno B, Gollnick H, Mobaken H, Shear N (January 2009). "Isotretinoin therapy and the incidence of acne relapse: a nested case-control study". Br. J. Dermatol. 160 (1): 217–8; author reply 218–9. doi:10.1111/j.1365-2133.2008.08935.x. PMID 19067687. 
  33. ^ "Isotretinoin 20 mg capsules, Summary of Product Characteristics". electronic Medicines Compendium (eMC). Datapharm Communications Ltd. 
  34. ^ (Label) (PDF). Drugs@FDA (Report). Roche Laboratories. January 2010. p. 41. NDA 018662/S-060. Retrieved 3 August 2014. 
  35. ^ Lawson JP, McGuire J (1987). "The spectrum of skeletal changes associated with long-term administration of 13-cis-retinoic acid". Skeletal Radiology. 16 (2): 91–7. doi:10.1007/BF00367754. PMID 3107131. 
  36. ^ David M, Hodak E, Lowe NJ (1988). "Adverse effects of retinoids". Medical toxicology and adverse drug experience. 3 (4): 273–88. doi:10.1007/bf03259940. PMID 3054426. 
  37. ^ Orfanos CE (1989). "Retinoide: der neue Stand. Erhaltungstherapie, Resorptionsstörungen bei 'non-responders', Interaktionen und Interferenzen mit Medikamenten, Behandlung von Kindern und Knochentoxizität, Acitretin und 13-cis-Acitretin" [Retinoids: the new status. Maintenance therapy, disorders of resorption in 'non-responders', interactions and interferences with drugs, treatment of children and bone toxicity, acitetin and 13-cis-acitretin]. Hautarzt (in German). 40 (3): 123–9. PMID 2523875. 
  38. ^ DiGiovanna JJ (2001). "Isotretinoin effects on bone". Journal of the American Academy of Dermatology. 45 (5): S176–82. doi:10.1067/mjd.2001.113721. PMID 11606950. 
  39. ^ Moy A, McNamara NA, Lin MC (September 2015). "Effects of Isotretinoin on Meibomian Glands". Optometry and Vision Science. 92 (9): 925–30. doi:10.1097/OPX.0000000000000656. PMID 26154692. 
  40. ^ Örsal E, Seven B, Erdem MT, Varoğlu E, Farimaz H, Ayan AK. "Evaluation of the effect of isotretinoin on salivary gland function by Tc-99m pertechnetate imaging in acne vulgaris patients". Turkish Journal of Medical Sciences. 45 (3): 674–7. doi:10.3906/sag-1402-131. PMID 26281338. 
  41. ^ Lupi-Pégurier L, Muller-Bolla M, Fontas E, Ortonne JP. "Reduced salivary flow induced by systemic isotretinoin may lead to dental decay. A prospective clinical study". Dermatology. 214 (3): 221–6. doi:10.1159/000099586. PMID 17377383. 
  42. ^ Oikarinen K, Salo T, Kylmäniemi M, Palatsi R, Karhunen T, Oikarinen A (December 1995). "Systemic oral isotretinoin therapy and flow rate, pH, and matrix metalloproteinase-9 activity of stimulated saliva". Acta Odontologica Scandinavica. 53 (6): 369–71. doi:10.3109/00016359509006003. PMID 8849870. 
  43. ^ Reynolds NJ, Gough M, Clamp JR, Burton JL (August 1991). "Effect of oral isotretinoin therapy on saliva volume and composition". The British Journal of Dermatology. 125 (2): 189–90. doi:10.1111/j.1365-2133.1991.tb06071.x. PMID 1832930. 
  44. ^ a b Lambert RW, Smith RE (March 1989). "Effects of 13-cis-retinoic acid on the hamster meibomian gland". J. Invest. Dermatol. 92 (3): 321–5. doi:10.1111/1523-1747.ep12277122. PMID 2918239. 
  45. ^ Mollan SP, Woodcock M, Siddiqi R, Huntbach J, Good P, Scott RA (August 2006). "Does use of isotretinoin rule out a career in flying?". The British Journal of Ophthalmology. 90 (8): 957–9. doi:10.1136/bjo.2006.092833. PMC 1857209 . PMID 16723361. 
  46. ^ Fraunfelder FT, Fraunfelder FW, Edwards R (September 2001). "Ocular side effects possibly associated with isotretinoin usage". American Journal of Ophthalmology. 132 (3): 299–305. doi:10.1016/S0002-9394(01)01024-8. PMID 11530040. 
  47. ^ Pittsley RA, Yoder FW (1983). "Retinoid Hyperostosis". New England Journal of Medicine. 308 (17): 1012–4. doi:10.1056/NEJM198304283081707. PMID 6403861. 
  48. ^ Tangrea JA, Kilcoyne RF, Taylor PR, Helsel WE, Adrianza ME, Hartman AM, Edwards BK, Peck GL (1992). "Skeletal hyperostosis in patients receiving chronic, very-low-dose isotretinoin". Archives of dermatology. 128 (7): 921–5. doi:10.1001/archderm.1992.01680170053004. PMID 1626958. 
  49. ^ Scheinfeld N, Bangalore S (May 2006). "Facial edema induced by isotretinoin use: a case and a review of the side effects of isotretinoin". J Drugs Dermatol. 5 (5): 467–8. PMID 16703787. 
  50. ^ Roche Products Pty Ltd. Roaccutane (Australian Approved Product Information). Dee Why (NSW): Roche; 2005.[page needed]
  51. ^ Leyden JJ, Del Rosso JQ, Baum EW (February 2014). "The use of isotretinoin in the treatment of acne vulgaris: clinical considerations and future directions". J Clin Aesthet Dermatol. 7 (2 Suppl): S3–S21. PMC 3970835 . PMID 24688620. 
  52. ^ BNF, edition 57[page needed]
  53. ^ a b Goodfield MJ, Cox NH, Bowser A, McMillan JC, Millard LG, Simpson NB, Ormerod AD (2010). "Advice on the safe introduction and continued use of isotretinoin in acne in the U.K. 2010" (PDF). British Journal of Dermatology. 162 (6): 1172–1179. doi:10.1111/j.1365-2133.2010.09836.x. ISSN 0007-0963. PMID 21250961. 
  54. ^ Bremner JD, Shearer KD, McCaffery PJ (January 2012). "Retinoic acid and affective disorders: the evidence for an association". The Journal of Clinical Psychiatry (Systematic Review). 73 (1): 37–50. doi:10.4088/JCP.10r05993. PMC 3276716 . PMID 21903028. 
  55. ^ a b Rowe C, Spelman L, Oziemski M, Ryan A, Manoharan S, Wilson P, Daubney M, Scott J (May 2014). "Isotretinoin and mental health in adolescents: Australian consensus". The Australasian Journal of Dermatology (Review). 55 (2): 162–7. doi:10.1111/ajd.12117. PMID 24283385. 
  56. ^ a b Bremner JD, Fani N, Ashraf A, Votaw JR, Brummer ME, Cummins T, Vaccarino V, Goodman MM, Reed L, Siddiq S, Nemeroff CB (May 2005). "Functional brain imaging alterations in acne patients treated with isotretinoin". The American Journal of Psychiatry. 162 (5): 983–91. doi:10.1176/appi.ajp.162.5.983. PMID 15863802. 
  57. ^ Bremner JD, Innis RB, Salomon RM, Staib LH, Ng CK, Miller HL, Bronen RA, Krystal JH, Duncan J, Rich D, Price LH, Malison R, Dey H, Soufer R, Charney DS (April 1997). "Positron emission tomography measurement of cerebral metabolic correlates of tryptophan depletion-induced depressive relapse". Archives of General Psychiatry. 54 (4): 364–74. PMID 9107153. 
  58. ^ Bremner JD, Shearer KD, McCaffery PJ (January 2012). "Retinoic acid and affective disorders: the evidence for an association". The Journal of Clinical Psychiatry. 73 (1): 37–50. doi:10.4088/JCP.10r05993. PMC 3276716 . PMID 21903028. 
  59. ^ Byrne A, Costello M, Greene E, Zibin T (1998-06-01). "Isotretinoin therapy and depression – evidence for an association". Irish Journal of Psychological Medicine. 15 (2): 58–60. doi:10.1017/S0790966700003530. 
  60. ^ Kontaxakis VP, Skourides D, Ferentinos P, Havaki-Kontaxaki BJ, Papadimitriou GN (January 2009). "Isotretinoin and psychopathology: a review". Annals of General Psychiatry. 8: 2. doi:10.1186/1744-859X-8-2. PMC 2637283 . PMID 19154613. 
  61. ^ Borovaya A, Olisova O, Ruzicka T, Sárdy M (September 2013). "Does isotretinoin therapy of acne cure or cause depression?". International Journal of Dermatology. 52 (9): 1040–52. doi:10.1111/ijd.12169. PMID 23962262. 
  62. ^ Snowden JS, Bathgate D, Varma A, Blackshaw A, Gibbons ZC, Neary D (March 2001). "Distinct behavioural profiles in frontotemporal dementia and semantic dementia". Journal of Neurology, Neurosurgery, and Psychiatry. 70 (3): 323–32. doi:10.1136/jnnp.70.3.323. PMC 1737271 . PMID 11181853. 
  63. ^ a b c d Brelsford M, Beute TC (September 2008). "Preventing and managing the side effects of isotretinoin". Seminars in Cutaneous Medicine and Surgery. 27 (3): 197–206. doi:10.1016/j.sder.2008.07.002. PMID 18786498. 
  64. ^ Kremer I, Gaton DD, David M, Gaton E, Shapiro A (1994). "Toxic effects of systemic retinoids on meibomian glands". Ophthalmic Res. 26 (2): 124–8. doi:10.1159/000267402. PMID 8196934. 
  65. ^ Griffin JN, Pinali D, Olds K, Lu N, Appleby L, Doan L, Lane MA (November 2010). "13-Cis-retinoic acid decreases hypothalamic cell number in vitro". Neurosci. Res. 68 (3): 185–90. doi:10.1016/j.neures.2010.08.003. PMID 20708044. 
  66. ^ Crandall J, Sakai Y, Zhang J, Koul O, Mineur Y, Crusio WE, McCaffery P (April 2004). "13-cis-retinoic acid suppresses hippocampal cell division and hippocampal-dependent learning in mice". Proc. Natl. Acad. Sci. U.S.A. 101 (14): 5111–6. Bibcode:2004PNAS..101.5111C. doi:10.1073/pnas.0306336101. JSTOR 3371827. PMC 387382 . PMID 15051884. 
  67. ^ Sakai Y, Crandall JE, Brodsky J, McCaffery P (June 2004). "13-cis Retinoic acid (accutane) suppresses hippocampal cell survival in mice". Ann. N. Y. Acad. Sci. 1021: 436–40. Bibcode:2004NYASA1021..436S. doi:10.1196/annals.1308.059. PMID 15251924. 
  68. ^ Nelson AM, Cong Z, Gilliland KL, Thiboutot DM (September 2011). "TRAIL contributes to the apoptotic effect of 13-cis retinoic acid in human sebaceous gland cells". Br. J. Dermatol. 165 (3): 526–33. doi:10.1111/j.1365-2133.2011.10392.x. PMC 3166444 . PMID 21564055. 
  69. ^ Nelson AM, Gilliland KL, Cong Z, Thiboutot DM (October 2006). "13-cis Retinoic acid induces apoptosis and cell cycle arrest in human SEB-1 sebocytes". J. Invest. Dermatol. 126 (10): 2178–89. doi:10.1038/sj.jid.5700289. PMID 16575387. 
  70. ^ Wachter K (2009). "Isotretinoin's Mechanism of Action Explored". Skin & Allergy News. 40 (11): 32. doi:10.1016/S0037-6337(09)70553-4. 
  71. ^ Isotretinoin’s Mechanism of Action Elucidated. Medconnect (2009-08-28). Retrieved on 2010-11-13.
  72. ^ Nelson AM, Zhao W, Gilliland KL, Zaenglein AL, Liu W, Thiboutot DM (April 2008). "Neutrophil gelatinase-associated lipocalin mediates 13-cis retinoic acid-induced apoptosis of human sebaceous gland cells". J. Clin. Invest. 118 (4): 1468–78. doi:10.1172/JCI33869. PMC 2262030 . PMID 18317594. 
  73. ^ a b Peck GL, Olsen TG, Yoder FW, Strauss JS, Downing DT, Pandya M, Butkus D, Arnaud-Battandier J (February 1979). "Prolonged remissions of cystic and conglobate acne with 13-cis-retinoic acid". N. Engl. J. Med. 300 (7): 329–33. doi:10.1056/NEJM197902153000701. PMID 153472. 
  74. ^ Shalita A (2001). "The integral role of topical and oral retinoids in the early treatment of acne". European Academy of Dermatology and Venereology (JEADV). 15: 47. doi:10.1046/j.0926-9959.2001.00012.x. 
  75. ^ Roche Laboratories (September 2007). "Accutane (Isotretinoin Capsules)" (PDF). FDA-Approved Official Product Label. U.S. Food and Drug Administration. NDA 018-662 S-058. Retrieved 05/02/2011.  Check date values in: |access-date= (help)
  76. ^ [unreliable medical source?]Farrell LN, Strauss JS, Stranieri AM (December 1980). "The treatment of severe cystic acne with 13-cis-retinoic acid. Evaluation of sebum production and the clinical response in a multiple-dose trial". J. Am. Acad. Dermatol. 3 (6): 602–11. doi:10.1016/S0190-9622(80)80074-0. PMID 6451637. 
  77. ^ [unreliable medical source?]Jones H, Blanc D, Cunliffe WJ (November 1980). "13-cis retinoic acid and acne". Lancet. 2 (8203): 1048–9. doi:10.1016/S0140-6736(80)92273-4. PMID 6107678. 
  78. ^ Pendino F, Flexor M, Delhommeau F, Buet D, Lanotte M, Segal-Bendirdjian E (June 2001). "Retinoids down-regulate telomerase and telomere length in a pathway distinct from leukemia cell differentiation". Proc. Natl. Acad. Sci. U.S.A. 98 (12): 6662–7. Bibcode:2001PNAS...98.6662P. doi:10.1073/pnas.111464998. JSTOR 3055868. PMC 34517 . PMID 11371621. 
  79. ^ Φαχαντίδης, Παναγιώτης Ε. (2007). Η επίδραση της ισοτρετινοϊνης και των αναστολέων της 5α-αναγωγάσης στις μεταλλοπρωτεάσες του συνδετικού ιστού σε ασθενείς με ακμή [The influence of isotretinoin and 5-a reductase inhibitors in metaloproteases of connective tissue in patients with ance] (in Greek). Aristotle University of Thessaloniki. [unreliable medical source?]
  80. ^ Toyoda M, Nakamura M, Makino T, Kagoura M, Morohashi M (June 2002). "Sebaceous glands in acne patients express high levels of neutral endopeptidase". Exp. Dermatol. 11 (3): 241–7. doi:10.1034/j.1600-0625.2002.110307.x. PMID 12102663. 
  81. ^ a b c d e "FDA information, side effects, and uses / Accutane (isotretinoin)". U. S. Food and Drug Administration (FDA). Retrieved 20 January 2014. 
  82. ^ "FDA information, side effects, and uses / Accutane (isotretinoin) : Table 2 Pharmacokinetic Parameters of Isotretinoin Mean (%CV), N=74". U. S. Food and Drug Administration (FDA). Retrieved 20 January 2014. 
  83. ^ "FDA information, side effects, and uses / Accutane (isotretinoin) : Drug Interactions". U. S. Food and Drug Administration (FDA). Retrieved 20 January 2014. 
  84. ^ Gina Kolata for the New York Times. April 22, 1988 Anti-Acne Drug Faulted in Birth
  85. ^ CDC. January 21, 2000 Accutane®-Exposed Pregnancies -- California, 1999 MMWR Weekly 49(02);28-31
  86. ^ Shari Roan (7 November 2009). "New study may deal final blow to acne drug Accutane". LA Times. 
  87. ^ "Roche Discontinues and Plans to Delist Accutane in the U.S." (Press release). Genentech. 2009-06-29. Retrieved 2010-11-12. 
  88. ^ Feeley J (2011-03-11). "Roche Accutane Acne Drug Caused 'Tragedy' for Actor, Brian Dennehy Says". Bloomberg. 
  89. ^ Silverman E (2011-11-04). "It's Curtains On Actor's Accutane Lawsuit". Pharmalot. UBM Canon. 
  90. ^ Voreacos D (May 30, 2007). "Roche Found Liable in First Of 400 Suits Over Accutane". The Washington Post. Bloomberg News. Retrieved April 30, 2012. 

Drugs@FDA referencesEdit

The following are queries against the Drugs@FDA database used as references.

  1. ^ For Roche's Accutane see database query run 3 August 2014.
  2. ^ For Mylan's Amnesteem see database query run 3 August 2014.
  3. ^ For Teva's Claravis see database query run 3 August 2014.
  4. ^ For Ranbaxy's Absorica see database query run 2 August 2014.
  5. ^ Label and approval history for Roche's Accutane, retrieved 3 August 2014.

External linksEdit